Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=1)=[O:5].C([NH2:25])=O.C[O-].[Na+]>CN(C=O)C>[CH3:1][N:2]([CH3:22])[CH:3]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH2:25])=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: NC=O
Reactant: COC(=O)c1ccc(NC(=O)C(c2ccsc2)N(C)C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(C(=O)Nc1ccc(C(N)=O)cc1)c1ccsc1
Temperature: 100 °C

Procedure:
Methyl 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)benzoate (E114) and formamide dissolved in DMF under Ar were heated to 100° C. The NaOMe was then added and the reaction heated for 2 hours. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)benzamide (E115).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH:5]2[N:4]=[C:3]1[C:17]([F:20])([F:19])[F:18].Cl>CO.C(OCC)(=O)C>[CH3:1][N:2]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[N:4]=[C:3]1[C:17]([F:19])([F:18])[F:20]
Reactant: CN1C(C(F)(F)F)=NC2CN(C(=O)OC(C)(C)C)CC21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)nc2c1CNC2
Reaction time: 2 h

Procedure:
To the product from Step A in 2 mL of methanol was added 2 mL of saturated hydrochloric acid in ethyl acetate. After stirring for 2 h the reaction was concentrated in vacuo and the residue purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (20% methanol/ethyl acetate, 2% ammonium hydroxide) to give the title compound as a white solid. LC/MS 192.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(CNCc2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (300 mg, 1.6 mmol), 2,4-dichlorobenzaldehyde (281 mg, 1.61 mmol) and acetic acid (0.09 mL, 1.61 mmol) in 1,2-dichloroethane (16 mL) at 0° C. is added sodium triacetoxy-borohydride (476 mg, 2.25 mmol). The reaction is warmed to ambient temperature and stirred overnight under N2. The reaction mixture is poured on to 2N NaOH (20 mL) and extracted with ethyl acetate (3×). The combined organic extracts are washed with aqueous saturated NaCl, dried (Na2SO4), filtered and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 5% EtOH (10% NH4OH)/chloroform to yield 360 mg (65%) of 3-[(2,4-dichlorobenzylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CD3OD) δH: 7.49-7.47 (2H, m), 7.36-7.34 (1H, m), 4.05-4.01 (2H, m), 3.88 (2H, s), 3.64-3.61 (2H, m), 2.8 (2H, m), 2.78-2.74 (1H, m), 1.46 (9H, s). Mass spectrum (ion spray): m/z=345.1 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:11]([NH:13][C:14](=[O:18])[CH:15](Br)[CH3:16])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[NH3:28]>ClC(Cl)C.C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH2:28])[CH3:16])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(NC(=O)C(C)Br)c2C(=O)c2ccccc2Cl)C1
Reactant: N
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2c(sc(NC(=O)C(C)N)c2C(=O)c2ccccc2Cl)C1

Procedure:
841 g of 6-acetyl-2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydro-thieno[2,3 -C]pyridine was dissolved in a 0.72 liters of dichloroethane and 1.08 liters of ethyl acetate, into which ammonia gas was introduced at -10° C. The mixture was subjected to reaction in an autoclave at 100° C. for 1 hour. After completion of the reaction, excess ammonia gas was removed and the reaction solution was poured into 3N HCl under ice-cooling conditions. After extraction with ethyl acetate, the aqueous phase was neutralized with a saturated sodium carbonate aqueous solution, followed by repeating extraction with chloroform. The resultant organic phase was washed with a saturated saline solution, followed by drying with anhydrous magnesium sulfate and removal of the solvent by distillation under reduced pressure to obtain 636.8 g of the intended compound.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[CH3:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH3:5])=[CH:9][CH:10]=1
Reactant: COCCl
Reactant: CC(=O)c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
Chloromethyl methyl ether (19.2 mL, 252 mmol) was added dropwise to a 0° C. solution of 4-hydroxyacetophenone (6.855 g, 50.35 mmol) and triethylamine (8.4 mL, 60.42 mmol) in dichloromethane (100 mL). The solution was then allowed to warm to rt overnight, quenched with MeOH (40 mL), filtered and the filtrate concentrated and purified by flash chromatography to give the title compound which was used as is in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([CH3:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH3:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 11 h
Yield: 86.4 %

