Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[N:14]=[C:13]([CH:18]=C)[CH:12]=[CH:11][C:10]=3[C:9]2=[O:20])=[CH:5][CH:4]=1.C[OH:24].[BH4-].[Na+]>C(Cl)Cl>[OH:24][CH2:18][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:20])[N:8]([CH2:7][C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: CO
Reactant: C=Cc1ccc2c(n1)CCN(Cc1ccc(OC)cc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN2CCc3nc(CO)ccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-(4-Methoxybenzyl)-2-vinyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1 g, 4.49 mmol) from above was dissolved in a 1:1 mixture of DCM:MeOH, (50 mL) and cooled to −78° C. Ozone was bubbled through for 30 min. The reaction was warmed to 0° C. then NaBH4 (400 mg, 10.8 mmol) was added and the cold bath removed. After 10 min, the reaction mixture was quenched with Rochelle's Salt (20% solution, 50 mL) and diluted with EtOAc (100 mL). The organics were dried and concentrated to give 980 mg (96%). LC-MS (M+H)=299.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[C:24](=O)[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][N:27]1[CH2:28][CH2:29][CH:30]([O:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH2:31][CH2:32]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(C(=O)N1CCC(Oc2ccc(F)cc2)CC1)c1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(OC2CCN(CCc3c[nH]c4ccc(OCc5ccccc5)cc34)CC2)cc1

Procedure:
By following the manipulative procedure described in Example 2(d), 5.6 g of lithium aluminum hydride in 165 ml. of tetrahydrofuran and 15.2 g of 1-(5-benzyloxyindol-3-ylglyoxyloyl)-4-(p-fluorophenoxy)piperidine in 160 ml. of tetrahydrofuran are reacted to produce a white powder. The powder is recrystallized twice from an ethanol and water mixture and once from 95% ethanol (charcoal treatment) to give colorless needles of 5-benzyloxy-3-{2-[4-(p-fluorophenoxy)piperidyl]ethyl}indole, m.p. 134.5°-136.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Cl.N[C@H:32](C1C=CC(C(OC)=O)=CC=1)C>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[CH3:32])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3): 1H-NMR (CDCl3) the data of the title compound were identical with that of the racemate (step 2 of Example 2); MS (ESI) m/z 413 (M+H)+, 411 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23](OS(C(F)(F)F)(=O)=O)[CH:24]=3)[C:19]2=[O:36])[CH:12]=1.O.C(OCC)(=O)C>O1CCCC1.[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:36])[N:18]([CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[C:26]3=[O:27])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccc(OS(=O)(=O)C(F)(F)F)cc2C(=O)N1Cc1cccnc1
Reactant: COc1cccc([Mg]Br)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccc3c(c2)C(=O)N(Cc2cccnc2)C3=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1.80 g of zinc chloride in 8.8 ml of tetrahydrofuran was added 8.8 ml of tetrahydrofuran solution (1.0M) of 3-methoxyphenylmagnesium bromide, and the resultant mixture was stirred at room temperature for 20 minutes. This solution was added to a mixture of 2.27 g of 2-(3-pyridylmethyl)-5-(trifluoromethanesulfonyloxy)-1H-isoindole-1,3 (2H)-dione, 27 mg of palladium acetate, 131 mg of 1,1'-bis (diphenylphosphino) ferrocene and 18 ml of tetrahydrofuran and stirred at room temperature for 17 hours. After finishing the reaction, the mixture was mixed with water under ice cooling and shaken with ethyl acetate. The organic layer was washed with water and saturated brine in order, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate and hexane (1:3) to (1:1) to give 1.71 g of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]2[O:12]CCO2)[CH:7]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>>[C:22]([C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:7]=1)[CH:8]=[O:12])(=[O:24])[CH3:23]
Reactant: Fc1ccc(Br)cc1C1OCCO1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Product: CC(=O)c1ccc(F)c(C=O)c1
Temperature: -40 °C
Reaction time: 0.42 h

Procedure:
