Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.[Br:9][C:10]1[CH:16]=[CH:15][C:13](N)=[C:12]([F:17])[CH:11]=1.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>Cl.O.[Zn].[Fe]>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([F:17])[CH:11]=1
Reactant: c1ccccc1
Reactant: Nc1ccc(Br)cc1F
Agent: [Fe]
Agent: CC(C)CCON=O
Agent: Cl
Solvent: O
Product: Fc1cc(Br)ccc1-c1ccccc1
Reaction time: 8 h

Procedure:
Solutions of 375 ml (325 g, 2.8 moles) of isoamyl nitrite, and of 378 grams (2.0 moles) of crude 4-bromo-2-fluoroaniline in 250 ml benzene are added separately and simultaneously dropwise over about 20 hours to 3500 ml of benzene vigorously stirred under a nitrogen atmosphere, and kept in a water bath at 65° C. The mixture is kept overnight at 65° C., then cooled, washed twice with 250 ml of water and evaporated. The dark oily residue is dissolved in 750 ml methanol and 450 ml concentrated hydrochloric acid, and treated with 138 grams (2.1 moles) of granular zinc, added in small portions over about 6 hours. In order to complete this "reductive upgrading", the solution is treated with 54 grams (1.0 mole) of fine iron filings over 0.5 hours. Within one hour the color of the mixture is visibly lighter. The solution is diluted with one liter of water and one liter of Skellysolve B hexanes, and the liquids are decanted from the remaining metals. The aqueous phase is extracted twice with one liter of Skellysolve B hexanes and the one liter of water, one liter of 1 N NaOH, and one liter of water. The solution is then passed through anhydrous sodium sulfate and evaporated to provide 389 grams of 4-bromo-2-fluoro-biphenyl.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:8]([C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:9][NH:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>>[O:21]=[C:12]1[C:8]2=[CH:9][NH:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]2=[N:14][N:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c[nH]cc2c(=O)n(-c3ccccc3)nc1-2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]cc2c(=O)n(-c3ccccc3)nc1-2
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 75.8 %

Procedure:
A mixture of 3,5-dihydro-3-oxo-2-phenyl-2H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester (0.9522 g, 3.36 mmol) in 1N aqueous NaOH (16 ml, 16.0 mmol) was stirred at room temperature for 3.25 h. The mixture was filtered, and the filtrate was neutralised to pH 5 by the addition of 5N aqueous HCl (3 ml). The resulting solid was collected by filtration, washed with water, then hexane, and dried under vacuum at 70° C. to leave 0.6498 g (76%) of the title compound as an orange solid; mp 287-302° C.; 1H NMR (360 MHz, DMSO-d6) δ7.18 (1H, t, J 7.4 Hz), 7.44 (2H, t, J 7.5 Hz), 8.12 (1H, s), 8.17 (2H, d, J 7.6 Hz), 8.56 (1H, s), 12.66 (1H, br s); MS (ES+) m/z 256 [MH]+. Anal. found: C, 59.81; H, 3.49; N, 16.27. C13H9N3O3.0.3H2O requires: C, 59.91; H, 3.71; N, 16.12%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH3:6].[Mg].[CH3:8][S:9][CH2:10][CH2:11][CH:12]=[O:13].[Cl-].[NH4+]>C1COCC1.CCOCC>[CH3:8][S:9][CH2:10][CH2:11][CH:12]([OH:13])[CH2:2][CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCCC=O
Reactant: CSCCCCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSCCCC(O)CCSC
Temperature: 50 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1-Chloro-3-methylthiopropane (3.73 g, 30 mmole) in dry THF (50 mL) was added to stirred magnesium turnings (0.72 g, 30 mmole) under argon. Once the addition was complete, the mixture was heated to 50° C. for 3 hours. The mixture was then allowed to cool to room temperature and 3-methylthiopropanal (3.12 g, 30 mmole) was added. The reaction was stirred at room temperature for 1 hour. 2M ammonium chloride solution (50 mL) was added, followed by ether (50 mL). The organics were separated, dried, filtered, and evaporated to give a pale yellow oil that was purified by chromatography in 40-60 petroleum ether/ether (4/5) to give 5 (2.1 g, 36%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1>>[NH:25]1[C:24]([NH:23][C:16]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:15]=2)=[O:18])=[N:28][N:27]=[N:26]1
Reactant: O=C(O)c1cccc(-c2cccc([N+](=O)[O-])c2)n1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nnn[nH]1)c1cccc(-c2cccc([N+](=O)[O-])c2)n1
Yield: 96.1 %

