Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][O:4][C:3]1=[O:7].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C[Al](C)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][C:3](=[O:7])[C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5][OH:4]
Reactant: NCc1ccccc1Cl
Reactant: CC1(C)CCOC1=O
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(CCO)C(=O)NCc1ccccc1Cl
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution of 3,3-dimethyl-dihydrofuran-2(3H)-one (2.04 g, 17.9 mmol) in THF (15 mL) were added 2-chlorobenzylamine (2.4 mL, 19.9 mmol, 1.1 equiv.) and AlMe3 (2M in toluene, 4.5 mL, 9 mmol, 0.5 equiv.). The reaction mixture was stirred for 3 days. The reaction mixture was saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4, and concentrated to give N-(2-chlorobenzyl)-4-hydroxy-2,2-dimethylbutanamide as a white solid (3.8 g, 83%), which was used without further purification. LRMS (M+H+) m/z 256.0.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:16]1([CH2:15][N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:39][CH3:40])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC1CN(CC2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CC1CCCC1)CC(C)C(=O)N2C
Yield: 56 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-2-chloro-9-cyclopentylmethyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-55), 0.050 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.047 g (0.00016 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.048 g of (rac)-4-(9-cyclopentylmethyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diaze-pin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-55) as white powder. HRMS (ES+) m/z Calcd for C29H41N7O3+H [(M+H)+]: 536.3344. Found: 536.3344.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:2]=1[NH2:1]
Reactant: CO
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Cl
Product: COC(=O)c1cccc(O)c1N

Procedure:
To a solution of 2 g (13.1 mmol) of 2-amino-3-hydroxybenzoic acid in 60 mL of CH3OH at 0° C. was bubbled HCl gas until the solution was saturated. The reaction was heated at reflux for 12 h. The reaction mixture was concentrated and dissolved in 30 mL of water. The solution was neutralized with sat'd NaHCO3 solution and extracted with EtOAc. The organic fractions were dried over MgSO4, filtered and the filtrate was concentrated to give 1.8 g of the title compound as a brown solid.
Reaction SMILES: CN1CCCC1=[O:7].[Cl:8][C:9]1[C:10]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:11]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:12]2=[N:13][C:14]=1[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:8][C:9]1[C:10]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[C:11]2[C:29]3[CH2:30][CH2:31][S:32](=[O:7])[CH2:33][C:28]=3[S:27][C:12]2=[N:13][C:14]=1[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: CN1CCCC1=O
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCSC4)cc1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To N-methylpyrrolidone (140.56 L) was added 2-{[3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (14.056 kg) and the mixture was dissolved by heating at about 40° C. Then, vanadium (IV) oxyacetylacetone (49.09 g) was added thereto and the 30% hydrogen peroxide was added dropwise, while maintaining at 20 to 23° C. The mixture was stirred at the same temperature for 1 hour and then cooled to 3° C., followed by adding dropwise 0.5 N sodium thiosulfate (5 L) and then water (281.14 L). The mixture was stirred for 1 hour under ice-cooling. The crystals deposited was filtered off, dried and dissolved in N-methylpyrrolidone (135.65 L). Active carbon (678 g) was added and the mixture was stirred at room temperature for 30 minutes. The active carbon was filtered off and washed with N-methylpyrrolidone (13.565 L). The filtrate and washings were combined and to the mixture was added dropwise isopropyl ether (298.43 L). The crystals deposited were filtered off, washed with isopropyl ether (67.83 L ×2) to obtain the titled compound (9.56 kg, 64.3%). 1H-NMR (CDCl3) δ: 2.01-2.19 (1H, m), 2.54-2.73 (2H, m), 3.00-3.07 (1H, m), 3.89 (3H, s), 3.95 (1H, d, J=16.9 Hz), 4.05 (1H, d, J=16.9 Hz), 5.20 (2H, s), 6.99-7.03 (2H, m), 7.16-7.20 (2H, m), 7.76-7.80 (2H, m), 7.91-7.95 (2H, m).
Reaction SMILES: N[C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([Br:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=[O:16].[Na+]>S(=O)(=O)(O)O>[Br:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:16])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)c(C)c(C)c1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc(Br)c(C)c(C)c1O
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 91.4 %