2-(5-bromo-2-fluorophenyl)-1,3-dioxolane (5.2 g, 21.2 mmol) is taken up in dry, preservative-free THF (30 mL) and the solution is cooled to −40° C. under N2. A 1.6 M solution of n-butyllithium in hexanes (13.2 mL, 1 eq) is added via syringe and the solution is stirred for 25 minutes @−40° C. The lithiated substrate is added dropwise via cannula to a −40° C. solution of N-methoxy-N-methylacetamide (2.36 mL, 22.2 mmol, Aldrich) in 10 mL of dry, preservative-free THF. The solution is warmed to RT with stirring for 1 hour. The solution is poured into a flask containing 1.0M HCl (100 mL) and heated to 65° C. with vigorous stirring overnight. Upon cooling the oily product is extracted into EtOAc (200 mL) and the organic layer is washed with water and brine (200 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 75L (800 g silica) cartridge using 30% MTBE in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding an oily yellow solid.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3]C)=[O:2].O.[OH-].[Na+].Cl>CC(C)=O.C(OCC)(=O)C>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:27](=[O:35])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Temperature: 0 °C
Reaction time: 1 h
Yield: 110.2 %

Procedure:
To a solution of 39 g of benzyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 628 ml of acetone is added 228 ml of water and then dropwise added 90.8 ml of 1.0 N aqueous solution of sodium hydroxide. The mixture is stirred for 1 hour under ice-cooling, diluted with 630 ml of ice water, covered with ethyl acetate, adjusted to pH 2 with 20% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried on sodium sulfate and concentrated under reduced pressure to yield 41.7 g of benzyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH2:18])[CH3:2].[C:22](OC)(OC)(OC)[CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][CH2:6][N:7]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:22]1[CH2:23][CH2:24][CH3:25])[CH3:2]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(CCNc1c(N)cnc2ccccc12)OCC
Product: CCCc1nc2cnc3ccccc3c2n1CCC(OCC)OCC
Yield: 91.3 %

Procedure:
The general method described in Step 3 of Example 15 was used to cyclize N4-(3,3-diethoxypropyl)quinoline-3,4-diamine (20.7 g, 71.5 mmol) by reaction with trimethyl orthobutyrate (13.2 g, 89.4 mmol) to provide 1-(3,3-diethoxypropyl)-2-propyl-1H-imidazo[4,5-c]quinoline (22.3 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]([N:9]1[CH:15]([CH2:16][CH2:17][CH2:18][N:19](C)[CH3:20])[C:14]2[CH:22]=[CH:23][CH:24]=[C:25]3[CH2:26][CH2:27][N:12]([C:13]=23)[C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]1=2)(=[O:8])[CH3:7].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1C=CC=CC=1.O.ClCCl>[CH2:36]([O:35][C:33](=[O:34])[N:19]([CH2:18][CH2:17][CH2:16][CH:15]1[C:14]2[CH:22]=[CH:23][CH:24]=[C:25]3[CH2:26][CH2:27][N:12]([C:13]=23)[C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=2[N:9]1[C:6](=[O:8])[CH3:7])[CH3:20])[CH3:37]
Reactant: CC(=O)N1c2ccccc2N2CCc3cccc(c32)C1CCCN(C)C
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N(C)CCCC1c2cccc3c2N(CC3)c2ccccc2N1C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 27.64 g of powdered anhydrous sodium bicarbonate in 415 ml of benzene containing 23.0 g of 7-acetyl-N,N-dimethyl-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-propanamine was treated with 19.0 ml of ethyl chloroformate. After an overnight reflux under nitrogen, 6.3 ml more of ethyl chloroformate was added, and reflux continued another 2 hours. TLC still showed the presence of the starting material at this point, and a further addition of 6.3 ml of ethyl chloroformate was made. After 2 hours another 12.6 ml of ethyl chloroformate was added, reflux continued for another 1.5 hours, and the mixture cooled to room temperature. The reaction mixture was diluted with 500 ml of distilled water, stirred for a while, and poured into a separatory funnel, and the phases were separated. The aqueous phase was extracted with 250 ml of ethyl acetate. The combined organic phases were extracted with 200 ml of 2N hydrochloric acid, washed with 200 ml of water and 200 ml of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded a gum weighing 24.37 g. This material was dissolved in 150 ml of dichloromethane, the resulting solution was divided into two halves, and each half was purified by flash chromatography on 500 g of silica gel, using dichloromethane and then 1% methanol/dichloromethane as solvent. The purest fractions were combined and concentrated in vacuo to a foam which partially crystallized upon standing. Trituration with hexane fully solidified this material, which was filtered, washed with hexane and dried in vacuo to afford 11.65 g of solid, m.p. 125°-128° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:10]=1)(=O)[CH2:2]C.[CH:23]([O-])([O-:26])[O:24][CH3:25].[Cl-].[Cl-].[Cl-].[Cl-].C=C.BrBr>[Br-].[Zn+2].[Br-].C(Cl)Cl.O.CO>[CH3:25][O:24][C:23]([CH:1]([C:5]1[CH:6]=[CH:7][C:8]([S:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:10]=1)[CH3:2])=[O:26]