Procedure:
In the same manner as described in Example 13-(1), 6-(3-nitrophenyl)-2-pyridinecarboxylic acid (4.0 g), thionyl chloride (12 ml) and 5-aminotetrazole (1.54 g) are reacted to give N-(5-tetrazolyl)-6-(3-nitrophenyl)-2-pyridinecarboxamide (4.9 g). M.P. 275°-279° C. (decomp.)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[H+].[B-](F)(F)(F)F.[N:16]([O-])=O.[Na+].CC([O-])=O.[K+]>O.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:16]=[CH:9]2
Reactant: Cc1cc(Br)ccc1N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
4-bromo-2-methylaniline (5.0 g, 27 mmol) was added to a mixture of water (12.3 ml) and HBF4 (48% by weight in water, 12.3 ml, 67 mmol) in a Nalger reaction vessel cooled in an ice water bath. Then, NaNO2 (1.85 g, 27 mmol) in water (3.8 ml) was added while maintaining the temperature of the reaction around 10 C. After 15 minutes, the was then recooled in an ice water bath and filtered via a Buchner funnel. The solid was washed with cold 5% aqueous HBF4, cold MeOH (20 ml) and diethyl ether (3×10 ml). The solid was dried on a Buchner funnel for 1 hour and then added to a flask containing KOAc (5.3 g, 54 mmol, dried in vacuo overnight) and 18-c-6 (0.35 g, 1.3 mmol) suspended in chloroform (250 ml). The reaction was stirred at room temperature for 2 hours and then filtered, and the solid was washed with chloroform. The filtrate was washed with water and brine, dried over sodium sulfate, filtered, concentrated, and diluted with water (250 ml). The suspension was filtered, and the solid was washed with hexanes (50 ml) and diethyl ether (50 ml), collected, and dried in vacuo to give title compound (3.6 g, 68%). MS (ESI pos. ion) m/z: 197 (M+H). Calc'd Exact Mass for C7H5BrN2: 196.
Reaction SMILES: C(O)C(O)[CH:3](O)[CH:4]([OH:7])[CH:5]=[O:6].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14].C(O)(=O)C>>[C:5]([OH:11])(=[O:6])[CH:4]([CH3:3])[OH:7].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14]
Reactant: O=CC(O)C(O)C(O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Solvent: CC(=O)O
Product: CC(O)C(=O)O

Procedure:
Pentose such as xylose may be converted by hetero-lactic fermentation to produce 1 mol of lactic acid and 1 mol of acetic acid from 1 mol of xylose. Hetero-lactic fermentation is conducted while neutralizing with ammonia to yield ammonium lactate and ammonium acetate. Ammonium lactate and ammonium acetate are esterified with ethanol to produce ethyl lactate and ethyl acetate, respectively. Ammonia generated at the time of esterification is recovered. Unreacted ethanol is distilled off, and purification of ethyl lactate is performed by distillation with removing and recovering ethyl acetate. Ethyl acetate is useful as a solvent.
Reaction SMILES: [Br:1][CH:2]([CH2:7]Br)[C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].[Na].[C:13](O)(=[O:15])C>CO.C(OCC)C.C[N+]([O-])(C)C>[Br:1][CH:2]([CH2:7][O:15][CH3:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CC(=O)O
Reactant: COC(=O)C(Br)CBr
Agent: C[N+](C)(C)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COCC(Br)C(=O)OC

