Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19])C1C=CC=CC=1>[Pd].CO.C(O)(=O)C>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reaction time: 8 h

Procedure:
Palladium on carbon (394 mg; 10% Pd/C) was added to a solution of the product of step 1 (1.81 g, 3.95 mmol) in methanol (50.6 mL) and the resulting mixture was stirred under hydrogen (balloon) overnight. LC/MS analysis indicated the reaction was not complete. Acetic acid (6 drops) and additional catalyst (159 mg of 10% Pd/C) were added to the reaction and the resulting mixture was stirred under hydrogen (balloon) for an additional 90 minutes. Additional catalyst (0.2085 g of 10% Pd/C) was added to the reaction and stirring under hydrogen was continued for an additional 2.5 hours at which time the reaction was judged complete by LC-MS analysis. The reaction was filtered through a celite pad and the collected solid was washed well with MeOH. The filtrate was concentrated under vacuum to afford the title compound as a colorless oil which was used without purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+]>CN(C=O)C>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.2 %

Procedure:
Methyl 2,4-dihydroxybenzoate (20.0 g, 0.119 mol) was dissolved in DMF (400 mL) and potassium carbonate (17.2 g, 0.125 mol) and benzyl bromide (21.4 g, 0.125 mol) were added using additional DMF (400 mL) to aid the transfer. Potassium iodide (3.0 g) was added, and the reaction was stirred at room temperature under nitrogen for 48 h. The DMF was removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried, and the solvent was removed in vacuo to give a white solid which was recrystallized from ethyl acetate:hexane to yield 17.9 g (61.1%) of a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13]1>ClCCl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCCC(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
25 gms of Aluminium chloride was added to 50 ml of dichloromethane and 4.5 ml of fluorobenzene. To this a solution of 50 ml of dichloromethane containing 10 gms of glutaric anhydride and 4.5 ml of fluorobenzene was added. Reaction mass was stirred at room temperature. After completion of reaction, reaction mass was quenched with ice & HCl solution at 0-10° C. Filtered the reaction mass. The obtained wet solid was dissolved in aq NaHCO3 solution at 60-70° C. and insoluable material was filtered. Cooled the filtrate and adjust pH to 2.0 by adding hydrochloric acid. Obtained solid was filtered and dried at 60-70° C. under vacuum to get 10 gm of 5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid.
Reaction SMILES: O.[C:2]([O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:6])[C:3]([CH3:5])=[CH2:4].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>CC(O)C>[CH3:5][C:3]([C:2]([O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])=[O:6])=[CH2:4].[CH3:14][C:13](=[O:16])[O:17][CH2:18][CH3:19]
Reactant: C=CC(=O)OCC
Agent: C=C(C)C(=O)OCCN(C)C
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCOC(C)=O

Procedure:
To a 2 liter glass vessel equipped with; reflux condenser, stirrer, means of temperature control, 300 g deionized water and 300 g propan-2-ol were charged then heated to a gentle reflux. A monomer mixture of dimethylaminoethyl methacrylate (134.6 g) and ethyl acrylate (200 g) was fed into the reactor over an approximate time frame of 3 hours. Sodium persulphate solution (3.4 g in 125 g of water) was fed concurrently with the monomer over a similar time period. When feeds were a propan-2-ol azeotrope was then distilled from the reactor, followed by neutralization with acetic acid (41.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:22]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=O)=[C:21]([CH3:29])[C:20](Br)=[CH:19][N:18]=2)=[CH:11][CH:10]=1)#[N:2].C(O)=O.C(N(CC)CC)C>[Pd].C1(C)C=CC=CC=1>[CH:26]1([C:24]2[N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)[C:17]3=[N:18][CH:19]=[CH:20][C:21]([CH3:29])=[C:22]3[N:23]=2)[CH2:28][CH2:27]1
Reactant: Cc1c(Br)cnc(NCc2ccc(-c3ccccc3C#N)cc2)c1NC(=O)C1CC1
Agent: [Pd]
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 83 %

