Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9](Br)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.N#N.[NH4+].[Cl-].C(O[CH2:20][CH3:21])C>>[CH2:20]([C:4]1[CH:3]=[CH:2][S:6][C:5]=1[C:7]1[S:8][C:9]([C:9]2[S:8][C:7]([C:5]3[S:6][CH:2]=[CH:3][C:4]=3[CH2:9][CH2:10][CH2:11][CH2:7][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:10][CH:11]=1)[CH2:21][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Brc1ccc(-c2ccc(Br)s2)s1
Reactant: CCOCC
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCc1ccsc1-c1ccc(-c2ccc(-c3sccc3CCCCCC)s2)s1
Temperature: 20 °C

Procedure:
The Grignard reagent prepared above, added dropwise to a suspension of 5.0 g (15.4 mmoles) of 5,5′-dibromo-2,2′-bithiophene and 0.084 g (0.154 mmoles) of Ni(dppp)2Cl2 in 50 mL dry ethyl ether. Typically, the Grignard is added from a feeding funnel under an inert gas (e.g., N2). The resulting mixture was heated to reflux for about 20 hours. The resulting mixture is cooled to about room temperature (e.g., to about 20° C.) and combined with about 200 mL of 5% aqueous NH4Cl to which some ice is added, to effect hydrolysis. The aqueous phase is extracted with about 2×100 mL of CH2Cl2. The organic phases combined are back washed with about 200 mL water and dried over MgSO4. The solvent is evaporated to give a raw product, 3,3′″-dihexyl-[2,2′;5′,2″;5″,2′″]quaterthiophene, which can be purified using, for example, a silica-gel column using hexanes 100% as eluant to give 6.4 g of material, (yield=83.4%). Proton NMR can be used to determine the presence of the raw product: 1HNMR: 7.25 ppm, (2H, d), 7.20 ppm, (2H, d), 7.10 ppm, (2H, d), 7.00 ppm, (2H, d), 2.83 ppm, (4H, t), 2.7 ppm, (4H, m), 1.41 ppm, (12H, m), 1.00 ppm, (6H, m).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:9]=[N:8][NH:7][C:6]=1[NH2:10])([O-:4])=[O:3].[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[N+:2]([C:5]1[CH:9]=[N:8][N:7]2[C:11]([OH:16])=[CH:12][C:13]([CH3:15])=[N:10][C:6]=12)([O-:4])=[O:3]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(O)n2ncc([N+](=O)[O-])c2n1
Yield: 84.5 %

Procedure:
50 g of 4-nitro-2H-pyrazol-3-ylamine hydrochloride (prepared in accordance with H. Dorn and H. Dilcher, Liebigs Ann. Chem., 707, 141, 1967) and 60 g of ethyl acetoacetate in 160 cc of acetic acid were introduced into a 500 cc three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer and a condenser. The reaction medium was refluxed for 12 hours. The precipitate which formed was filtered off at about 90° C. It was washed with diisopropyl ether and dried under vacuum over phosphoric anhydride. This gave 50 g of 3-nitro-5-methylpyrazolo[1,5-a]pyrimidin-7-ol in the form of yellow crystals (yield=84.5%; melting point=290° C. with decomposition), whose elemental analysis, calculated for C7H6N4O3 (MW=194.15 g), was as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([NH2:30])=[S:29])=[CH:24][CH:23]=1>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]=[C:28]([CH2:27][O:26][C:25]3[CH:31]=[CH:32][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[S:29][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: COc1ccc(OCC(N)=S)cc1
Solvent: CC#N
Product: COc1ccc(OCc2nc(-c3ccc(F)cc3)c(-c3ccc(SC)cc3)s2)cc1
Yield: 54 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone, (Example 1, Step 3) (2.30 g, 6.8 mmol) and 4-methoxyphenoxy thioacetamide (1.35 g, 6.8 mmol) in 20 mL of acetonitrile was heated to reflux for 1.1 hours. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford a solid that was recrystallized from a mixture of ethyl acetate and isooctane to provide pure 4- (4-fluorophenyl) -5- (4-methylthiophenyl)-2-((4-methoxyphenoxy) methyl) thiazole (1.60 g; 54%): mp 89°-92° C., 1H NMR (CDCl3) 300 MHz 7.47 (dd, J=3.2, 8.7Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5Hz, 2H), 6.98 (m, 4H), 6.86 (d, J=9.1 Hz, 2H), 5.33 (s, 2H), 3.78 (s, 3H), 2.49 (s,3H). 19F NMR (CDCl3) -114.07 (m). Mass spectrum M+H+=438.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:20]=2[O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: Oc1cccc2c1OCCN2CCCNCc1ccc2ccccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1OCCN2CCCNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
(4-(3-(2-naphthylmethylamino)propyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine (166 mg) was dissolved in DMF (3 ml), and potassium carbonate (63 mg) and methyl bromoacetate (0.045 ml) were added. to the resultant solution at 0° C., followed by stirring at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel:ethyl acetate/n-hexane=2:3) to obtain the object compound (140 mg, yield 73%).
Reaction SMILES: CO[C:3]([O:6][CH3:7])([CH3:5])[CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:20]([O:24][C:25]([NH:27][C@@H:28]([CH2:31][CH2:32][OH:33])CO)=[O:26])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([O:24][C:25]([N:27]1[C@@H:28]([CH2:31][CH2:32][OH:33])[CH2:7][O:6][C:3]1([CH3:4])[CH3:5])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Yield: 47.8 %

Procedure:
2,2-Dimethoxypropane (87 ml, 0.707 mol) and p-toluenesulphonic acid monohydrate (1.33 g, 7 mmol) were added to a stirred solution of the diol 4 (14.39 g, 70 mmol) in dichloromethane (319 ml) at 25° C. The reaction was monitored by TLC (ethyl acetate-hexanes 2:1) until complete (36 h). The reaction mixture was then washed with aqueous NaHCO3 (5%, 2×50 ml), brine (50 ml), dried (MgSO4) and concentrated to form a colourless oil, which crystallised upon standing. The ratio of the desired five-membered ring product 5 to the undesired six-membered ring product 6 was 6.4:3.6. Recrystallisation from heptane gave 5 as colourless needles (8.2 g, 48%). Spectral data for this sample were consistent with those given in the literature3. 1 H NMR (200 MHz, CDCl3) 4.17 (m, 1H), 3.97 (m, 1H), 3.86-3.42 (m, 3H), 3.33 (br, 1H), 1.76 (m, 2H), 1.5 (s, 3H), 1.46 (s, 9H); 13C NMR (50 MHz, CDCl3) 153.9, 93.6, 80.9, 68.2, 58.6, 53.9, 37.7, 27.7, 26.3, 243.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:7]2.[C:21]([Li])(C)(C)C.CN(C)C=O>CCOCC>[CH3:21][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:7]2
Reactant: CC(C)(C)COS(=O)(=O)c1ccc2c(Br)cccc2c1
Reactant: [Li]C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccc2cc(S(=O)(=O)OCC(C)(C)C)ccc12
Reaction time: 1 h

Procedure:
To a cooled (-80° C.) solution of neopentyl 5-bromonaphthalene-2-sulfonate (300 mg; 0.84 mmol) in anhydrous ether (12 mL) is added tert-butyllithium (1.7M in ether) (1 mL; 1.7 mmol), immediately followed by a solution of dimethylformamide (125 mg; 1.7 mmol) in ether (2 mL). The external cooling bath is removed and stirring is allowed to proceed for 1 hour. The reaction mixture is quenched with water (10 mL), the two solution phases are separated and the aqueous phase is extracted with ether (2×10 mL). The combined organic phase is dried (MgSO4), filtered and concentrated under reduced pressure to afford crude neopentyl 5-methylnaphthalene-2-sulfonate.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:26]>O1CCOCC1.CO>[ClH:26].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-n2ccnc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-n2ccnc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.63 mL) was added to a solution mixture of the obtained methyl 2-(benzyloxy)-4-(1H-imidazol-1-yl)benzoate (0.13 g) in dioxane (0.65 mL) and methanol (0.65 mL), followed by stiffing at room temperature for 3 hours. Under ice-cooling, 6 mol/L hydrochloric acid (0.21 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid substance was collected by filtration. Dioxane (1 mL) and a 4 mol/L hydrogen chloride-dioxane solution (0.5 mL) were added to the obtained solid substance, followed by stirring at room temperature for 1 hour. The solid substance was collected from the reaction mixture by filtration to obtain 0.097 g of 2-(benzyloxy)-4-(1H-imidazol-1-yl)benzoic acid hydrochloride as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1.ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: N#CCCCOC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(OCCCc1nnn[nH]1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
Heat a solution of 3-cyanopropyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.24 g; 1.0 equiv; 0.64 mmoles), azidotrimethylsilane (0.85 mL; 10 equiv; 6.38 mmoles) and dibutyloxostannane (0.040 g; 0.25 equiv; 0.16 mmoles) in toluene (5 mL) to 100° C. for 24 hours, then cool to ambient temperature and concentrate. Purify the crude material by reverse phase chromatography to afford impure product. Dissolve the impure product in 50 mL dichloromethane and wash with saturated sodium bicarbonate, and further extract the aqueous layer 2× dichloromethane. Dry the combined organic extracts over sodium sulfate, filter, and concentrate to afford 3-(1H-tetrazol-5-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.110 g; 41%) as a yellow solid: MS (m/z): 421 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12]Br.C(#N)C>C(Cl)Cl>[Cl:10][CH2:11][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: ClCCBr
Solvent: ClCCl
Solvent: CC#N
Product: ClCCN1CCc2ccccc21

Procedure:
A microwave vial was charged with indoline (0.5 g, 4.19 mmol), 2-chloro-1-bromoethane (0.502 ml, 6.25 mmol), TEA (0.7 ml, 6.25 mmol) and acetonitrile (10 ml). The vial was irradiated with microwaves for 1 hour at 80° C. The mixture was diluted with DCM and washed with water (1×10 ml). The organic layer was dried and concentrated and the residue was purified by flash column chromatography (silica, Hexane/EtOAc 95:5 to 0:1). The product was isolated as a violet solid (400 mg; 52%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][CH:13]([CH3:15])[CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Br)nc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
2-Bromo-5-hydroxypyridine (2 mmol) is dissolved in DMF (10 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min 1-Bromo-2-methylpropane (1.1 eq.) is added and the reaction solution is stirred 3 days at 100° C. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-isobutoxy-pyridine is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as a yellow oil in a yield of 19%; HPLC (method C): 2.08 min; LC-MS (method A): 2.05 min, 241.95 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC1C([O:38][C:39](=O)[CH2:40][CH2:41][CH2:42][CH2:43][O:44][N+:45]([O-:47])=[O:46])=C(F)C(F)=C(F)C=1F>CN(C1C=CN=CC=1)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][O:12][C:39]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][N+:45]([O-:47])=[O:46])=[O:38])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CCCCO[N+](=O)[O-])Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CN(C)c1ccncc1
Product: CCCCc1nc(Cl)c(COC(=O)CCCCO[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the same procedure described in Example 1 but starting from 2-Butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (Losartan) (0.93 g, 2.19 mmol) and 5-(nitrooxy)pentanoic acid pentafluorophenyl ester (0.72 g, 2.19 mmol) TEA (0.30 ml, 2.19 mmol), DMAP (0.27 g, 2.19 mmol) after purification with Flash chromatography of the residue (CH2Cl2/MeOH 98:2) the title compound (0.72 g, 60%) was obtained as a white foam.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH2:18][C:19]#[N:20].O>C1C=CC=CC=1>[CH:4]([CH:18]([C:11]1[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH3:9])[C:19]#[N:20])=[O:5]
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C)c(C(C#N)C=O)c(C)c1

Procedure:
To a stirred mixture of sodium methoxide (2.78 g, 51 mmol) and ethyl formate (4.0 g, 54 mmol) in 100 mL of benzene was added 2,4,6 trimethylphenylacetonitrile (8.0 g, 50 mmol) over 5 min. After stirring for an additional hour it was treated with water (100 mL) and the layers were separated. The aqueous layer was separated and acidified with 10% HCl and extracted with ethyl acetate. After drying the solvent was removed in vacuo to afford a-formyl-2,4,6-trimethylphenylacetonitrile as colorless crystals melting at 120°-122° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:44])[C:30]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)([CH3:35])[CH2:31][S:32]2)=[CH:27][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:29]1([OH:44])[C:28]2[C:33](=[CH:34][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[S:32][CH2:31][C:30]1([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[CH3:35])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Reactant: C#CCCCCCCCO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To 9-(t-butyldimethylsilyloxy)-1-nonyne (2.23 g, 8.75 mmol) was added dry tetrahydrofuran (30 ml). Then n-butyl lithium (4.65 ml, 7.87 mol, 1.69 mol/l tetrahydrofuran solution) was added dropwise thereto at -78° C. and the resulting mixture was stirred for one hour at -20° C. At the same temperature, to the reaction solution was added 7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (550 mg, 1.75 mmol), as obtained in Example 26, dissolved in tetrahydrofuran (20 ml), and then the mixture was stirred for 24 hours at -10° C. When the reaction is completed, saturated ammonium chloride solution was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=9:1) to obtain 946 mg (yield: 95%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:4](Cl)[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2ncn(CC3CCOC3)c2n1
Solvent: CCO
Product: Clc1nc(N2CCOCC2)c2ncn(CC3CCOC3)c2n1

Procedure:
2,6-Dichloro-9-(tetrahydrofuran-3-ylmethyl)-9H-purine (41 g) was dissolved in ethanol (200 ml) followed by the addition of morpholine (20 ml) and the resulting mixture was heated to reflux for 2 hours. The solvent was evaporated under reduced pressure, the residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 5:5 to 2:8 to 0:10) to give the title compound (41 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:9][CH3:10])[CH:7]([CH3:8])[CH2:6][NH:5][CH2:4]1.C([O:13][C:14]([C:16]1[CH2:17][N:18]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([F:26])=[C:21](Cl)[N:20]=2)=[O:15])C.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1([O:9][CH3:10])[CH:7]([CH3:8])[CH2:6][N:5]([C:21]2[N:20]=[C:19]3[C:24]([CH:25]=[C:16]([C:14]([OH:15])=[O:13])[CH2:17][N:18]3[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])=[CH:23][C:22]=2[F:26])[CH2:4]1
Reactant: COC1(OC)CNCC1C
Reactant: CCOC(=O)C1=Cc2cc(F)c(Cl)nc2N(c2ccc(F)cc2F)C1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC1(OC)CN(c2nc3c(cc2F)C=C(C(=O)O)CN3c2ccc(F)cc2F)CC1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
In a reaction similar to that of Step 1, Example 387, into oven-dried glassware maintained under dry N2 were placed 0.132 g (0.91 mmol) of 3,3-dimethoxy-4-methylpyrrolidine (from Step 5 Example 183), 0.300 g (0.78 mmol) of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester, 12 mL of dry pyridine and 0.437 mL (3.1 mmol) of triethylamine. The reaction was stirred at room temperature for 15 hours, then the solvent was removed in a rotary evaporator. The residue was dissolved in methylene chloride and the product purified by column chromatography over silica gel, eluting with 0.5% increasing to 3% methanol/methylene chloride which was evaporated to afford 0.240 g of the title compound. This material was taken directly to the next step.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[O:9][N:8]=[C:7]([C:10]2[N:14]3[N:15]=[C:16]([OH:23])[C:17]4[C:22]([C:13]3=[N:12][N:11]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=1.O>CN(C)C=O>[OH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2=[N:12][N:11]=[C:10]([C:7]3[CH:6]=[C:5]([O:2][CH3:1])[O:9][N:8]=3)[N:14]2[N:15]=1
Reactant: C[O-]
Reactant: Oc1nn2c(-c3cc(Cl)on3)nnc2c2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3c4ccccc4c(O)nn23)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (165 mg, 0.3 mmol) was added to a stirred suspension of 3-(5-chloroisoxazol-3-yl)-6-hydroxy-1,2,4-triazolo[3,4-a]phthalazine (400 mg, 0. 14 mmol) (prepared from Intermediate 7 using the procedure described in Example 15 part b) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 3 h then water was added (5 ml) and the solvents evaporated in vacuo. The residue was taken up in water and acidified to pH 2 using 2M hydrochloric acid. The resulting precipitate was filtered off, washed with hexane and azeotroped with ethanol to give crude 6-hydroxy-3(5-methoxyisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine, MS (ES30) 284 [MH]+. The title-compound was prepared from this material using the procedure described in Example 103 part a, 1H NMR (250 MHz, CDCl3) δ 2.49 (3H, s, CH3), 4.15 (3H, s, CH3), 6.10 (1H, s, Ar—H), 7.45 (2H, d, J=8.5 Hz, Ar—H), 7.92 (1H, m, Ar—H), 8.06 (1H, m, Ar—H), 8.26-8.32 (3H, m, 3 of Ar—H), 8.64 (1H, d, Ar—H); MS (ES30) 438 [MH]+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.[OH-].[Na+].O>C(O)C>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:10]/[C:9](=[O:11])/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccs1
Reactant: CC(=O)/C=C/c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)/C=C/c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.2 %

Procedure:
A mixture of 65.1g (0.45 mol)of E-4-phenyl-3-buten-2-one, 50 g (0.45 mol)of 2-thiophenecarboxaldehyde, 4 mL of aqueous 10% sodium hydroxide, 50 mL of water, and 75 mL of ethanol was stirred at ambient temperature for 15 hours. The solid which separated was collected by filtration and air dried to give 85.6 g (80% yield) of E,E- 1-(2-thienyl)-5-phenyl- 1,4-pentadien-3-one as a yellow solid. 1H NMR, IR, and FDMS analyses were consistent with the expected structure.
Reaction SMILES: ClOC(C)(C)C.[CH2:7]1[S:10][CH2:9][CH2:8]1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.CCCCCCC=CCCC>ClCCl>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[CH2:9][CH2:8][CH2:7][S:10]2)=[CH:14][CH:13]=1
Reactant: C1CSC1
Reactant: Nc1ccc(Br)cc1
Agent: CC(C)(C)OCl
Agent: CCCC=CCCCCCC
Solvent: ClCCl
Product: Brc1ccc(N2CCCS2)cc1
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
A solution of tert.-Butyl hypochlorite (947 mg) in dichloromethane (15 mL) is added drop wise over a period of 1 h to a solution of trimethylene sulfide (0.63 mL) and 4-bromoaniline (1.50 g) in dichloromethane (60 mL) at −70° C. The reaction mixture is stirred for 15 min prior to the addition of a solution of 1,8-diazabycyclo[5.4.0]undec-7-ene (1.37 mL) in dichloromethane (10 mL). The reaction mixture is allowed to warm to −15° C. and quenched with water. The organic phase is separated, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20-40:60) to give the title compound. LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=244, 246 [M+H]+.