Procedure:
Methyl 2,3-dibromopropionate (21.9 g) and trimethylamine N-oxide (0.1 g) in methanol (8 ml) were cooled to −5° C. with stirring under an atmosphere of nitrogen. A methanolic solution of sodium methoxide, freshly prepared from sodium (2.25 g) and methanol (24 ml), was added dropwise over 15 minutes to the mixture, which was maintained below 0° C. by cooling. On completion of addition, the mixture was stirred for a further 30 minutes and acetic acid (1 ml) was added followed by diethyl ether (100 ml). The mixture was filtered to remove insoluble salts and the filtrate evaporated under reduced pressure to give an oil, which was re-dissolved in a small volume of diethyl ether and re-filtered. The filtrate was evaporated under reduced pressure to give the required product (17.4 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][O:20][C:21](=[O:24])[CH2:22]Br>CN(C=O)C>[CH3:19][O:20][C:21](=[O:24])[CH2:22][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1
Reactant: COC(=O)CBr
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a stirred solution of 6.65 g (0.0265 mol, 1 eq.) of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 25 ml of DMF at 0° C. were added 1.23 g of NaH (55% in oil, 0.0282 mol, 1.05 eq). After 30 minutes, 4.31 g (0.0282 mol, 1.05 eq.) of bromo-acetic acid methyl ester were added and the temperature raised to RT, and stirring was continued overnight. The reaction was quenched by the addition of aq.HCl 0.1 M, and the product was extracted with EtOAc and the combined organic phases dried over Na2SO4. Recrystallisation in Et2O/Heptane afforded 6.90 g (80%) of [6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic acid methyl ester as white crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[N:19]=[C:18]([CH:20]2[CH2:25][NH:24][CH2:23][CH2:22][N:21]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[C:16](Cl)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:34][NH2:35]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[N:19]=[C:18]([CH:20]2[CH2:25][NH:24][CH2:23][CH2:22][N:21]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[C:16]([NH:34][NH2:35])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Clc1cc(C2CNCCN2Cc2ccccc2)nc(C2CNCCN2Cc2ccccc2)n1
Solvent: C1COCCO1
Product: NNc1cc(C2CNCCN2Cc2ccccc2)nc(C2CNCCN2Cc2ccccc2)n1
Yield: 96.4 %

Procedure:
A solution of 2,4-di(N-benzylpiperazinyl)-6-chloropyrimidine (48.4 g, 104 mmol), hydrazine (96 g, 3 mol), in p-dioxane (1000 mL) was heated at 75° C. for 16 hours. The reaction was concentrated, dissolved in CH2-Cl2, washed with H2O, and dried (MgSO4). Filtration and concentration of the resulting solution gave 46 g (97%) of the title compound as a foam. 1H NMR (CDCl3) δ 2.44 (m, 8H, piperazine), 3.52-3.59 (m, 8H, piperazine), 3.71 (m, 4H, CH2), 5.22 (s, 1H, C5H), 5.72 (bs, 2H, NH2), 7.30 (m, 10H, Ar).
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][CH2:12][C:13]([OH:15])=[O:14].[F:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)[CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Fc1ccc(I)cc1
Reactant: O=C(O)CCc1c[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)CCc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12
Temperature: 165 °C
Yield: 104.9 %