Procedure:
A mixture of 0.70 g (3.07 mmol) of 4-benzyloxy-2-methylbenzyl alcohol, 2.67 g (30.7 mmol) of manganese dioxide, 0.5 ml of methanol and 20 ml of chloroform was stirred at room temperature for 11 hours. Then insoluble matters were filtered off and the filter-rate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 0.60 g of 4-benzyloxy-2-methylbenzaldehyde.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][O:18][CH3:19]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH2:16][CH2:17][O:18][CH3:19])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COCCCBr
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 0.15 g, 3.75 mmol) was added, at room temperature, to a solution of 4-chloro-2-nitrophenol (0.5 g, 2.88 mmol) in anhydrous N,N-dimethylformamide (15 mL) and the resulting mixture was stirred for 5 minutes. 1-Bromo-3-methoxy-propane (0.485 g, 3.17 mmol) was then added and the reaction mixture was heated at 80° C. for 62 hours. The resulting mixture was partitioned between an aqueous solution of sodium hydroxide (3 M) and ethyl acetate, the organic layer was separated, washed twice with an aqueous solution of sodium hydroxide (3 M) and once with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 90/10 to 50/50) to give 0.455 g (64% yield) of 4-chloro-1-(3-methoxy-propoxy)-2-nitro-benzene as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:13])[CH3:12].[N+:14]([O-])([O-:16])=[O:15].[K+]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[NH:10][C:11](=[O:13])[CH3:12]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(NC(C)=O)c(C)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(NC(C)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 46.3 %

Procedure:
N-[2-methyl-4-(methyloxy)phenyl]acetamide (1.95 g, 10.88 mmol) was dissolved in TFA (20 mL) and cooled to 0° C. in an ice bath. Potassium nitrate (1.210 g, 11.97 mmol) was added slowly. The reaction was monitored by tic and quenched by pouring into ice and diluting with EtOAc. A solution of saturated sodium bicarbonate was added until solution was a neutral pH. Organics were washed with water and saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure to afford a yellow solid. Efforts to dissolve the solid in ethyl acetate resulted in a suspension that was let sit for several hours. Hexanes were added and the solids filtered to afford N-[2-methyl-4-(methyloxy)-5-nitrophenyl]acetamide (1.13 g, 5.04 mmol) as yellow fluffy solid. The filtrate was purified via SiO2 chromatography to afford N-[2-methyl-4-(methyloxy)-5-nitrophenyl]acetamide (1.02 g, 4.55 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.00-2.11 (m, 3 H) 2.29 (s, 3 H) 3.90 (s, 3 H) 7.24 (s, H) 7.99 (s, 1 H) 9.42 (s, 1 H)
Reaction SMILES: C1C[O:17][C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:15][OH:16])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH3:4])O1.N1C=CC=CC=1[CH2:25][C:26](OC(=O)CC1C=CC=CN=1)=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[C:26]([O:16][CH2:15]/[C:8](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])=[CH:7]\[CH2:6][CH2:5][C:3](=[O:17])[CH3:4])(=[O:27])[CH3:25]
Reactant: CC(C)=CCCC(=CCCC1(C)OCCO1)CO
Reactant: O=C(Cc1ccccn1)OC(=O)Cc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)CC/C=C(/CCC=C(C)C)COC(C)=O
Reaction time: 8 h

Procedure:
7.2 g of the alcohol thus obtained was acetylated with anhydrous pyridine-acetic anhydride in the usual way and dissolved in 70 ml of methanol. To this solution was added 70 mg of p-toluenesulfonic acid, and the mixture was allowed to stand overnight at room temperature. The resultant was neutralized with an aqueous sodium hydrogencarbonate solution and extracted with n-hexane. There was obtained 7.2 g of the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([C:10]2[C:11](Cl)=[N:12][CH:13]=[N:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[OH:9])=[C:6]([C:21]([F:24])([F:23])[F:22])[N:5]=[CH:4][N:3]=1.[O-2].[Mg+2].[H][H]>CO.[Pd]>[F:24][C:21]([F:22])([F:23])[C:6]1[C:7]([CH:8]([C:10]2[C:15]([C:16]([F:17])([F:18])[F:19])=[N:14][CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:2][N:3]=[CH:4][N:5]=1
Reactant: OC(c1c(Cl)ncnc1C(F)(F)F)c1c(Cl)ncnc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CO
Product: OC(c1cncnc1C(F)(F)F)c1cncnc1C(F)(F)F
Yield: 87.6 %

Procedure:
To a solution of 0.44 g of 1,1-bis-(4-chloro-6-trifluoromethylpyrimid-5-yl)methanol in 4.0 ml methanol were added 0.246 g magnesium oxide and 66 mg of 10% Pd/C (50% wet, Degussa). The mixture was then shaken on a Parr hydrogenation apparatus for 6 hours under 50 psi of hydrogen. The palladium catalyst and excess magnesium oxide were removed by filtration through dicalite, and the methanol filtrate was concentrated in vacuo to afford 318 mg of 1,1-bis-(4-trifluoromethylpyrimid-5-yl)methanol as an orange oil.
Reaction SMILES: [C:1](=[S:3])=[S:2].C[O-].[Na+].Cl[C:8]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:9]=1[NH2:10].Cl>CN(C=O)C.O>[Cl:16][C:12]1[C:13]([Cl:15])=[CH:14][C:8]2[S:2][C:1]([SH:3])=[N:10][C:9]=2[CH:11]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nc2cc(Cl)c(Cl)cc2s1
Temperature: 115 °C
Yield: 88.2 %