Reactant: COC([O-])[O-]
Reactant: CCC(=O)c1ccc(Sc2ccccc2)c(CC(=O)OC)c1
Agent: BrBr
Agent: C=C
Agent: [Br-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(C)C(=O)OC)ccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred mixture of 15.72 g (50 mmol.) of methyl 5-propionyl-2-phenylthiophenylacetate, 13.32 g (125.5 mmol.) of methyl orthoformate, 20 ml of methanol and 20 ml ethylene tetrachloride was dropwise added under stirring 8.39 g (52.5 mmol.) of bromine for a period of 30 minutes. The resulting mixture was further stirred at room temperature for 30 minutes, and then was heated slowly to 110° C. for 1 hour, under distilling off materials having a low boiling point. To the reaction mixture was added 0.90 g (4.0 mmol.) of zinc bromide, and the mixture was heated to 110° C. under reflux for 3 hours. The reaction mixture was cooled, and 75 ml of water and 40 ml of methylene chloride were added. The organic layer was separated and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 13.78 g of the desired product as a yellow oil (yield 80%, b.p. 212°-215° C./2 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].Cl.[CH3:15][NH:16][O:17][CH3:18].Cl.CN(C)CCCN=C=NCC.C(N(C1C=CC=CN=1)CC)C>ClCCl>[CH3:15][N:16]([O:17][CH3:18])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CNOC
Agent: CCN(CC)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
Dissolve 3-Fluoro-4-nitro-benzoic acid (10.7 g, 57.71 mmol) in 1000 mL anhydrous dichloromethane. Add N,O-Dimethylhydroxylamine hydrochloride (4.5 g, 46.17 mmol), followed by 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.60 g, 86.57 mmol) and 4 diethylaminopyridine (6.77 g, 55.4 mmol). Stir at room temperature under nitrogen atmosphere overnight. Concentrate under reduced pressure and partition the residue between ethyl acetate (300 mL) and water (100 mL). Wash the organic layer with saturated aqueous sodium chloride (4×30 mL) and dry over magnesium sulfate. Concentrate under reduced pressure to provide the desired compound (7.4 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18]C)=[C:14]([Cl:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[N:9][N:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:12][C:13]=1[OH:18]
Reactant: COc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Fluorophenyl)-6-chloro-5-methoxy-1H-indazole (99d) (0.91 mmol, 253 mg) was dissolved in dichloromethane (4 mL) and BBr3 (4 mL, 1 M/CH2Cl2) was added. The reaction mixture was stirred in room temperature overnight before it was quenched with water (20 mL). The product was extracted with dichloromethane (2×20 mL) and washed with sat NaHCO3. The organic phase was dried over Na2SO4, concentrated and purified by flash chromatography on silica gel (heptane-ethyl acetate). Yield: 219 mg (91%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[CH3:25][C:26]1[NH:27][C:28]([CH3:37])=[C:29]([C:34](=[O:36])[CH3:35])[C:30]=1C(O)=O>>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([C:4]([OH:3])=[O:24])[NH:6][C:30]2[C:29]([C:34](=[O:36])[CH3:35])=[C:28]([CH3:37])[NH:27][C:26]=2[CH3:25])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Reactant: CC(=O)c1c(C)[nH]c(C)c1C(=O)O
Agent: Cl
Product: CC(=O)c1c(C)[nH]c(C)c1N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 2,5-dimethyl-4-acetyl-pyrrole-3-carboxylic acid. Freeze drying afforded the title compound as a white amorphous solid (203 mg). δH (DMSO-d6) 11.2 (1H, s), 8.83 (1H, d, J 8.0 Hz), 7.56 (2H, app.d. J 8.0 Hz), 7.45 (1H, app.t, J 8.0 Hz), 7.21 (2H, d, J 8.5 Hz), 6.95 (2H, d, J 8.5 Hz), 5.17 (2H, s), 4.61-4.52 (1H, m), 3.11 (1H, dd, J 13.8, 4.3 Hz), 2.86 (1H, dd, J 13.8, 10.4 Hz), 2.31 (3H, s), 2.08 (3H, s), 2.07 (3H, s); m/z (ESI, 60V) 503 and 505 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)=[O:22])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:17](=[N:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)=[O:22])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
