Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[CH3:6].P(Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.Cl.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[CH:27][CH:28]=1>C(OCC)(=O)C>[CH3:6][C:5]1[N:22]([C:23]2[CH:24]=[C:25]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[CH:27][CH:28]=2)[CH2:2][CH2:3][N:4]=1
Reactant: CCOC(=O)c1ccoc1-c1cccc(N)c1
Reactant: CC(=O)NCCCl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccoc1-c1cccc(N2CCN=C2C)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was added over 10 min to a stirred suspension of phosphorus pentachloride (2.08 g) in ethyl acetate (2 mL) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min at 0° C. toluene (12 mL) was added, and ethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was added in one portion into the above solution at 0–5° C. The mixture was stirred at 0–5° C. for 10 min and then allowed to warm up to 20° C. After 2 h formation of the amidine is essentially complete (HPLC ethyl 2-(3-aminophenyl)-3-furoate hydrochloride <2% @ 220 nm, a/a). The mixture was cooled to 0–5° C., crushed ice (18 g) was added over 20 min to destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min). After 1 h at 20° C. additional ethyl acetate (12 mL) added to the above mixture, the organic layer was separated, washed with deionized water (2×12 mL), and concentrated under reduced pressure. The residue was dissolved in acetone (5 mL) and ethyl acetate (5 mL), and treated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at <20° C. for at least 12 h, the precipitate was collected by filtration, washed with acetone (2×0.5 vol), and dried in vacuo at 45–50° C. to yield 1.9 g (73%) of white solid. 1H NMR (400, d6-DMSO) δ: 8.00 (s, 1H), 7.92–7.90 (m, 2H), 7.64–7.55 (m, 2H), 6.90 (d, 1H), 4.32 (t, 2H), 4.22 (q, 2H), 3.93 (t, 2H), 2.22 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1)[CH3:12].[NH4+].[Cl-]>C1COCC1>[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[OH:10])=[CH:15][CH:14]=1)[CH3:12]
Reactant: COc1ccccc1C=O
Reactant: CCc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2ccccc2OC)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1.01 g of o-anisaldehyde are dissolved in THF and cooled to 0° C. 16.29 ml of 4-ethylphenylmagnesium bromide (0.5 M in THF) are added to the mixture. The reaction solution is stirred at room temperature overnight and then poured into 20% NH4Cl solution and extracted with ethyl acetate. 1.92 g of the product are obtained, and this can be employed without further purification. C16H18O2 (242.32) MS (ESI+) 225.15 (M−OH)+
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[CH:26][N:25]=1>>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[O:20][N:30]=[C:28]([C:27]5[CH:32]=[CH:33][C:24]([NH2:23])=[N:25][CH:26]=5)[N:29]=4)=[CH:16][N:17]=3)[CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnc4ccc(-c5ccc(C(F)(F)F)cc5)cn34)n2)cn1

Procedure:
The title compound was prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.35) (153 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate) and further purification by crystallization (MeOH/diethyl ether) as a white solid (27 mg, 13%). MS (ISP) 423.3 [(M+H)+]; mp 258° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10]/[C:11](/[CH3:22])=[CH:12]\[C:13]([O:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])=[O:14].[N+:23]([CH2:26][C:27](=O)[CH3:28])([O-:25])=[O:24]>C(O)C>[CH3:28][C:27]1[NH:10][C:11]([CH3:22])=[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])=[O:14])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[C:26]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(=O)OCCOC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1Cl
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: CCO
Product: CC(=O)OCCOC(=O)C1=C(C)NC(C)=C([N+](=O)[O-])C1c1ccccc1Cl

Procedure:
28.1 g (200 mmol) of 2-chlorobenzaldehyde are boiled under reflux with 37.4 g (200 mmol) of 2-acetoxyethyl β-aminocrotonate and 32.6 g (320 mmol) of nitroacetone in 400 ml of ethanol for 4 hours. The mixture is cooled and concentrated. The evaporation residue is taken up in ethyl acetate and the mixture is washed with water, sodium bicarbonate solution and water again, dried and concentrated. The semi-solid evaporation residue is stirred with ethanol, filtered off with suction and washed with ethanol. 23.2 g (29.4% of theory) of a yellow-colored product of melting point 158°-160° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[CH2:6][CH2:5]2.Cl[CH2:16][C:17]([CH3:19])=[CH2:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][C:10]1[C:9]([CH3:12])=[C:8]2[C:4]([CH2:5][CH2:6][N:7]2[CH:13]=[O:14])=[CH:3][C:2]=1[O:1][CH2:18][C:17]([CH3:19])=[CH2:16]
Reactant: Cc1c(O)cc2c(c1C)N(C=O)CC2
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COc1cc2c(c(C)c1C)N(C=O)CC2
Temperature: 60 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
A suspension of 2,3-dihydro-5-hydroxy-6,7-dimethyl-1H-indole-1-carbaldehyde (21.8 g, 0.11 mol), 3-chloro-2-methyl-1-propene (15 mL, 0.15 mol) and potassium carbonate (23.6 g, 0.17 mol) in DMF (200 mL) was stirred at 60° C. for 15 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate four times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, treated with active carbon, filtered, and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to obtain 20.6 g of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=[CH:14][O:15]C>Cl.O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH:14]=[O:15]
Reactant: COC=Cc1c(OC)ccc2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ccccc2c1CC=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
120 mg of 2-methoxy-1-(2-methoxyvinyl)naphthalene was dissolved in 4 ml of 2 N hydrochloric acid-tetrahydrofuran (1:1). The obtained mixture was then stirred at 70° C. for 2 hours. The reaction solution was cooled to a room temperature and then diluted with ethyl acetate. The resultant product was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 115 mg of (2-methoxynaphthalen-1-yl)acetaldehyde. This compound was used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][NH:12][CH3:13].Cl.[CH2:15](O)C>>[CH3:11][N:12]([CH3:15])[CH2:13][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10]
Reactant: CNC
Reactant: CCO
Reactant: CC(=O)c1cccc(F)c1
Agent: Cl
Product: CN(C)CCC(=O)c1cccc(F)c1
Yield: 88 %

Procedure:
1-(3-Fluorophenyl)ethanone (17 g, 0.123 mol), dimethylamine (13.7 g, 0.172 mol), and paraformaldephyde (5.5 g, 0.185 mol) were suspended in ethanol (50 mL), and conc HCl solution (0.3 mL) was added. The mixture was heated at reflux overnight. The solvent was removed under vacuum, and the residue was washed with EtOAc (3×) to give 3-(dimethylamino)-1-(3-fluorophenyl)propan-1-one (20.7 g, 88%), which was used for the next step without purification.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:11][C:12]#[N:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH:11]([C:12]#[N:13])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:20]
Reactant: N#CCC(=O)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C#N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
A heptane washed suspension of 7.6 g (0.189 mole) of 60% NaH/mineral oil in 400 ml of anhydrous toluene was treated portion-wise with 25.0 g (0.172 mole) of benzoylacetonitrile under a nitrogen atmosphere. After stirring for 1 hour, 33.0 g (0.189 mole) of ethyl bromoacetate (97%) was added in one portion. The reaction was heated at reflux for 4 hours, then allowed to cool to room temperature and stirred for 20 hours. Water (500 ml) was added, and the toluene layer was extracted with water (500 ml). The toluene layer was dried over MgSO4, filtered, and the solvent evaporated under reduced pressure (42.9 g). The residual oil was fractionally distilled under vacuum to give 21.4 g (54%) of pure product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OC)=O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(F)cc1
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(F)cc3)nc21

Procedure:
Analogously to the procecure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.92 g (11.4 mmol) of methyl 4-fluorophenylacetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:52])[C@H:26]([NH:34]C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[S:7].N1CCCCC1>CN1C(=O)CCC1.CCCCCC>[CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:52])[C@H:26]([NH2:34])[CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[S:7]
Reactant: CCc1cccc(C)c1C(=S)N[C@@H](Cc1ccc(NC(=O)[C@@H](Cc2cccnc2)NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)OC
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Solvent: C1CCNCC1
Product: CCc1cccc(C)c1C(=S)N[C@@H](Cc1ccc(NC(=O)[C@H](N)Cc2cccnc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
N-[(2-ethyl-6-methylphenyl)thioxomethyl]-4-[[(2R)-2-(Fmoc-amino)-1-oxo-3-(pyridin-3-yl)propyl]amino]-L-phenylalanine methyl ester from example 26 (0.308 mmol, 224 mg) was treated with 25% piperidine in NMP (3 mL) and the solution was stirred at room temperature. Within 1 h, TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with hexane (25 mL) and the formed layers were separated. The bottom yellow layer was washed with hexane, then was diluted with water and extracted with ethyl acetate and THF (2:1, 3×25 mL). The combined extracts were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and the solvents were removed under vacuum. The resulting residue was dried under high vacuum to afford 126 mg (81%) of 4-[[(2R)-2-amino-1-oxo-3-(pyridin-3-yl)propyl]amino]-N-[(2-ethyl-6-methylphenyl)thioxomethyl]-L-phenylalanine methyl ester as an amorphous colorless solid. HR MS: Obs. mass, 505.2270. Calcd. mass, 505.2274 (M+H).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@@H:18]3[CH2:33][C:32]4=[CH:34][CH:35]=[C:29]([CH:30]=[CH:31]4)[O:28][CH2:27][CH:26]=[CH:25][CH2:24][O:23][CH2:22][C@H:21]([CH:36]([CH3:38])[CH3:37])[NH:20][C:19]3=[O:39])C3C(=CC=CC=3)C=2C=CC=1>CO.[Pd]>[NH2:17][C@@H:18]1[CH2:33][C:32]2=[CH:31][CH:30]=[C:29]([CH:35]=[CH:34]2)[O:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH2:22][C@H:21]([CH:36]([CH3:37])[CH3:38])[NH:20][C:19]1=[O:39]
Reactant: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
A mixture of 6.82 g (12.62 mmol) of 9H-fluoren-9-ylmethyl((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-12-yl)-carbamate and 4.4 g of 10% Pd/C in 880 ml of methanol was stirred under a hydrogen atmosphere at RT. After 6 h, it was filtered and freed of solvent. The residue was separated by preparative HPLC. The required fractions were combined, acetonitrile was evaporated off, and the resulting aqueous solution was made slightly alkaline with sodium bicarbonate. The aqueous phase was extracted several times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel with ethyl acetate/methanol mixtures afforded the title compound (2.90 g).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Fe]>[C:9]([C:2]1[CH:3]=[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:1]=1[O:7][CH3:8])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Fe]
Product: COc1ccc(C(=O)c2ccccc2)cc1C(=O)c1ccccc1

Procedure:
Direct reaction of anisole, which is highly activated, with benzoyl chloride in the presence of iron powder to give 2,4-dibenzoylanisole is described in Zh. Org. Khim. 6 (1970) 535.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=O)[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].BrC[C:27](=[O:30])[CH2:28][CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:16]([C:27](=[O:30])[CH2:28][CH3:29])=[C:15]([CH3:19])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: CCC(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(=O)c1oc2ccc(OCc3ccccc3)cc2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution (150 mL) of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethanone (7.8 g) synthesized in Example 82(1) in N,N-dimethylformamide were added potassium carbonate (13.2 g) and 1-bromobutan-2-one (5.0 mL) at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (100 mL) again, 1,8-diazabicyclo[5.4.0]undec-7-ene (4.9 mL) was added to the solution, and the mixture was stirred at 110° C. with heating for 1 hr. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title object compound (6.2 g, 66%) as a colorless solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH:25](O)[CH3:26])[C:5]1=O)[CH:2]=[CH2:3].[OH2:32].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39]([OH:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH3:43][C:33]1[CH:34]=[CH:35][C:36]([S:39]([O-:42])(=[O:41])=[O:40])=[CH:37][CH:38]=1.[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N+:6]2[C@@H:24]([CH2:25][CH3:26])[CH:28]([CH3:29])[O:32][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)O)C1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC(C)[C@@H]2CC
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one (2.25 g, 4.89 mmol; Example 151, Step C) in toluene (65 mL) was added p-toluenesulfonic acid monohydrate (930 mg, 4.89 mmol). After being heated to reflux using a Dean-Stark trap for 2.5 h, the reaction was concentrated under reduced pressure to provide the title compound as a pale yellow powder.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[H][H]>>[OH:8][C@H:7]1[C@H:6]([OH:9])[C@@H:5]([OH:10])[CH2:4][CH2:3][C:2]1=[O:1]
Reactant: [H][H]
Reactant: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Product: O=C1CC[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The present embodiment relates a method for producing catechol in which 2-deoxy-scyllo-inosose is dehydrated while heating to give (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one, and then the (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one is reduced with hydrogen in the presence of a metal catalyst to give (2S,3R,4S)-2,3,4-trihydroxycyclohexane-1-one represented by the following formula (3), and then the (2S,3R,4S)-2,3,4-trihydroxycyclohexane-1-one is dehydrated while heating. In the method of this Embodiment, catechol is produced by the reaction represented by the formula (7).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:45]1[CH2:46][CH2:47][CH:42]([C:40]([C:32]2[N:31]([CH2:30][C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=2)=[O:41])[CH2:43][CH2:44]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3n2Cc2ccco2)CC1)c1ccccc1)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(Cl)cc12
Yield: 39.4 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (15 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 8 mg (40%) of the title product. MS (ESI+) calcd for C16H12ClN5O2S2 405.012094, found 405.012744.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([C:26](=[O:30])[C:27]([OH:29])=O)[CH:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C(Cl)=O.[NH:37]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:37]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:27](=[O:29])[C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=1)=[O:30])[CH3:43]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of 1.0 g (2.4 mmol) of 3-(octadecyloxy)-alpha-oxobenzeneacetic acid in 50 ml of anhydrous methylene chloride and 2 drops of DMF stirred in an ice bath was added 1.1 ml (11.9 mmol) of oxalyl chloride. The cooling bath was removed and stirring was continued at room temperature for 2 hours. The solvent was removed at reduced pressure and the residual acid chloride was dissolved in 40 ml of anhydrous methylene chloride and added dropwise to a stirred, ice bath cooled solution of 0.6 ml (3.6 mmol) of diethyl iminodiacetate and 0.66 ml (4.8 mmol) of triethylamine in 10 ml of methylene chloride. The mixture was stirred for 30 minutes in the ice bath and then at room temperature for 19 hours when it was washed with NaHCO3 solution, dried and concentrated to an oil which was purified by chromatography on 35 g of 230-400 mesh silica gel using 20% ethyl acetate-hexane to give 1.3 g (93% yield, mp 27°-29°) of N-(2-ethoxy-2-oxoethyl)-N-[2-[3-(octadecyloxy)phenyl]-1,2-dioxoethyl]glycine ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[CH:15]=1)[N:6]=[C:5]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]2.Br[CH2:47][CH2:48][O:49][CH3:50].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]4)=[N:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=4)[CH:15]=3)=[N:8]2)=[CH:3][C:2]=1[O:1][CH2:47][CH2:48][O:49][CH3:50]
Reactant: COc1cc2nc(-c3cccc(NC(=O)c4cccnc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)c4cccnc4)c3)nc2cc1OC
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-(nicotinamido)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.108 g, 0.179 mmol), 1-bromo-2-methoxyethane (0.054 g, 0.389 mmol) and K2CO3 (0.052 g, 0.449 mmol) in DMF (2 mL) were heated at 85° C. for 3 h. The mixture was allowed to cool to RT and the volatiles were removed in vacuo. The residue was purified by preparative tic (SiO2, CH2Cl2/MeOH 9:1) to give tert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. The material was taken directly on to the next step. HPLC retention time 5.802 mins.