Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][O:11][S:27]([CH3:26])(=[O:29])=[O:28])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CCO)C1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.4 %

Procedure:
To a solution of [3-hydroxy-1-(tetrahydro-pyran-4-yl)-propyl]-carbamic acid tert-butyl ester (0.200 g, 0.770 mmol) and NEt3 (192 μL, 0.920 mmol) in CH2Cl2 (8 mL) was added MsCl (72 μL, 0.92 mmol) at 0° C. and the mixture was stirred at room temperature for 10 h. The solvent was evaporated to dryness and EtOAC was added. The ethyl acetate layer was washed with aq. NaHCO3, dried (Na2SO4), filtered, and solvent was evaporated under reduced pressure to afford methanesulfonic acid 3-tert-butoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propyl ester (0.162 g). LC-MS [M+Na] 360.2. The product was sufficiently pure for the next step and used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COCc1ccccc1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
60% Sodium hydride in mineral oil (2.3 g, 56.8 mmol) is added to a solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (5.0 g, 37.8 mmol) in THF (80 mL) at 0° C., followed by the addition of benzylbromide (7.3 g, 42.6 mmol). The reaction mixture is slowly brought to room temperature, stirred for 8 h and then quenched with ice water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over Na2SO4 filtered and concentrated. The crude product is purified by column chromatography to afford 5.0 g of 3-benzyloxy-2,2-dimethyl-propionic acid methyl ester as a brown liquid; m/z 223 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[Br-:13].[Br-].O1CCOCC1>O1CCOCC1>[Br:13][CH:10]([CH3:11])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)=[O:12]
Reactant: [Br-]
Reactant: CCC(=O)c1ccc(F)c(F)c1
Solvent: C1COCCO1
Product: CC(Br)C(=O)c1ccc(F)c(F)c1
Yield: 98.9 %

Procedure:
To 3',4'-difluoropropiophenone (Alfa Products, Danvers, Mass. 01923) (90.5 g, 0.53 mole) was added a solution of dioxane dibromide (131.4 g, 0.53 mole) in dioxane (500 ml). The reaction was worked up as in Example 1 to yield crude 2-bromo-3',4'-difluoropropiophenone (130.5 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[C:13]([S-:14])=[CH:12][N:11]=[N:10]1.[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([S:14][C:13]1[N:9]=[N:10][NH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [S-]c1cnn[nH]1
Reactant: BrCc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1ccc(CSc2c[nH]nn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
Benzyl bromide (11.79 ml, 99 mmol) was added dropwise to a solution of sodium 1H-1,2,3-triazole-5-thiolate (12.2 g, 99 mmol) in ethanol (100 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL), brine (100 mL) and dried (sodium sulphate). The solvent was removed to give 4-(benzylthio)-1H-1,2,3-triazole (16.9 g) as a white solid. LCMS (Method F, ES-API): RT 1.66 min, m+H=191.9; 1H NMR (400 MHz, CDCl3): δ 9.72 (1H, v br s), 7.47 (1H, s), 7.30-7.21 (5H, m), 4.12 (2H, s).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC1C(O)=C(Cl)C(Cl)=C(Cl)C=1Cl.C([N+]#[C-])(C)C.Cl.[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH3:42]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH:46][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:42]
Reactant: CCOC(=O)CN
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [C-]#[N+]C(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 82 %