Procedure:
Toluene (30 ml) was added to 2.0 g (4.3 mmol) of 2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropanecarboxamido-5-bromo-4-methyl-pyridine, 1.0 g (21.7 mmol) of formic acid, 3.5 g (34.6 mmol) of triethylamine and 10% Pd-C (300 m), followed by heating under reflux for 6 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (100 ml) and water (50 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.3 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 82%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)([CH3:13])([CH3:12])[CH3:11]>O.CO>[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[NH:24])[NH:2][OH:3])[CH:18]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1

Procedure:
Hydroxylamine hydrochloride (179 mg, 2.60 mmol) and Na2CO3 (138 mg, 1.30 mmol) was dissolved in 1 mL water. A solution of (3-cyano-phenyl)-carbamic acid tert-butyl ester (560 mg, 2.60 mmol) in 10 mL of methanol was added and the combined solution was stirred at reflux overnight. The solvent was removed and the resulting precipitate was extracted with water and ethyl acetate to yield [3-(N-hydroxycarbamimidoyl)-phenyl]-carbamic acid tert-butyl ester which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:22]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([NH:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])([CH3:28])[CH3:30])[N:22]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
A solution of (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (1.3 g, 4.87 mmol) in dichloromethane (25 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 830 mg, 5.36 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (2.60 g, 5.84 mmol) and triethylamine (1.48 g, 14.61 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 80 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (1.0 g, 51%) as a heavy yellow oil: LR-ES-MS m/z calculated for C21H32N4O4 [M]+ 404, observed [M+H]+ 405.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[H-].[Na+]>>[O:1]=[C:2]1[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-hydroxybenzimidazole (4.00 g, 29.8 mmol) and tert-butyl bromoacetate (5.53 g, 28.3 mmol) in DM (50 mL) at 0° C. was added sodium hydride (1.31 g of a 60% dispersion in mineral oil, 32.8 mmol). The mixture was stirred at 0° C. for 1 h, then quenched with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was partitioned between EtOAc (500 mL) and H2O (300 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12](=[O:13])[C:11]3([CH2:25][C:16]4=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]4[CH2:14]3)[N:10]([CH3:26])[C:9]2=[O:27])=CC=1>C(#N)C.O>[CH3:26][N:10]1[C:11]2([CH2:25][C:16]3=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]3[CH2:14]2)[C:12](=[O:13])[NH:8][C:9]1=[O:27]
Reactant: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)N(Cc2ccc(OC)cc2)C(=O)N1C
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)NC(=O)N1C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 1′-(4-methoxybenzyl)-3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (100 mg, 0.25 mmol) in acetonitrile (8.4 mL) at ambient temperature was added ceric ammonium nitrate (4.1 g, 7.6 mmol) as a solution in H2O (5 mL). After 20 min, the reaction mixture was partitioned between H2O (50 mL) and 9:1-CH2Cl2:i-PrOH (50 mL). The aqueous was extracted further with 9:1 CH2Cl2:i-PrOH (5×50 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was washed with MTBE (3×10 mL) then partitioned between saturated aqueous sodium bicarbonate (5 mL) and EtOAc (10 mL). The aqueous layer was extracted further with EtOAc (10 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound in sufficient purity for use in the next step. MS: m/z=276.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=1.[Br:9]N1C(=O)CCC1=O>ClCCl>[Br:9][C:4]1[C:5](=[O:8])[CH2:6][CH2:7][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC1=CC(=O)CC1
Solvent: ClCCl
Product: COC1=C(Br)C(=O)CC1
Yield: 76.2 %

Procedure:
A mixture of Example 7A (500 mg, 4.46 mmol) and N-bromosuccinimide (794 mg, 4.46 mmol) in dichloromethane (5 mL) was stirred at 25° C. for 16 hours. The mixture was concentrated in vacuo. The residue was purified on a silica column (dichloromethane/methanol=200:1, v/v) to afford the title compound (650 mg, 3.40 mmol, 76% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.12 (s, 3H), 2.79-2.82 (m, 2H), 2.62-2.65 (m, 2H); LC/MS (ESI) m/z 191 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)[C:6]([O:8]C)=[O:7])#[N:2].C(C1C=C(C=C(OC(C)C)C=1)C(O)=O)#N>>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:16][CH2:17]1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OCC2CC2)c(C#N)c1
Agent: CC(C)Oc1cc(C#N)cc(C(=O)O)c1
Product: N#Cc1cc(C(=O)O)ccc1OCC1CC1