Procedure:
To an aqueous solution (160 mL) of methyl 2-amino-5-bromo-3,4-dimethylbenzoate (28.0 g) in 25% sulfuric acid was added dropwise an aqueous solution (80.0 mL) of sodium nitrite (11.2 g) over 50 min at the internal temperature of 2-3° C. under ice-cooling. Then, 5% aqueous sulfuric acid solution (1600 mL) was added dropwise thereto over 50 min at 0-15° C. The reaction mixture was stirred at 100° C. for 2 hr. The reaction mixture was allowed to be cooled to room temperature, and the precipitate was collected by filtration, and washed with water to give the title compound (25.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16](N(CC)CC)[CH3:17].ClC(OCC)=O.CN(C1C=CC=CN=1)C>O1CCCC1.C(O)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (28) (1.0 g, 0.0046 mol) and triethylamine (0.78 mL, 0.0056 mol) were dissolved in 20 mL tetrahydrofuran and cooled over ice water. Ethyl chloroformate (0.4 mL, 0.0051 mol) was added dropwise at 0-5° C. and the reaction was stirred for 30 minutes. A catalytic amount of dimethylaminopyridine was added followed by 5 mL ethanol and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated and partitioned between water (50 mL) and ethyl acetate (1×100 mL). The aqueous layer as extracted with an additional 50 mL ethyl acetate. The combined organics were washed with 1×50 mL water, 1×25 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to an oil. The residue was chromatographed with 10 g silica gel, 20% ethyl acetate/hexanes, to obtain 0.92 g of clear colorless oil. MS (ESI) m/z 282 [M+K]+. 1H NMR (CDCl3) δ 1.25-1.31 (t, 3 H), 1.49 (s, 9H), 1.57 (s, 2 H), 3.01-3.07 (m, 1 H), 3.30-3.36 (m, 1 H), 3.47-3.65 (m, 3 H), 4.13-4.20 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26].ClC1C=CC=CC=1Cl.Cl>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[NH:26][CH2:25][CH2:24][N:11]=2)[CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: N#CCSc1ccc(O)c(Cl)c1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Clc1ccccc1Cl
Solvent: CC(C)O
Product: Oc1ccc(SCC2=NCCN2)cc1Cl
Reaction time: 1.5 h

Procedure:
A mixture of 19.95 g of 2-chloro-4-(cyanomethylthio)-phenol, 23.3 g of ethylenediamine p-toluenesulfonate and 75 ml of 1,2-dichlorobenzene was heated at 160°-175° C. with stirring under a small flow of nitrogen for 1.5 hours. After cooling the reaction mixture, the 1,2-dichlorobenzene was decanted off. The residue was slurried in water and CH2Cl2 and then basified. The CH2Cl2 layer was separated from the mixture and an insoluble gum obtained. The gum was put in solution in isopropyl alcohol, acidified with hydrochloric acid in isopropyl alcohol and then cooled. The crude product was removed by filtering and recrystallized from isopropyl alcohol. Recrystallized 2-chloro-4-(((2-imidazolin-2-yl)methyl)thio)-phenol hydrochloride was found to have a m.p. of 181°-183° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:16])([CH2:13][CH2:14]O)[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:1]([O:9][CH2:14][CH2:13][C:11]([CH3:12])([OH:16])[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCO
Reactant: O=C(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(O)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Three parts of benzoic acid was mixed with 2.6 parts of 2-methyl-butane-2,4-diol, 0.6 part of 4-dimethylaminopyridine and 45 parts of dehydrated tetrahydrofuran. To the obtained mixture, 5.6 parts of N,N′-dicyclohexylcarbodiimide was added, and then the obtained mixture was stirred at room temperature for 24 hours. The resultant mixture was filtrated and the filtrate was concentrated. To the residue, 33 parts of methyl tert-butyl ether was added and then, 17 parts of 2% aqueous oxalic acid solution was added. The resultant mixture was stirred and filtrated. The filtrate was separated into an organic layer and an aqueous layer. The organic layer was washed five times with ion-exchanged water and then dried over 3.1 parts of magnesium sulfate. The mixture was filtrated and the obtained filtrate was concentrated. The obtained residue was mixed with 6 parts of methyl tert-butyl ether and the resultant mixture was filtrated. The filtrate was concentrated to obtain 4.8 parts of 3-methyl-3-hydroxybutyl benzoate as colorless oil. This compound is called as Compound (G).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.[H-].[Na+].[F:13][CH:14]([F:21])[CH2:15]OS(C)(=O)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH2:15][CH:14]([F:21])[F:13])[C:3]=1[F:10]
Reactant: CS(=O)(=O)OCC(F)F
Reactant: Oc1c(Cl)ccc(Br)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1c(Br)ccc(Cl)c1OCC(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A solution of 3-bromo-6-chloro-2-fluorophenol (15.4 g, 0.068 mol) in DMF (25 mL) was slowly added to a suspension of sodium hydride (60% dispersion in mineral oil) (4.0 g, 0.10 mol) in DMF (100 mL) and the mixture was stirred 1 hour. A solution of methanesulfonic acid 2,2 difluoroethyl ester (17.5 g, 0.109 mol) in DMF (10 mL) was slowly added. The resulting solution was heated to 70° C. for 18 hours. The solution was diluted with water (200 mL) and extracted with ethyl ether. The combined organic phases were dried (sodium sulfate) and concentrated. The residual oil was purified by chromatography (in hexanes) to give 1-bromo-4-chloro-3-(2,2-difluoroethoxy)-2-fluorobenzene (9.0 g, 0.031 mol): 1H NMR (CDCl3): δ 7.3 (m, 1H), 7.10 (dd, 1H), 6.15 (dt, 1H), 4.35 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[CH2:19][C:20]1[N:25]=[C:24]([C:26]([OH:28])=O)[CH:23]=[CH:22][CH:21]=1.C(N1C=CN=C1)([N:31]1C=CN=C1)=O.N.O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[CH2:19][C:20]1[N:25]=[C:24]([C:26]([NH2:31])=[O:28])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2[nH]c(-c3ccccc3)c(Cc3cccc(C(=O)O)n3)c2cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2[nH]c(-c3ccccc3)c(Cc3cccc(C(N)=O)n3)c2cc1F
Temperature: 25 °C
Reaction time: 9 h
Yield: 98.4 %