Procedure:
A solution of 6.0 (20 mM) N-carbobenzoxy-L-phenylalanine, 5.3 g (20 mM) pentachlorophenol, and 2.0 g (30 mM) is isopropyl isonitrile in 40 ml chloroform was mixed with a solution of 2.8 g (20 mM) glycine ethyl ester hydrochloride and 2.02 g (20 mM) triethylamine in 30 ml chloroform. The mixture was heated at 50°C for 24 hours and evaporated. The residue was taken up in 150 ml ethyl acetate. The solution was washed sequentially with 100 ml water, 120 ml 1-N hydrochloric acid, four times 120 ml 5% sodium bicarbonate solution, and again with 100 ml water, then dried with desiccated sodium sulfate and evaporated. When the residue was crystallized from ethyl acetate and petroleum ether, 6.3 g N-carbobenzoxy-L-phenylalanyl-glycine ethyl ester was obtained (82 percent yield). Recrystallizing from ethyl acetate and petroleum ether reduced the yield to 5.4 g (70%). M.P. 107°-108.5°C. [ α]D25 = - 17.1° (C = 2, in ethanol).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:30][CH:31]3[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[CH2:32][CH:31]([NH:30][C:9]2[N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[O:29])=[CH:17][CH:18]=3)[N:10]=2)[CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)nc(N3CCOCC3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2nc(NC3CNC3)nc(N3CCOCC3)n2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(4-fluoro-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 30 mg (0.053 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 20 (83%); (M+H) 465.5.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([S:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[Br:17]Br>C(Cl)Cl>[Br:17][C:5]1[C:4](=[O:16])[N:3]([CH2:1][CH3:2])[C:8]2[N:9]=[C:10]([S:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=1
Reactant: CCn1c(=O)ccc2c(C)nc(SC)nc21
Reactant: BrBr
Solvent: ClCCl
Product: CCn1c(=O)c(Br)cc2c(C)nc(SC)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.31 g, 26.84 mmol) in DCM was added Br2 (4.79 g, 29.52 mmol) dropwise at room temperature. Then the reaction mixture was stirred at room temperature overnight. After filtration the solid was suspended in DCM (100 mL), and triethylamine (20 mL) was added. The mixture was washed with water and dried with Na2SO4, and the product 6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.96 g, 83% yield) was obtained after evaporation of DCM. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 4.56 (q, J=7.2 Hz, 2H), 2.68 (s, 3H), 2.62 (s, 3H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][C:25]3([F:38])[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:20]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[F:38][C:25]1([CH2:24][NH:23][C:21]2[C:20]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:19][N:18]=[C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=3)[CH:22]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2(F)CCNCC2)cc1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
5-Aminopyrazine-2-carbonitrile (5.45 mg, 0.045 mmol), Xantphos (1.749 mg, 3.02 μmol), tris(dibenzylideneacetone)dipalladium(0) (1.384 mg, 1.511 μmol), and cesium carbonate (24.62 mg, 0.076 mmol) were added to tert-butyl 4-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (17 mg, 0.038 mmol) in a 0.2 mL microwave reaction vial. The vial was sealed and an inert atmosphere was introduced before dry dioxane (291 μL) was added. Nitrogen was bubbled through the mixture for 5 min. The mixture was heated at 150° C. for 1 hr by microwave irradiation. After cooling the mixture was diluted with 20% dichloromethane in MeOH and loaded onto a preparative thin layer chromatography plate. Elution with 50% EtOAc in hexane gave tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (1.5 mg, 2.81 μmol, 7% yield) as a light yellow powder. LCMS (4) Rt=2.35 min; m/z (ESI+) 534 (MH+). Trifluoroacetic acid (0.1 mL, 1.298 mmol) was added to tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (1.5 mg, 2.81 μmol) dissolved in dichloromethane (0.5 mL) and the solution was stirred for 1 hr. The volatiles were removed in vacuo and the crude product was purified by ion exchange on Isolute SCX II acidic resin (1 g), followed by preparative thin layer chromatography, eluting with 10% MeOH/1% NH3/89% dichloromethane, to give 5-(4-((4-fluoropiperidin-4-yl)methylamino)-5-(4-methoxyphenyl)pyridin-2-ylamino)pyrazine-2-carbonitrile (1 mg, 2.307 μmol, 82% yield) as a yellow powder.
Reaction SMILES: ClCCl.[CH2:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([CH:14]=[CH:15][CH2:16][OH:17])=[CH:12][CH:11]=1)[CH3:5].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>C([O-])(=O)C.[Na+].CCCCCC>[C:23]([O:17][CH2:16][CH:15]=[CH:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:4][CH3:5])=[CH:19][CH:18]=1)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=C1CC(=O)O1
Reactant: CCOCCOc1ccc(C=CCO)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOCCOc1ccc(C=CCOC(=O)CC(C)=O)cc1
Yield: 90.7 %

Procedure:
36 Milliliters of dichloromethane was added to 12 g of 4-[(1-ethoxy)ethoxy]cinnamyl alcohol, then 60 mg of anhydrous sodium acetate was added thereto. Under refluxing condition, 5 g of diketene was added dropwise to the reaction mixture, and 2 hours later, 0.42 g diketene was further added thereto, the whole reaction mixture was refluxed for 1.5 hours. After the reaction was completed, the dichloromethane was removed by evaporation under reduced pressure, and the residue thus obtained was stirred for 30 minutes with 27 ml of hexane and 1.2 g of activated carbon. The activated carbon was removed by filtration, and the filtrate was concentrated to obtain 15 g of 4-[(1-ethoxy)ethoxy]cinnamyl acetoacetate as in the form of an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=2)[C:7]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: O=C1CCc2cc(F)c(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2cc(F)c(F)cc2C1=O
Yield: 38 %

Procedure:
A solution of 10.6 g of 5,6-difluoro-1-indanone, 13.1 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 2:1). In addition to 3.6 g of educt there were obtained 5.32 g (38%) of (RS)-2-(2-buten-1-yl)-5,6-difluoro-1-indanone as a brown oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>CN(C=O)C>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:5]2[C:6]([CH:8]=[O:9])=[CH:7][N:3]=[CH:4]2)=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]cn1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cncc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH 60% (37.65 g, 0.94 mol) in DMF (175 ml) was carefully added a solution of 1-H-imidazole-4-carboxaldehyde (75.36 g, 0.784 mol) in DMF (350 ml). The mixture was stirred at room temperature for 0.5 h, then a solution of 4-bromomethylbenzoic acid methyl ester (215.6 g, 0.94 mol) in DMF (475 ml) was added and the reaction was stirred overnight. The solvent was evaporated under vacuum, the residue taken in ethyl acetate and water. The organic phase was separated, washed with brine and dried over MgSO4. The crude oil was purified several times by flash chromatography on silica gel using (toluene/ethyl acetate/NH4OH: 60/40/1) as eluent to give quantitatively the desired products.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11]Br.C([O-])([O-])=O.[K+].[K+].O>C(O)(=O)C>[Br:11][C:2](=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:1]=[O:10]
Reactant: O=CC=Cc1ccccc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=CC(Br)=Cc1ccccc1

Procedure:
1.33 g (10 mmol) cinnamaldehyde was dissolved in 5 mL glacial acetic acid and cooled on an ice-water bath. 1.62 g bromine was added, and anhydrous K2CO3 was then added, and it was stirred until no gas was evolving. After refluxing for 30 min, the reaction mixture was poured into 100 mL cold water with stirring, extracted with 50 mL ethyl ether three times. The combined ethyl ether layers were washed with water one time, saturated aqueous NaCl solution one time, dried over MgSO4 for 2 hours, filtrated, and the filtrate was dried under vacuum, and washed with anhydrous ethyl ether: petroleum ether (1:1) to give the title compound as light yellow powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:32]1[CH:31]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:37])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-n4cccc4)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)ccn1
Yield: 62.3 %

Procedure:
Prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example M99) (0.46 g, 0.90 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (220 mg, 62%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](Cl)(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)=C(Cl)Cl>[C:12]([C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)=C(Cl)Cl
Product: COC(=O)c1cc(C(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 75 g. (0.5 m.) of methyl salicylate in 200 ml. of tetrachloroethylene is cooled in an ice bath and treated with a solution of 40 g. (0.5 m.) of acetyl chloride in 200 ml. of tetrachloroethylene. To the chilled mixture is added 133 g. (1.0 m.) of aluminum chloride over a fifteen minute period, maintaining the temperature below 25° C. After the adddition is completed the mixture is stirred for 4 hours at 25° C. and then poured into ice water. The organic layer is separated, washed with water and saturated aqueous sodium bicarbonate solution, dried and evaporated. The residual oil is crystallized from hexane to give methyl 5-acetylsalicylate, m.p. 60°-62° C.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl-].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[C:35]12[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2)[C:29](O)=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C.CCCCCC>[CH2:10]([O:9][C:7]1[CH:6]=[CH:5][C:3]([NH:4][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([C:35]34[CH2:36][CH:37]5[CH2:38][CH:39]([CH2:40][CH:41]([CH2:43]5)[CH2:42]3)[CH2:44]4)=[C:26]([O:25][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:27]=2)=[C:2]([NH2:1])[CH:8]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OCc2ccccc2)c1
Reactant: Nc1ccc(OCc2ccccc2)cc1N
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1cc(OCc2ccccc2)ccc1NC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OCc2ccccc2)c1

Procedure:
2.7 g (12.7 mM) of 2-amino-4-(benzyloxy)aniline and 5 g (12.7 mM) of the chloride of 3-benzyloxy-4-(1-adamantyl)benzoic acid are treated under the conditions described in Example 1(f) to lead, after the same treatment andchromatography on silica in the ethyl acetate/hexane (30/70) eluent, to 4.2g (59.3%) of the expected derivative, of melting point 178° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)#[CH:36]>O1CCCC1.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:6]=[CH:7][C:2]([C:36]#[C:35][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:3][CH:4]=2)/[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccccn3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (370 mg, 0.636 mmol; example 4) in a mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed and 2-ethynylpyridine (118 mg, 1.144 mmol) was added under argon atmosphere. The solution was cooled; tetrakis(triphenylphosphine)palladium (59.0 mg, 0.051 mmol) and copper(I) iodide (19.3 mg, 0.102 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h. The mixture was evaporated in vacuo and the residue was dissolved in dichloromethane (60 mL). The solution was washed with water (2×20 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-[4-(pyridin-2-ylethynyl)phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate.
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.[Cl:10][C:11]1[N:12]=[C:13]([CH:16]([C:22]2[NH:23][C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)=[C:25]3[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[N:27]([CH3:34])[C:26]=23)[CH:17]([CH2:20]O)[CH2:18]O)[S:14][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:9][S:6]([O:5][CH2:20][C:17]([CH:16]([C:13]1[S:14][CH:15]=[C:11]([Cl:10])[N:12]=1)[C:22]1[NH:23][C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[C:25]2[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[N:27]([CH3:34])[C:26]=12)=[CH2:18])(=[O:7])=[O:8]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(c3nc(Cl)cs3)C(CO)CO)c2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(COS(C)(=O)=O)C(c1nc(Cl)cs1)c1[nH]c(-c2cccc(F)c2)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic anhydride (1699 mg, 9.75 mmol) was added to a solution of 7-(1-(4-chlorothiazol-2-yl)-3-hydroxy-2-(hydroxymethyl)propyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (934 mg, 1.950 mmol) and triethylamine (1.631 mL, 11.70 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 16 hours. Further portions of triethylamine (1.631 mL, 11.70 mmol) and methanesulfonic anhydride (1699 mg, 9.75 mmol) were added as necessary to allow the reaction to run to completion. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N+:18]([O-])=O)[C:14](=[O:21])[NH:13][C:12]2=[O:22].O.O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:18][C:17]1[CH:16]=[C:15]2[C:11]([C:12](=[O:22])[NH:13][C:14]2=[O:21])=[CH:10][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)Cc1ccc(Oc2cc3c(cc2[N+](=O)[O-])C(=O)NC3=O)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2N)C(=O)NC3=O)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 30.1 (162 mg, 0.42 mmol) in 10 mL of EtOAc was added SnCl2.2H2O (469 mg, 2.1 mmol). The mixture was heated to reflux for 3 h. After cooling to room temperature, the mixture was poured into 20 mL of water. Saturated NaHCO3 was added to adjust the pH value of the mixture to 3. The mixture was filtered through Celite to remove solid precipitates. The filtrate was extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na2SO4, and evaporated in vacuo to give 30.2. MS ESI (pos.) m/e calcd for (M+H)+ 361.1. found 361.0.