Procedure:
Prepared from methyl 3-cyano-4-(cyclopropylmethoxy)benzoate according to the procedure for 3-cyano-5-isopropoxybenzoic acid. LCMS-ESI (m/z) calculated for C12H11NO3: 217.2; no m/z observed, tR=2.92 min. 1H NMR (400 MHz, CDCl3) δ 8.24-8.08 (m, 2H), 7.32 (d, J=8.9 Hz, 1H), 4.09 (d, J=7.1 Hz, 2H), 1.28 (s, 1H), 0.71-0.52 (m, 2H), 0.49-0.31 (m, 2H).
Reaction SMILES: CCN=C=NCCCN(C)C.CS(C)=O.[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:32][OH:33].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH:32]=[O:33]
Reactant: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
EDCI (36 mg, 0.19 mmol) and DMSO (18 μL, 0.25 mmol) were added sequentially to a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester (16.7 mg, 0.062 mmol) in benzene (1.0 mL) at rt. The mixture was cooled to 0° C. and pyridinium trifluoroacetate (13.2 mg, 0.068 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 2.5 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×1 mL). The combined benzene phases were concentrated in vacuo to afford crude 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-enoic acid methyl ester that was used without further purification.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[I-].[K+].[CH2:15](Cl)[CH2:16][OH:17].Cl>C(O)C.O>[OH:17][CH2:16][CH2:15][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: OCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCCO)cc1
Yield: 81.9 %

Procedure:
300 g of potassium hydroxide were dissolved in a mixed solution of 700 ml of ethanol and 100 ml of water. After dissolving 276 g of 4-hydroxybenzoic acid and a catalytic amount of potassium iodide in the solution, 177 g of ethylene chlorohydrin was gradually added to the mixture in a heated state followed by refluxing for about 15 hours. After distilling off ethanol from the reaction mixture obtained, the residue was added to 2 liters of water. After washing the aqueous solution obtained twice with diethyl ether, the solution was acidified by the addition of hydrochloric acid, and the precipitates thus formed were collected by filtration and dried, and recrystallized from ethanol to obtain 298 g (yield 82%) of 4-(2-hydroxyethoxy)benzoic acid.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:16])[CH2:14]2)[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>>[NH:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:16])[CH2:14]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC2(CCNCC2)c2ccccc21

Procedure:
N-boc-1-[4-spiro-piperidine]-3-indanone and trifluoroacetic acid were processed according to the method of Example 137D to provide the product. No purification was required. MS (ESI+) m/z 202 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[OH:17].[O:18]=O>C(Cl)(Cl)Cl>[CH3:16][C:12]1[C:13](=[O:18])[C:14]([CH3:15])=[C:9]([CH3:8])[C:10](=[O:17])[CH:11]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1=CC(=O)C(C)=C(C)C1=O

Procedure:
3.96 g of cobalt di-(salcylal)-3,3'-diimino -di-n-propylamine (0.1 mole) and 1.01 g of triethylamine (0.01 mole) were dissolved in 100 ml of chloroform and oxygen gas (100 ml/min) was then bubbled into the resulting solution for 5 seconds at a temperature of 10°C to form an oxygen complex. To this was added a solution of 13.6 g of 2,3,5-trimethylphenol (0.1 mole) in 100 ml of chloroform in three portions and oxygen gas (250 ml/min) was again introduced into the solution for a period of 8 hours to complete the reaction. After completion of the reaction, chloroform was distilled off and the residue was steam distilled by introducing steam thereinto. The distillate was extracted with ether and the ether was then distilled off to give 15.0 g of pseudocumoquinone (0.1 mole) having a melting point of 32°C, that is, the yield was quantitative.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1.[F-].[K+].Br[CH2:26][CH2:27][CH2:28][CH3:29]>C(#N)C>[CH2:26]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCBr
Reactant: CCCn1nc(C(=O)NC2CCNCC2)c2ccccc21
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(NC(=O)c2nn(CCC)c3ccccc23)CC1
Yield: 69 %