Procedure:
A mixture of 3-(5-chloro-3-1H-indolyl)propanoic acid (17.5 g, 0.078 mol), 4-fluoroiodobenzene (20.8 g, 0.094 mol), Cul (2.4 g), K2CO3 (21.6 g, 0.16 mol) and N-methyl-2-pyrrolidone (0.20 L) was heated at 165° C. for 7 h. The reaction mixture was cooled to room temperature and water (0.25 L) was added. After acidification with concentrated hydrochloric acid, the mixture was extracted with diethyl ether (2×0.30 L) . The combined organic phases were washed with brine (3×0.40 L) and dried (Na2SO4). Evaporation of the solvents afforded crude 3-[5-chloro-1-(4-fluorophenyl)-3-1H-indolyl]propanoic acid (26 g) as an oil. The oil was dissolved in dry diethyl ether and added to a suspension of lithium aluminum hydride (15 g, 0.40 mol) in dry diethyl ether (0.20 L) over 30 min. After reflux for further 2 h the reaction mixture was cooled to 0° C. and carefully treated with water (15 ml), 4N aqueous NaOH (15 ml) and then water (75 mL). The resulting mixture was filtered and dried (Na2SO4). Evaporation of the solvents afforded the title compound (1a) as an oil (17.6 g, 74%). An analytical sample was crystallized from heptane: mp. 67°-69° C.; 1H NMR (CDCl3) δ 1.55 (broad s, 1 H), 2.00 (qui, 2 H), 2.90 (t, 2 H), 3.75 (t, 2 H), 7.10 (s, 1 H), 7.15 (broad d, 1 H), 7.20 (t, 2 H), 7.35 (d, 1 H), 7.40 (dd, 2 H), 7.60 (broad s,1 H). Anal. (C17H15ClFNO) C, H, N.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:35]>CN(C)C=O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:35])[CH:14]=[C:13]3[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
A solution of methyl 4-[5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]-3-methoxybenzoate (C) (1.52 g) in N,N-dimethylformamide (5 ml) was added to a slurry of sodium hydride (0.088 g) in N,N-dimethylformamide (3 ml) at 0° C. The mixture was stirred under a nitrogen atmosphere for 20 minutes at 0° C. and for 15 minutes at 25°0 C. The reaction was cooled to 0° C., treated with a cold solution of iodomethane (0.57 g) in N,N-dimethylformamide (2 ml), and then allowed to warm to 25°. The mixture was recooled to 0°, quenched with saturated aqueous ammonium chloride, and evaporated. The residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The amber residue was purified by flash chromatography on silica gel (500 ml), eluting with 1:9 v/v ethyl acetate:chloroform, to yield the title compound (0.86 g, 55%) as a white foam; partial NMR (80 MHz, CDCl 3): 3.4(dd, 2H, CH2N), 3.73(s, 3H, NCH3), 3.89(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.12(s, 2H, ArCH2), 6.11(t, 1H, NH), 6.8(s, 1H, H2 -indole), 8.00(br s, 1H, H4 -indole).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[N:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1>C1(C)C=CC=CC=1.O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[C:14]([Cl:15])=[N:13][CH:12]=[N:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc(Cl)c1OCc1ccccc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ncnc(Cl)c2OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
The compound from step 3 (12.78 g, 0.05 mol) was dissolved in (4:1:1) PhMe/H2O/DME (111 ml). Pd(Ph3P)4 (2.9 g, 0.05 eq), K2CO3, and p-tolylboronic acid (6.81 g, 1 eq) were added, the mixture was degassed and heated at 100° C. overnight. After cooling to room temperature the organic layer was purified by silica gel chromatography (0-10% EtOAc in hexane) to give 5.5 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]CC3C=CC=CC=3)[CH:9]=2)[N:4]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cn(Nc2ccncc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(Nc2ccncc2)c2ccc(O)cc12

Procedure:
3-Methyl-5-phenylmethoxy-1-(4-pyridinylamino)-1H-indole (2.20 g) was subjected to hydrogenolysis in absolute ethanol (80 ml) with 10% Pd-C (0.26 g) at 50 psig hydrogen at 50° C. for 2 hours. The catalyst was removed by filtration through a pad of celite and the solids washed with methanol. Concentration and recrystallization from methanol afforded 0.50 g of highly crystalline product, m.p. 239°-241° C. (dec.).
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=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][C:39]([CH:42]=[O:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH2:57]([Mg]Br)[CH:58]([CH3:60])[CH3:59].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[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][C:39]([CH:42]([OH:43])[CH2:57][CH:58]([CH3:60])[CH3:59])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: CC(C)C[Mg]Br
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C=O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(O)CC(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.7 %