Procedure:
To a suspension of CS2 (0.64 mL, 10.6 mmol) and sodium methylate (0.55 g, 10.2 mmol) in DMF (10 mL) was added 2,4,5-trichloroaniline (7, 1.00 g, 5.09 mmol) in DMF (5 mL) under N2. The reaction mixture was heated at 110-120° C. for 16 h. After cooling, the reaction mixture was diluted with water (30 mL) and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried over P2O5 under vacuum to give yield compound 8 (1.06 g). This crude material was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]Br)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.[I-].[K+]>[CH3:8][O:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1CSc1ccccc1
Yield: 52.8 %

Procedure:
1.5 g (0.014 mole) of thiophenol and 4 g (0.014 mole) of methyl 2-(bromomethyl)-phenylglyoxylate O-methyloxime (Method 3) are dissolved in 100 ml of acetone. 2.2 g of potassium carbonate and 0.1 g of potassium iodide are added. The stirred mixture is refluxed for 17 hours and then cooled, after which 100 ml of water are added. The aqueous phase is extracted with methylene chloride and the extract is dried over sodium sulfate and evaporated down. The crude product is crystallized by trituration with n-pentane. 2.33 g (55%) of the abovementioned compound are obtained as a colorless solid (mp.=60°-65° C.)
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.Cl.[CH:20]1([C:23]2[C:24]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:25][CH:26]=[C:27]([CH:29]3[CH2:31][CH2:30]3)[CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[C:24]([N:32]3[CH2:33][CH2:34][N:35]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:8][C:9]=4[O:16][CH3:17])=[O:13])[CH2:36][CH2:37]3)=[N:25][CH:26]=[C:27]([CH:29]3[CH2:31][CH2:30]3)[CH:28]=2)[CH2:21][CH2:22]1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Agent: Cl
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 69.9 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (271 mg) described in Preparation Example 19 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (316 mg) described in Preparation Example 87 and by the reaction and treatment in the same manner as in Example 86, the title compound (347 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1cc(C(=O)OC)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OC)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A solution of methyl 4-hydroxy-3-propylbenzoate (7.00 g, 36.0 mmol), benzyl bromide (11.48 g, 0.15 mol) and potassium carbonate (20.73 g, 0.15 mol) in N,N-dimethylformamide (20 mL) was heated with stirring at 80° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 10.25 g of the title compound (yield: 100%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[CH:15]3[CH:17]([OH:20])[CH:18]([OH:19])[CH:8]([C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:7]=2[C:6]([O:21][CH3:22])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=O.[K+]>C(O)C>[CH3:22][O:21][C:6]1[C:7]2[C@H:8]([CH:18]=[O:19])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C@H:15]([CH:17]=[O:20])[C:16]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(OC)c2c1C1c3ccccc3C2C(O)C1O
Agent: [K+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCO
Product: COc1ccc(OC)c2c1[C@H](C=O)c1ccccc1[C@@H]2C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
One gram of 1,4-dimethoxy-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, is suspended in 30 ml. of an aqueous solution containing 0.77 g. of potassium periodate and one ml. of ethanol. After stirring at room temperature for 24 hours the insoluble material is removed by filtration, washed well with water and dried leaving a yellow product, m.p. 129°-132° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]3[C:23](=O)[C:24](=[O:30])[C:25]=3[O:26]C(C)C)[CH:9]=2)[O:4][C:3]1([CH3:33])[CH3:32].CC#[N:36]>>[NH2:36][C:23]1[C:24](=[O:30])[C:25](=[O:26])[C:22]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[O:4][C:3]([CH3:32])([CH3:33])[C@@H:2]([OH:1])[C@@H:11]2[N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21]
Reactant: CC#N
Reactant: CC(C)Oc1c(-c2ccc3c(c2)[C@@H](N2Cc4ccccc4C2=O)[C@H](O)C(C)(C)O3)c(=O)c1=O
Product: CC1(C)Oc2ccc(-c3c(N)c(=O)c3=O)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Reaction time: 16 h