Procedure:
To a solution of 6-(5-fluoro-6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (105 mg) in tetrahydrofuran (2.8 mL) was added 1,1′-carbonyldiimidazole (90.5 mg), and this mixture was stirred at room temperature for 9 hours. Then, 28% aqueous ammonia (0.56 mL) was added thereto, followed by stirring at room temperature for 14 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (103 mg). 1H-NMR (CDCl3) δ ppm: 3.94 (3H, s), 4.37 (2H, s), 5.30-5.60 (1H, br), 6.97 (1H, d, J=7.0 Hz), 7.16 (1H, d, J=11.5 Hz), 7.23-7.28 (1H, m), 7.34-7.41 (1H, m), 7.41-7.49 (2H, m), 7.49-7.57 (2H, m), 7.66-7.94 (2H, m), 7.98-8.13 (2H, m).
Reaction SMILES: [F:1][S:2]([F:9])=[C:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[N+:10]([C:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:14][CH2:15]O)([O-:12])=[O:11].S(=O)(=O)(O)O>ClCCCl>[F:1][S:2]([F:9])=[C:3]([O:8][CH2:15][CH2:14][C:13]([N+:17]([O-:19])=[O:18])([N+:10]([O-:12])=[O:11])[N+:20]([O-:22])=[O:21])[C:4]([F:7])([F:6])[F:5]
Reactant: O=[N+]([O-])C(CCO)([N+](=O)[O-])[N+](=O)[O-]
Reactant: OC(=S(F)F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=[N+]([O-])C(CCOC(=S(F)F)C(F)(F)F)([N+](=O)[O-])[N+](=O)[O-]
Yield: 95.6 %

Procedure:
A mixture of 0.57 g (0.003 mole) of pentafluorothioacetic acid, 1.2 g (0.006 mole) of 3,3,3-trinitropropanol and 0.3 ml of concentrated sulfuric acid in 10 ml of 1,2-dichloroethane was stirred at reflux temperature for 24 hr in a flask with a reverse Dean Stark trap attached. The reaction mixture was cooled and the organic layer was decanted from the insoluble sulfuric acid. After the removal of volatiles from the organic layer, the residue (oil) was chromatographed on silica gel 40 using methylene chloride as eluent to give 0.99 g (89%) of product, mp 32° C.;
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[NH:17][CH:18]1[CH2:23][O:22][C:20](=[O:21])[CH2:19]1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:17]([CH:18]1[CH2:23][O:22][C:20](=[O:21])[CH2:19]1)[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH3:6])=[O:4]
Reactant: Cc1ccc2ccccc2c1NC1COC(=O)C1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: Cc1ccc2ccccc2c1N(C(=O)CCl)C1COC(=O)C1

Procedure:
A 2.4-g (0.021 mol) sample of chloroacetyl chloride was added to a refluxing solution of 5.0 g (0.021 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone in 100 ml toluene. The reaction mixture was heated under reflux for 30 minutes. Gas was evolved and a white precipitate formed during the 30-minute reflux period. The reaction mixture was cooled, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give 4.3 g of product, as a white solid, m.p. 121°-122° C. The infrared spectrum of the product showed two strong carbonyl absorption bands at 5.62 microns and 5.88 microns. The product is tabulated in Table C as Compound No. C-1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[Cl:19])[NH2:15]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[C:18]([Cl:19])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1cc(N)ccc1Cl
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1Cl

Procedure:
(2-amino-5-chloro-4-methoxyphenyl)-(2-chlorophenyl)-methanone (Xcc) was prepared by reacting 2-chlorobenzaldehyde with 0.019 moles of 3-methoxy-4-chloro aniline in a manner analogous to Example 1. MH+/Z=296.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1I)([CH3:6])[CH3:5].[CH2:37]([Sn](CCCC)(CCCC)CCCC)[CH:38]=[CH2:39]>>[CH3:1][O:2][C:3](=[O:36])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH2:39][CH:38]=[CH2:37])([CH3:6])[CH3:5]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1I
Product: C=CCc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OC

Procedure:
The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-iodo-phenoxy)-2-methyl-propionic acid methyl ester (0.200 g, 0.330 mmole) and allyl tributyltin (0.218, 0.659 mmole) to produce a colorless oil (0.102 g, 59%). Mass [EI+] 521 (M+H)+.
Reaction SMILES: [C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:36])/[C:10](=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)/[CH2:11][CH2:12][CH2:13][O:14]C2CCCCO2)[CH:2]=1>CO>[C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:36])/[C:10](=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)/[CH2:11][CH2:12][CH2:13][OH:14])[CH:2]=1
Reactant: COc1cc(/C=C(\CCCOC2CCCCO2)C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Solvent: CO
Product: COc1cc(/C=C(\CCCO)C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
To the methanol (5 mL) solution of (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-5-(tetrahydropyran-2-yloxy)valeric acid (biphenyl-3-ylmethyl)amide (168 mg), Dow-X™50W X-8 (300 mg) was added, and the reaction solution was agitated at 45° C. for 5 hours. The resin was filtered off, the ammonia water (1 mL) was added to the filtrate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=9:1), and 120 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH:16](O)[CH:17]([CH3:19])[CH3:18])[C:6]=1[CH3:21])(=[O:3])[CH3:2].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]2[O:15][C:17]([CH3:19])([CH3:18])[CH2:16][C:7]=2[C:6]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C(O)C(C)C)c1C
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C)CC(C)(C)O2
Temperature: 25 °C
Yield: 18.6 %

Procedure:
0.40 g of 4-acetoxy-5-t-butyl-2-(1-hydroxy-2-methylpropyl)-3-methylphenol was dissolved in 10 ml of anhydrous toluene, 0.35 ml of boron trifluoride ethyl ether was added dropwise, and the mixture was stirred at room temperature for a whole day and night. After the reaction was quenched with water, the mixture was extracted with ethyl acetate. The organic layers were washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1%-2% ethyl acetate) to give 70 mg of 5-acetoxy-6-t-butyl-2,2,4-trimethyl-2,3-dihydrobenzofuran as a pale yellow oil (yield 19%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:10]3([C:14](=[O:15])[NH:13][C:12](=[S:16])[NH:11]3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([N:13]1[C:14](=[O:15])[C:10]2([C:4]3[CH:3]=[C:2]([Br:1])[S:6][C:5]=3[CH2:7][CH2:8][CH2:9]2)[N:11]=[C:12]1[S:16][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:5]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NC(=S)NC12CCCc1sc(Br)cc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N(Cc2ccccc2)C(SCc2ccccc2)=NC12CCCc1sc(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 111.7 %

Procedure:
2-Bromo-2′-thioxo-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazolidin]-5′-one (0.285 g, 0.9 mmol) was dissolved in THF (20 mL) and cooled to 0° C. in an ice bath. Sodium hydride (50% dispersion in oil, 26 mg, 1.08 mmol) was added and the mixture was stirred for 15 min. Benzyl bromide (0.13 ml, 1.08 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled to 0° C. again and a further portion of sodium hydride (50% dispersion in oil, 26 mg, 1.08 mmol) was added. The mixture was stirred for 15 min, benzyl bromide (0.13 mL, 1.08 mmol) was added and the reaction mixture was stirred at room temperature for 18 hr. Solvent was evaporated under reduced pressure. The residue was dissolved in water and extracted with dichloromethane (×3). The organic extracts were combined, dried (MgSO4), and concentrated in vacuo. The crude residue purified on silica gel using ethyl acetate in iso-hexane (1:1) to afford the title compound as a colourless oil (0.25 g, 56%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15]I>C1CCCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC=CCC1
Reactant: CI
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CN(C(=O)OC(C)(C)C)C1CC=CCC1
Yield: 64 %

Procedure:
Cyclohex-3-enyl-carbamic acid tert-butyl ester (Kampferer, P.; Vasella, A. Helvetica Chimica Acta 2004, 87, 2764-2789) (3 g, 15.2 mmol) and methyl iodide (0.95 ml, 15.2 mmol) were treated for 1 hour according to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=10/1) the title compound (Rf=0.22, 2.04 g, 64% yield) was obtained as colorless solid.