Procedure:
To a solution of 294 mg (0.377 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 16, in 5 ml of tetrahydrofuran, 0.5 ml (0.5 mmol) of 1.0 mol/L isobutylmagnesium bromide-tetrahydrofuran solution was added under an argon gas atmosphere, and the reaction solution was stirred at room temperature for 0.17 hour. Then, 1.0 ml (1.0 mmol) of 1.0 mol/L isobutylmagnesium bromide-tetrahydrofuran solution was further added thereto and the reaction solution was stirred at room temperature for 0.33 hour. After completion of the reaction, the reaction solution was poured into saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and then the solvent was distilled off under reduced pressure to provide 328 mg of the title compound as a foam (yield: quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(N(CC)CC)C.[CH3:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26](Cl)=[O:27].O>C1COCC1>[CH3:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2)=[O:27]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.76 g (18.4 mmol) of ethyl 5-amino-1H-indole-2-carboxylate from Example LXI and 2.05 g (2.82 ml, 20.3 mmol) of triethylamine are added to 40 ml of THF. The mixture is cooled to 0° C., and a solution of 2.48 g (2.56 ml, 18.4 mmol) of 3,3-dimethylbutyryl chloride in 20 ml of THF are added. The mixture is stirred at RT for 2 h and, for work-up, poured into water. The pH is adjusted to 7 and the mixture is extracted 3 times with ethyl acetate. The combined organic phases are dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][NH:13][C:14]2[C:15]([NH2:32])=[CH:16][C:17]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:18][CH:19]=2)=[N:4]1)[CH3:2].[CH3:33][C:34]1([CH3:42])[C@@H:39]2[C@H:35]1[C:36](=[O:41])[O:37][C:38]2=O.Cl>C(#N)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][N:13]2[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)=[CH:16][C:15]=3[N:32]=[C:38]2[C@@H:39]2[C@H:35]([C:36]([OH:41])=[O:37])[C:34]2([CH3:42])[CH3:33])=[N:4]1)[CH3:2]
Reactant: CCn1nc(CNc2ccc(OCc3ccc4ccccc4n3)cc2N)c2ccccc21
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Agent: Cl
Solvent: CC#N
Product: CCn1nc(Cn2c([C@@H]3[C@H](C(=O)O)C3(C)C)nc3cc(OCc4ccc5ccccc5n4)ccc32)c2ccccc21
Temperature: 80 °C

Procedure:
To a 25 mL round-bottomed flask was added N1-((1-ethyl-1H-indazol-3-yl)methyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine (37 mg, 0.09 mmol), cis-6,6-dimethyl-3-oxa-bicyclo[3.1.0]hexane-2,4-dione (12 mg, 0.09 mmol) and acetonitrile (0.8 mL). The solution was heated to 80° C. for 4 h. To this solution was added HCl (0.4 mL, 6 N) and the mixture heated to 90° C. for 15 h. The mixture was cooled to RT over 30 minutes. The resulting solids were filtered off and the liquid purified by reverse phase HPLC to afford the title compound. MS (ESI): mass calcd. for C33H31N5O3, 545.24; m/z found, 546.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.57 (d, J=8.5, 1H), 8.37 (d, J=8.7, 1H), 7.99 (d, J=8.2, 1H), 7.95-7.89 (m, 2H), 7.76-7.72 (m, 1H), 7.55 (d, J=9.1, 1H), 7.42-7.37 (m, 4H), 7.25-7.22 (m, 1H), 7.16-7.11 (m, 1H), 5.72 (s, 2H), 5.66 (s, 2H), 4.36 (q, J=7.3, 2H), 2.50 (s, 2H), 1.45 (t, J=7.3, 3H), 1.29 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[H-].[Na+].CS(O[CH2:26][CH2:27][CH2:28][C:29]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)(=O)=O>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:18])[N:15]2[CH2:26][CH2:27][CH2:28][C:29]2([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31][CH2:30]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Reactant: CCOC(=O)C1(CCCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To 7 mL of an N,N-dimethylformamide solution containing 0.64 g of 7-methoxyquinolin-2(1H)-one, 0.15 g of 60% sodium hydride was added at room temperature, and the mixture was stirred at 60° C. for 20 minutes. Thereto was added 1.50 g of 1-tert-butyl 4-ethyl 4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate, the mixture was stirred at 70 to 80° C. for 1 hour and 30 minutes, and thereto was further added 75 mg of 60% sodium hydride, and the mixture was stirred for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to obtain 0.72 g of a yellow oily substance, 1-tert-butyl 4-ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate.