Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][CH:8]=[CH:9][N:10]=1.C([N-]C(C)C)(C)C.[Li+].[I:19]N1C(=O)CCC1=O.[Cl-].[NH4+]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:10][C:9]([I:19])=[CH:8][N:7]=1
Reactant: c1csc(-c2ncc[nH]2)c1
Reactant: O=C1CCC(=O)N1I
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Ic1cnc(-c2cccs2)[nH]1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-[2-(trimethylsilyl)ethoxy]methyl]-2-thiophenyl-imidazole (1.06 g, 3.46 mM) was dissolved in 40 ml of dry THF and the solution cooled to -78° C. under N2. Lithium diisopropylamide (3.46 ml, 5.19 mM, 1.5M solution in cyclohexane from Aldrich) was added via syringe, and the reaction solution stirred for 1 hour at -78° C. N-iodosuccinimide (0.85 g, 3.77 mM) in 10 ml of dry THF was added via syringe, and the reaction stirred for 30 minutes. The reaction mixture was added to 200 ml of saturated ammonium chloride, and extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed with saturated sodium bisulfite solution (150 ml), separated, dried over Na2SO4, filtered, and evaporated in vacuo to give a crude red brown oil. Purification by silica gel column chromatography using ethyl acetate/hexanes 1:9 gave 1.089 grams of 1-[2-(trimethylsilyl)ethoxy]methyl]-2-thiophenyl-5-iodo-imidazole (orange viscous oil).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([CH2:12][C:13]([OH:15])=O)[NH:11][CH:10]=[CH:9][S:8]2)=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].C(Cl)CCl.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[NH:16][C:13](=[O:15])[CH2:12][C:7]1([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[NH:11][CH:10]=[CH:9][S:8]1)=[O:20]
Reactant: Nc1ccccc1C=O
Reactant: O=C(O)CC1(c2ccncc2)NC=CS1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: O=Cc1ccccc1NC(=O)CC1(c2ccncc2)NC=CS1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
In an oven-dried, 50-mL, round-bottomed flask were placed 2-(4-pyridyl)-thiazole acetic acid (Step b, 140 mg, 0.64 mmol), 2-aminobenzaldehyde (Aldrich, 270 mg, 2.22 mmol), EDC (Aldrich, 244 mg, 1.27 mmol), and DIEA (Aldrich, 148 mg, 0.20 mL, 1.15 mmol) in CH2Cl2 (20 mL). The mixture was cooled to 0° C., and 1-hydroxy-7-azabenzotriazole (Aldrich, 173 mg, 1.27 mmol) was added in one portion. The reaction was warmed to RT slowly, stirred for 12 h, and concentrated in vacuo. The resulting crude product was purified by flash chromatography (EtOAc/hexanes, 50:50) to afford N-(2-formylphenyl)-2-(4-pyridyl)-thiazole acetamide as a white solid. Mp: 136-137° C. MS m/z: 324 (M+1). Calc'd for C17H13N3O2S: 323.07.
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19]([O:21]CC)=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:4][N:3]=[CH:2]1.C1COCC1.[OH-].[Na+].Cl>O.CCO>[O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19]([OH:21])=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Temperature: 50 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a mixture of ethyl 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (2.47 g), THF (75 mL) and EtOH (25 mL) was added 8N aqueous sodium hydroxide solution (1.42 mL), and the mixture was stirred at 50° C. for 4 hr. To the reaction mixture was added 1N hydrochloric acid at 0° C., and the mixture was diluted with water. The insoluble substance was collected by filtration, and washed with cooled IPE to give the title compound (2.21 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:42])[CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NC1CCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclobutylamine according to conditions described in general procedure C. Mp: 110-112° C.; 1H NMR (400 MHz, CDCl3) δ 1.63 (s, 2 H), 1.73-1.80 (m, 2 H), 2.42 (s, 2 H), 3.19-3.29 (m, 4H), 3.79-3.92 (m, 4 H), 4.30 (s, 1 H), 5.27 (s, 1 H), 6.08 (s, 1H), 6.75-6.78 (m, 1 H), 7.05 (d, J =7.6 Hz, 1 H), 7.24-7.26 m, 1 H), 7.32 (s, 1 H), 7.47-7.57 (m, 2 H), 7.88-8.02 (m, 3 H), 8.16 (m, 1 H), 8.25 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:28]3[CH2:31][CH2:30][CH2:29]3)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CNC1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCC1)CO2

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), azetidine (0.1 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 301 (M+, 1), 244 (3), 71 (5), 70 (bp), 69 (4).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]([CH2:11][O:12][C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])([CH2:6][O:7][C:8]([NH2:10])=[O:9])[CH3:5].[CH:19]1[CH:20]=[CH:21][C:22]([NH:29][C:30]2[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=2[Cl:36])=[C:23]([CH2:25][C:26]([O-:28])=[O:27])[CH:24]=1.[Na+]>>[CH3:1][CH2:2][CH2:3][C:4]([CH2:11][O:12][C:13]([NH:15][CH:16]([CH3:17])[CH3:18])=[O:14])([CH2:6][O:7][C:8]([NH2:10])=[O:9])[CH3:5].[CH:19]1[CH:20]=[CH:21][C:22]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:37])=[C:23]([CH2:25][C:26]([OH:28])=[O:27])[CH:24]=1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: CCCC(C)(COC(N)=O)COC(=O)NC(C)C
Agent: [Na+]
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reaction time: 0.08 h

Procedure:
A second composition to cover the perforated coated cores is prepared as follows: carisoprodol, diclofenac sodium, a diluent and a hinder are placed in a high shear mixer and mix for 5 minutes. The granulation process is initiated by the gradual addition of a granulating solution containing a plasticizer and purified water to the high shear with continuous blending to produce a wet blend. Next, the wet blend is granulated and dried at 40-500 for 20 minutes in a fluid bed to remove the water. Then, the dry granules are screened through a 20 USP mesh screen for size reduction. Next, the screened granules are mixed with a glidant and a lubricant, that have been previously passed through a 60 mesh screen, in a V-Blender during 5 minutes. The granulate is applied over the perforated cores through compression to obtain carisoprodol-diclofenac coated osmotic devices. The coated device has an outer diameter of about 14 mm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17](C=O)[C@@H:7]2[C@H:8](OC(OCC)C)[O:9][CH:10]=1)=[O:4].C(Br)CCCC.[Mg].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]2[CH2:19][CH:18]=[CH:17][CH:7]2[CH2:8][O:9][CH:10]=1)=[O:4]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(C=O)[C@H]12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCBr
Product: COC(=O)C1=COCC2C=CCC12
Temperature: -78 °C
Yield: 154.9 %

Procedure:
1.55 g of (1S,4aS,7aR)-1-[1-(ethoxy) ethoxy]-7-formyl-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester were dissolved in anhydrous tetrahydrofuran, followed by dropping 20 ml of magnesium pentylbromide (0.3 M tetrahydrofuran solution) while stirring and cooling at −78° C., and then stirring for 4 hours at the same temperature. After addition of saturated aqueous ammonium chloride solution to the reaction mixture, it was extracted with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ether eluate in the form of (1S,4aS,7aR)-1-[1-(ethoxy) ethoxy]-7-(2-hydroxy)-n-hexyl]-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (1.46 g, yield: 76%). The physicochemical properties of this compound are described below.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH3:3].[CH3:11][C:12](C)(O)C#C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:11]#[CH:12])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C#Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.3 %

Procedure:
A solution of 10 grams (0.050 mole) of 4-(1-methylethyl)bromobenzene and 8.4 grams (0.10 mole) of 1,1-dimethyl-2-propyn-1-ol in 75 mL of triethylamine was stirred, and 0.7 gram (0.001 mole) of bis(triphenylphosphine)palladium(II) chloride and 0.2 gram (0.001 mole) of copper (I) iodide were added. Upon completion of addition the reaction mixture was heated under reflux for four hours. The reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether and was washed first with an aqueous 10% ammonium chloride solution, then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was dissolved in 100 mL of toluene, 4.0 grams of sodium hydroxide was added to the solution, and the mixture was heated under reflux for four hours. The mixture was allowed to cool to ambient temperature where it stood for 18 hours. After this time the mixture was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with 1-20% chloroform in hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 2.4 grams of 4-(1-methylethyl)phenylethyne as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([S:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:14](=[O:21])[C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17]Cl>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:22][C:13]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:14]2[C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][O:21]2)=[CH:24][CH:25]=1
Reactant: CC(C)(CCCl)C(=O)C(Br)Sc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)CCOC1=C(Sc1ccc(Cl)cc1)n1ccnc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 40.7 %

Procedure:
64.9 g (0.94 mole) of imidazole and 129.7 g (0.94 mole) of potassium carbonate are dissolved in 1,300 ml of toluene. 173.9 g (0.47 mole) of 1-bromo-1-(4-chlorophenylthio)-5-chloro-3,3-dimethyl-2-pentanone in 360 ml of toluene are added dropwise to this mixture at 80° C. The reaction mixture is subsequently stirred at 90° C. for 15 hours and is cooled, and the inorganic residue is filtered off with suction. The filtrate is washed with water, dried over sodium sulphate and concentrated. The residue is recrystallized from diethyl ether. 61.4 g (40.8% of theory) of 4-chlorophenylthio-(imidazol-1-yl)-(3,3-dimethyl-tetrahydrofuran-2-ylidene)-methane of melting point 134° C. are obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2].[CH3:10][O:11]CCN.C(N)C>>[CH3:10][O:11][CH:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2]
Reactant: CCNC(=NC#N)SC
Reactant: COCCN
Agent: CCN
Product: COC(C)NC(=NC#N)SC

Procedure:
1-Methoxyethyl-2-methyl-3-cyanoisothiourea was prepared following the same procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250) except methoxyethylamine was used in lieu of ethylamine. 1H NMR (CDCl3) δ 2.53 (br s, 3H), 3.37 (s, 3H), 3.52 (m, 4H), 6.29 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:25])[C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:25])[C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(CCNS(=O)(=O)c2ccc(F)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCNS(=O)(=O)c2ccc(F)cc2)ccc1CC(=O)O

Procedure:
0.5 g (1.3 mmol) of ethyl [2-(2-(4-fluorobenzenesulphonylamino)-ethyl)-1-methylpyrrol-5-yl]acetate are stirred into 4.5 ml of 1N sodium hydroxide solution overnight at ambient temperature. The mixture is then extracted with ethylene chloride and the aqueous phase is acidified with 1N hydrochloric acid. The precipitate obtained is suction filtered and dried.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:32]2[C:28]([S:29][CH:30]=[CH:31]2)=[N:27][C:26]=1[C:33](O)=[O:34]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[N:27]=[C:28]3[N:32]([C:25]=2[CH3:24])[CH:31]=[CH:30][S:29]3)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1c(C(=O)O)nc2sccn12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nc3sccn3c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Methyl-imidazo[2,1-b]thiazole-6-carboxylic acid. LC-MS (basic): tR=0.84 min; [M+H]+=491.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1>>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:13][C:12]=13)=[O:20])[CH2:25]2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Product: COc1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cccc3o2)cc1
Yield: 60 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamide was prepared from 2-(4-methoxyphenyl)benzoxazole-4-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 60% yield as a white solid: mp 103-105° C.; 1H NMR (500 MHz, CDCl3) δ 9.07 (m, 1H), 8.19 (m, 3H), 7.66 (dd, J=8.0, 1.1 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.07 (m, 2H), 4.60 (m, 1H), 3.92 (s, 3H), 3.11 (m, 2H), 2.66 (m, 2H), 2.54 (s, 3H), 2.13 (m, 1H), 2.03 (m, 2H), 1.53 (m, 3H), 1.17 (m, 2H); MS (ESI) m/z 406 [M+H]+
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]/[CH2:4][OH:5].[H-].[Na+].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.[Na+].[Cl-]>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:5][CH2:4]/[CH:3]=[CH:2]/[CH2:1][OH:6])=[CH:13][CH:12]=1
Reactant: OC/C=C/CO
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC/C=C/CO)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 20.5 %

Procedure:
A solution of 11.8 g (133.4 mmol) of trans 2-butene-1,4-diol in 100 ml of DMF was treated with 6.4 g (147 mmol) of sodium hydride dispersion on oil (55%), stirred at 0° C. for 45 min., and treated dropwise with 25.1 g (160 mmol) of 4-methoxybenzylchloride. The mixture was stirred during 5 hrs at RT and then poured into a saturated aqueous solution of NaCl. Extraction with AcOEt, drying of the combined organic phases over Na2SO4, filtration, evaporation of the solvent and chromatography on silica gel with heptane/AcOEt 9:1 gave 5.7 g (21%) of trans 4-(4-methoxy-benzyloxy)-but-2-en-1-ol. Light yellow oil. MS: 207 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=4)=[N:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[C:48][C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1>CC(C)=O>[F:55][C:52]1[CH:53]=[CH:54][C:49]([C:48]#[C:47][CH2:46][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]4[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=5)=[N:11][C:10]=4[N:9]=3)=[CH:6][CH:7]=2)=[CH:50][CH:51]=1
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCC#Cc4ccc(F)cc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Yield: 42.9 %

Procedure:
A mixture of 8-(4-Hydroxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.115 g, 0.21 mmol), potassium carbonate (0.067 g, 0.48 mmol), 1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (0.67 g, 0.27 mmol) and acetone (10 ml) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature and filtered through sintered funnel, washed with acetone. Solvent was evaporated and the residue was purified by preparative TLC to obtain pure 8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.061 g, 43%) as pale yellow oil.
Reaction SMILES: CI.[Mg].Br[C:5]1[C:13]2[O:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:20](=[O:22])=[O:21].Cl>O1CCCC1>[C:14]1([C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:20]([OH:22])=[O:21])[C:13]=3[O:12][CH:11]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=O
Reactant: Brc1cccc2c(-c3ccccc3)coc12
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: O=C(O)c1cccc2c(-c3ccccc3)coc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3)-(i) 2.4 ml of methyl iodide are added dropwise to a solution of 3.9 g of magnesium in 16 ml of tetrahydrofuran and the mixture is stirred at room temperature for 20 minutes. A solution of 11.0 g of 7-bromo-3-phenylbenzofuran in tetrahydrofuran is added dropwise to the mixture and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is poured to dry ice, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate to give 6.31 g of 3-phenylbenzofuran-7-carboxylic acid as pale yellow prisms.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10](S(C(F)(F)F)(=O)=O)[CH:9]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH:9]=1
Reactant: COC(=O)c1ccc(OC)cc1S(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(OC)cc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 131 %

Procedure:
Saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to a solution of methyl 4-methoxy-2-trifluoromethanesulphonylbenzoate (6.3 g.) and 4-fluorobenzeneboronic acid (3.36 g.) in DME (150 ml) at ambient temperature under an argon atmosphere. Tetrakis(triphenylphosphine) palladium (928 mg.) was added and the reaction heated and stirred at reflux for 3.5 hours resulting in a homogeneous solution. After cooling to ambient temperature, the reaction was partitioned between ethyl acetate and water. The organic phase was washed with 2N hydrochloric acid, water and brine, filtered through 1PS filter paper and the solvent removed to give methyl 4-methoxy-2-(4-fluorophenyl)benzoate as a yellow-oily solid (7.2 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.C([O:12][CH2:13][C:14](=O)[CH2:15]Cl)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[C:14]([CH2:13][OH:12])[N:1]=2)[N:4]=1
Reactant: CC(=O)OCC(=O)CCl
Reactant: Nc1ccc(I)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OCc1cn2nc(I)ccc2n1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a solution of 3-amino-6-iodopyridazine (2.0 g, 9.0 mmol) in ethanol (40 mL) was added 3-chloro-2-oxopropyl acetate (2.73 g, 18.1 mmol), and the mixture was heated under reflux for 24 hr. After cooling the mixture to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate/hexane to give the title compound (498 mg, 20%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:2].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[CH:26][O:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[CH:26][O:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23])[CH3:2]
Reactant: CCON=Cc1ccccc1O
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCON=Cc1ccccc1OCc1ccccc1C(=COC)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6.9 g (42 mmol) of 2-hydroxybenzaldehyde O-ethyloxime and 10.0 g (35 mmol) of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate are dissolved in 100 ml of dimethylformamide, and 7.3 g (53 mmol) of potassium carbonate are added. The mixture is stirred at room temperature for 48 hours and then concentrated, and the residue is taken up in methylene chloride. The organic phase is washed with water, dried over MgSO4 and concentrated. The resulting oil is purified by chromatography on silica gel (cyclohexane/ethyl acetate). 8.4 g (65% of theory) of the title compound are obtained in the form of colorless crystals (melting point 86°-88° C., compound no. 23).