Procedure:
To a solution of 154 mg (0.344 mmol) of 3-[trans-3-hydroxy-2,2-dimethyl-4-(1-oxo-1,3-dihydroisoindol-2-yl)-chroman-6-yl]-4-isopropoxy-cyclobut-3-ene-1,2-dione as prepared in Example 3 in CH3CN was bubbled ammonia gas for 30 min. The reaction mixture was then sealed and stirred for 16 h. The reaction mixture was concentrated. Flash chromatography (CH2Cl2 : MeOH: NH4OH (94.75/3.5/1.75)) followed by crystallization from THF and petroleum ether gave 136 mg of the title compound as a white solid, mp>250° C.: 1H-NMR (DMSO-d6 ; 400 MHz) δ8.90 (br s, 1 H), 8.76 (br s, 1 H), 7.7-7.8 (m, 3 H), 7.51-7.63 (m, 3 H), 6.98 (d, 1 H), 1.48 (s, 3 H), and 1.27 ppm (s, 3 H); IR (KBr) 1780, 1730, 1670, and 1640 cm-1 ; mass spectrum (+CI), m/e 405. Anal. Calcd. for C23H20N2OS: C, 68.31; H, 4.98; N, 6.93 Found.: C, 67.91; H, 5.12; N, 6.78.
Reaction SMILES: [Li]CCCC.C[N:7]([CH3:12])[CH2:8][CH2:9]NC.N1C=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])C=1.IC.[Na+].[Cl-]>C1COCC1>[CH3:17][C:16]1[CH:9]=[CH:8][N:7]=[CH:12][C:15]=1[CH:19]=[O:20]
Reactant: CNCCN(C)C
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccncc1C=O
Reaction time: 0.25 h

Procedure:
n-BuLi (1.6M in hexanes) (2.2 mmol, 1.37 ml) was added dropwise to a stirred solution of N,N,N'-trimethylethylenediamine (2.4 mmol, 0.245 g) in THF at -78° C. A solution of 3-pyridinecarboxaldehyde (2 mmol, 0.214 g) in THF was added and the mixture stirred for 15 min before adding a further portion of n-BuLi (1.6M in hexanes) (4 mmol, 2.5 ml). After stirring for 2 h at -70° C., iodomethane was added, the mixture stirred at RT for 30 min, then poured into aqueous NaCl solution, extracted twice with Et2O, dried (MgSO4), filtered and concentrated in vacuo. The residue was subjected to chromatography (SiO2 ; Et2O) to afford the title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1.[C:16]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([CH2:33][CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([CH2:33][CH2:34][N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][C:11]3=[O:15])=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: O=c1cc(OCc2ccccn2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ccc(OCc4ccccn4)cc3=O)cc2C1

Procedure:
7-{2-[2-Oxo-4-(pyridin-2-ylmethoxy)-2H-pyridin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared following example 24.1 from 530 mg (2.23 mmol) 4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 22.4) and 1.06 g (2.45 mmol) 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7).
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].C([O:16][C:17](=[O:54])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([C:36]3[CH:40]=[C:39]([C:41]([NH:43]C(OC(C)(C)C)=O)=[NH:42])[S:38][C:37]=3[S:51][CH3:52])(=[O:35])=[O:34])[CH:28]=2)=[C:22]([CH3:53])[CH:21]=1)(C)(C)C>>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[C:41]([C:39]1[S:38][C:37]([S:51][CH3:52])=[C:36]([S:33]([C:29]2[CH:28]=[C:27]([C:23]3[C:24]([CH3:26])=[CH:25][C:20]([O:19][CH2:18][C:17]([OH:54])=[O:16])=[CH:21][C:22]=3[CH3:53])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH:40]=1)(=[NH:42])[NH2:43]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(OCC(=O)OC(C)(C)C)cc2C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cc(OCC(=O)O)cc2C)c1
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of dichloromethane/trifluoroacetic acid (1/1) [2 mL] was added to {3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2,6-dimethyl-biphenyl-4-yloxy}-acetic acid tert-butyl ester (0.020 g, 0.030 mmol) [example 215, step a] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound (0.011 g, 75%) as a solid. 1H-NMR (MeOD): δ 8.36 (s, 1H), 8.01 (md, 1H, J=7.6 Hz), 7.81 (m, 1H), 7.72 (m, 1H), 7.51 (d, 1H, J=7.6 Hz), 7.26 (d, 1H, J=8.0 Hz), 6.74 (s, 2H), 4.67 (s, 2H), 2.73 (s, 3H), 1.96 (s, 6H). ESI-MS (m/z): Calcd. for C22H22N2O5S3: 490.07; found: 491.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH2:10])[C:4]=1[NH:11][C:12](=[O:28])[CH2:13][CH:14]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.[H][H]>O1CCCC1.[Pd]>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH:11][C:12](=[O:28])[CH2:13][CH:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:10]
Reactant: C=Cc1cccc(OC)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cccc(OC)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Yield: 42.8 %

Procedure:
A solution of 258 mg (0.62 mmol) of N-(2-methoxy-6-vinylphenyl)-2-(9H-xanthen-9-yl)acetamide in 54 ml of tetrahydrofuran was vigorously stirred at room temperature for 10 hours in the presence of 20 mg of 10% palladium on charcoal in a stream of hydrogen. The reaction mixture was filtered with the aid of Celite and the catalyst was washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated. The residue was recrystallized from a mixture of dichloromethane and hexane to give 99 mg (57%) of the title compound as crystals.