To methyl 4-[(2-{1-[4-hydroxy-5-(4-isopropylphenyl)-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)-carbonyl]benzoate (0.037 mmol, 16.0 mg), methanol (3 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.184 mL) was added at room temperature. After 15 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.184 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (6.8 mg, yield 44%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:11])=[CH:7][C:6]=2[C:5]([F:12])=[CH:4][CH:3]=1.[CH:13](=[O:16])[CH2:14][CH3:15].Cl>O1CCCC1>[F:12][C:5]1[C:6]2[CH:7]=[C:8]([CH3:11])[O:9][C:10]=2[C:2]([CH:13]([OH:16])[CH2:14][CH3:15])=[CH:3][CH:4]=1
Reactant: CCC=O
Reactant: Cc1cc2c(F)ccc(Br)c2o1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)c1ccc(F)c2cc(C)oc12
Temperature: 10 °C
Yield: 68.9 %

Procedure:
A solution of 5.75 g (25.1 mmol) of 7-bromo-4-fluoro-2-methylbenzofuran in 90 ml of tetrahydrofuran was added dropwise to a suspension of 0.625 g (27.5 mmol) of Mg in 100 ml of boiling tetrahydrofuran and the mixture was stirred at reflux for 2.5 hours. Subsequently, it was cooled to 10° C., 2.75 ml (37.5 mmol) of propionaldehyde were added dropwise thereto and the mixture was stirred for 30 minutes. The mixture was poured into 200 ml of 1N hydrochloric acid and extracted three times with 150 ml of dichloromethane. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloro-methane/hexane 4:1). 3.6 g (55%) of 1-(4-fluoro-2-methyl-benzofuran-7-yl)-propan-1-ol were obtained as a pale yellow oil.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:36]=[CH:35][C:25]([O:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[CH:24][CH:23]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=O)C>CCOC(C)=O>[N:10]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:36]=[CH:35][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Solvent: CCOC(C)=O
Product: O=C(O)COc1ccc(C(=O)Nc2ccc(N3CCNCC3)cc2)cc1
Reaction time: 1.5 h
Yield: 40.4 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and a gas dispersion tube was added tert-butyl 4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylaminocarbonyl)phenoxyacetate (0.78 g, 1.52 mmol) and EtOAc (40 mL). This solution was cooled in an ice bath and HCl gas was sparged through the solution for 15 min. The resulting mixture was aged 90 min. The excess HCl and EtOAc were removed in vacuo and the crude product was purified by preparative reverse phase HPLC. There was obtained 0.218 g of 4-(4-(piperazin-1-yl)phenylaminocarbonyl)phenoxyacetic acid as a crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=2)=[O:23])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc1

Procedure:
A solution containing 5.49 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 5.37 g of 4'-methylacetophenone in 50 ml of tetrahydrofuran was added a catalytic amount of gaseous hydrogen chloride and refluxed for 4.5 h. The solvent was evaporated in vacuo and the residue crystallized from ether-petroleum-ether, yield 1.85 g (21%), m.p. 184°-186° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[CH:18]([C:21](OCC)=O)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].BrC[CH2:36][F:37].[OH-].[Na+].Cl>CC(N(C)C)=O.C(OCC)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[CH:18]([CH2:21][CH2:36][F:37])[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1Cc2c(ccc3nn(Cc4ccccc4)cc23)C1=O
Reactant: FCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: O=C1c2ccc3nn(Cc4ccccc4)cc3c2CC1CCF
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-benzyl-6-oxo-2,6,7,8-tetrahydrocyclopenta[e]indazole-7-carboxylate (crude product from the previous step, 14 g, approximately 39 mmol) in 160 mL of dimethylacetamide were added potassium carbonate (11 g, 80 mmol), potassium iodide (13.3 g, 80 mmol) and 1-bromo-2-fluoroethane (3.8 mL, 51 mmol) and the stirred mixture was heated at 65° C. under nitrogen for 19 hours. The heating bath was removed and the reaction mixture was allowed to cool for 40 minutes and then water (160 mL) and TIM (160 mL) were added followed by 5N aqueous sodium hydroxide (24 mL, 120 mmol). After 3 hours, additional 5N aqueous sodium hydroxide (5 mL, 25 mmol) was added. After 30 minutes more, analysis of an aliquot by LC/MS showed the reaction to be complete and 1N aqueous HCl (150 mL) was added. The reaction mixture was extracted thoroughly with ethyl acetate and the combined extracts were washed with 5% aqueous NaHCO3 and brine and dried over MgSO4. Evaporation of the solvent under vacuum gave an oil which was twice treated with ethyl ether and evaporated under vacuum to give 2-benzyl-7-(2-fluoroethyl)-7,8-dihydrocyclopenta[e]indazol-6(2H)-one as a brown solid.