Procedure:
To a suspension of N-(4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride (0.52 g) obtained in Example 20 in acetonitrile were successively added 50% potassium fluoride--Celite (1.10 g) and 1-bromobutane (0.22 ml), and the mixture was heated under reflux for 11 hours. The reaction solution was filtered off, distilled off under reduced pressure, and to the residue was added chloroform and saturated aqueous sodium hydrogencarbonate. After extraction with chloroform, the chloroform layer was dried over anhydrous potassium carbonate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (0.42 g) as a yellow oily substance. Yield=69%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ncccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 112 %

Procedure:
To a solution of the compound of Example 12 (17.12 g, 0.11 mol) in ethanol (180 mL) in a Parr bottle, was added 4% Pd/C (3.43 g). The bottle was sealed, purged with nitrogen and was pressurized (5 psi) with hydrogen. After stirring at room temperature for 2 hr, the reaction vessel was vented, purged with nitrogen and filtered. The clear filtrate was concentrated to give the title compound (15.3 g, 90%). 1H NMR (CDCl3): 7.58 (dd, J=5, 2 Hz, 1H); 6.87 (dd, J=8, 2 Hz, 1H); 6.72 (dd, J=8, 5 Hz, 1H); 3.98 (s, 3H).
Reaction SMILES: O.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:10]([C:14]1[C:15](=[O:25])[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18](=[O:20])[CH:19]=1)([CH3:13])([CH3:12])[CH3:11]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1CCCCC1>[C:10]([C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCCCC1
Product: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To 1.2 L of water, 223.2 g (1.09 mol) of sodium hydrosulfite, 1.0 L of cyclohexane, 200.0 g (908 mmol) of 2,6-di-tert-butyl-1,4-benzoquinone and 20.7 g (90.9 mmol) of benzyltriethylammonium chloride were added and the mixture was stirred for 1 hour at 40° C. The reaction mixture was subjected to liquid-liquid separation and the aqueous layer was discarded. The organic layer was washed with 400 mL of water to give a solution of 2,6-di-tert-butylhydroquinone in cyclohexane.
Reaction SMILES: CO[CH:3]([O:15]C)[CH2:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[I:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[O:15][CH:3]=[CH:4][N:5]=2)=[CH:12][CH:11]=1
Reactant: COC(CNC(=O)c1ccc(I)cc1)OC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Ic1ccc(-c2ncco2)cc1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
A solution of N-(2,2-dimethoxyethyl)-4-iodobenzamide (10 g, 30 mmol) in Eaton's reagent (100 mL) was heated at 135° C. for 17 hours. The reaction was allowed to cool and poured into ice water. The brown solid was isolated by filtration. Purification on silica gel eluting with dichloromethane gave 6.7 g of 2-(4-iodophenyl)oxazole, 1H NMR (400 MHz, CDCl3) δ 7.79 (q, 4H), 7.72 (s, 1H), 7.27 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)#[N:2].CO[Na]>CO>[C:1]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)#[N:2]
Reactant: Cc1ccc(C(=O)c2ccccc2OCC#N)cc1
Agent: CO[Na]
Solvent: CO
Product: Cc1ccc(-c2c(C#N)oc3ccccc23)cc1
Yield: 40.4 %

Procedure:
To a solution of 2'-cyanomethoxy-4-methylbenzophenone (8.9 g) in methanol (750 ml) was added CH3ONa (2.0 g) and molecular sieves (3A, 5 g) and the mixture was heated under reflux for 30 hours. After removal of insoluble materials by filtration, the filtrate was concentrated to dryness. The residue was dissolved in ethyl acetate, followed by removal of insoluble materials by filtration and concentration of the filtrate. The residue was purified by column chromatography on silica gel to afford pale yellow powders (3.34 g, 40%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CN(C=O)C>[Br:3][C:4]1[N:5]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
NaH (1.4 eq, 60% dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in published International Patent application WO 2004/065367, from commercially available methyl indole-6-carboxylate) in DMF (0.2 M) and the solution stirred at RT for 1 h. Then tert-butyl bromoacetate (1.1 eq) was added and the mixture stirred at RT for 40 min. The solvent was removed in vacuo and the residue taken up in EtOAc. The organic phase was washed with H2O (twice) and then brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound as a brownish solid (90%); MS (ES+) m/z 450 (M+H)+, m/z 452 (M+H)+