Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:18]([OH:24])[CH2:19][CH2:20][CH2:21][C:22]#[CH:23]>O>[S:7]([O:24][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: C#CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
In this preparation 1.0 mole of p-toluenesulfonyl chloride is dissolved in 700 ml. of pyridine at 0° C, under nitrogen, and then 0.5 mole of hex-5-yn-1-ol is added dropwise. The mixture is stirred for 2 hours and then 10 ml. of water is added slowly, keeping the temperature below 10° C. The pyridine is then removed by evaporation under vacuum and the residue poured into 1 liter of ethyl acetate, then washed twice with excess 2N aqueous hydrochloric acid, and then with water. The organic layer is separated and dried over anhydrous magnesium sulfate, filtered, and the filtrate then evaporated to dryness, under vacuum, affording hex-5-yn-1-ol tosylate.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].O.[CH2:6]([CH:13]([C:19](=[O:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[CH2:6]([CH:13]([CH:19]([OH:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(Cc1ccccc1)C(C)O
Yield: 85 %

Procedure:
0.05 Mol of NaBH4 and 0.4 g of NaOH were added into 25 ml of water. While cooling the reactor in ice bath, a mixture of 0.07 mol of ethyl 2-benzyl-3-oxo-butyrate and 30 ml of methanol was added dropwise with stirring, and the reaction was stirred at room temperature for 5 hours. After removing the solvent, the product was extracted with ethyl acetate, and the extract was dried over anhydrous Na2SO4. Removing the solvent gave a colorless liquid of 0.06 mol. Yield 85%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:26][C:27]([C@@H:29]3[CH2:31][C@H:30]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])[CH:23]=2)[CH2:18]1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:26][C:27]([C@@H:29]4[CH2:31][C@H:30]4[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])[CH:23]=3)[CH2:18]2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)Nc1ccc2c(c1)CC(N)C2
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)Nc1ccc2c(c1)CC(NC(=O)c1nc(Cl)c(CC)[nH]1)C2
Yield: 93.7 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.23 g, 1.32 mmol), thionyl chloride (4 mL), ethyl trans(±)-2-[(2-amino-2,3-dihydro-1H-inden-5-yl)carbamoyl]cyclopropanecarboxylate obtained in Example (98a) (95 mg, 0.24 mmol) and pyridine (5 mL). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/2, 3/2, 1/0) gave 0.10 g of the title compound as a light yellow solid (92%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: O=C(O)C1CCOCC1
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (41 mg, 47%), MS (ISP) m/z=441.4 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N+:8]([C:3]1[C:2]([S:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ncccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
3-chloro-2-nitropyridine (30.6 g, 193 mmol) was dissolved in DMSO (200 mL). Benzenethiol (20.7 mL, 203 mmol) was added followed by cesium carbonate (69.3 g, 212 mmol) and stirred at ambient temperature for 1.5 hours. The solution was diluted with water (750 mL) and the solids filtered. The crude material was recrystallized from EtOAc (400 mL) and with adding hexanes (1L) to give an A-crop of 23.5 g. The filtrate was concentrated and recrystallized from EtOAc/hexanes to give 7.87 g. The solids were dried on high vacuum to provide the title compound (31.38 g, 69.8% yield).
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:5][C:4]1[C:3]([F:9])=[C:2](/[CH:12]=[CH:11]/[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1cccc(Br)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1cccc(N)c1F
Temperature: 145 °C
Reaction time: 8 h

Procedure:
400 mg (2.10 mmol) of 3-bromo-2-fluoroaniline, 809.42 mg (6.32 mmol) of tert-butyl acrylate and 1.47 ml (10.53 mmol) of triethylamine were initially charged in 2.4 ml of DMF. The reaction vessel was evacuated three times and in each case vented with argon. 47.26 mg (0.21 mmol) of palladium(II) acetate and 128.14 mg (0.42 mmol) of tri-2-tolylphosphine were then added, and the reaction vessel was evacuated two more times and again vented with argon. The mixture was stirred at 145° C. overnight. The reaction mixture was then cooled, added to saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 210 mg (42% of theory) of the title compound.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[C:11]1([CH:21]=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[H-].[Na+]>C(O)C>[CH2:9]([O:8][C:1]([C:2](=[CH:21][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:7])[CH3:10]
Reactant: CCOC(=O)CCC(=O)[O-]
Reactant: O=Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccc2ccccc12)CC(=O)O
Yield: 83 %

Procedure:
To a solution of 17.40 g of ethyl succinate and 15.62 g of 1-naphthaldehyde in 100 ml of absolute ethanol was added 6.00 g of sodium hydride (50% dispersion in mineral oil), and the mixture was heated under reflux for 3 hours. The reaction mixture was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether to remove neutral materials. The aqueous layer was acidified by adding concentrated hydrochloric acid, and extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 23.60 g of 3-ethoxycarbonyl-4-(1-naphthyl)-3-butenoic acid as a yellow oil. A mixture of 200 ml of a 1N-aqueous sodium hydroxide solution and 170 ml of ethanol was added to 23.50 g of the butenoic acid obtained. The mixture was heated at 50° C. for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether to remove neutral materials. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 15.30 g of 2-(1-naphthylmethylene)succinic acid as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=1)(C)(C)[CH3:2].C(Cl)(=[O:27])C.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCl>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=1)(=[O:27])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(CCc2ccc(F)cc2)c1C
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(C)=O)n(CCc2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Bioorganic & Medicinal Chem. Lett., 14 (2004), 1295-1298, was used as a reference. A 1.00 g portion of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in 15 ml of toluene, 0.26 ml of acetyl chloride was added thereto, and 3.6 ml of tin(IV) chloride (a 1 M dichloromethane solution) was added dropwise thereto at 0° C., followed by stirring at room temperature for 6 hours. After adjusting to pH 12 by adding 25 ml of a 1 M sodium hydroxide aqueous solution at 0° C., extraction was carried out with ethyl acetate, followed by washing with saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:7-1:5) to obtain 668 mg of ethyl 5-acetyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate as a beige solid.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(S(F)(F)[F:20])CC)C.C([O-])(O)=O.[Na+]>ClC(Cl)C.O>[C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([F:20])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a well stirred and cooled (−30° C.) solution of Step 1 intermediate (1.5 g, 8.01 mmol) in dichloroethane (50 ml) was added diethylaminosulphur trifluoride (1.94 mg, 12.01 mmol) under nitrogen and the reaction mixture was maintained at this temperature for 1 h. The reaction mixture was gradually allowed to warm to room temperature and stirring was continued for another 14 h. The reaction mixture was poured onto a mixture of ice and solid NaHCO3 and stirred till no effervescence was seen. The mixture was diluted with water and extracted with dichloromethane (3×100 ml). The combined organic extracts were washed with water, brine and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether) to give 840 mg of the desired compound as yellow oil; IR (neat) 3500, 2978, 1698, 1407 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.44 (s, 9H), 1.89-2.28 (m, 2H), 3.44-3.77 (m, 4H), 5.11-5.31 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].Cl.N1C=CC=CC=1>C(OCCO)C>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 89.6 %

Procedure:
A solution of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 309.7 mg (1.8 mmol) of 3-bromoaniline and 173.3 mg (1.5 mmol) of pyridine hydrochloride in 15 ml of 2-ethoxyethanol was refluxed under nitrogen for 0.5 hours. The solvent was removed and the residue was diluted with water followed by neutralization to pH 7-8 with diluted sodium carbonate solution. The precipitate was collected and washed with ether and dried in vacuo to give 476.1 mg (89.6%) of the product as a yellow solid, m.p. 210-212° C.; mass spectrum (electrospray, m/e): M+H 353.8, 355.8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:21])=O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:21])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C(=O)Cl

Procedure:
4-Chloro-2-methoxy-benzoic acid (0.50 g, 2.7 mmol) and DMF (50 μl) were added to dichloromethane (9 ml). Oxalyl chloride (0.47 ml, 5.4 mmol) was then added to the mixture and the resultant solution stirred at room temperature for 2 hours. The reaction was monitored to completion by LC-MS. The reaction was concentrated in vacuo to afford crude 4-chloro-2-methoxy-benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[NH:12][N:11]=[N:10]1.[CH3:15]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: CN(C)C=O
Reactant: Cc1c(F)cccc1-n1nn[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cc1c(F)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the above-mentioned 1-(2-methyl-3-fluorophenyl)-1,4-dihydrotetrazole-5-one 10.00 g and N,N-dimethylformamide 100 mL was added 55% sodium hydride 2.47 g under ice-cooling. The mixtures were raised to room temperature and were stirred for one hour. To the reaction mixtures was added methyl iodide 3.5 mL under ice-cooling. The mixtures were raised to room temperature and were stirred for fourteen hours. To the reaction mixtures was added water and the mixtures were extracted with ethyl acetate. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-fluorophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 2.19 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][C:7](=[N:9][OH:10])[NH2:8].[CH:15](OCC)(OCC)OCC>B(F)(F)F.CCOCC>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][C:7]1[N:8]=[CH:15][O:10][N:9]=1
Reactant: Cc1c(Cl)cccc1OCC(N)=NO
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Product: Cc1c(Cl)cccc1OCc1ncon1
Yield: 57.4 %

Procedure:
7.0 g (32.6 mmol) of 3-chloro-2-methyl-phenoxy-acetamide oxime are introduced into 70 ml of triethyl orthoformate, and 5 drops of boron trifluoride etherate are added at room temperature. The mixture is subsequently stirred at reflux temperature until the reaction is complete (approximately 1 hour) and the entire batch is concentrated in vacuo. The residue is taken up in 100 ml of methylene chloride and washed in succession with 100 ml of 2N hydrochloric acid, saturated sodium carbonate solution and water. The organic phase is dried over sodium sulphate and the solvent is subsequently distilled off. The oily residue which remains is distilled using a bulb tube. 4.2 g (57.4% of theory) of 3-(3-chloro-2-methyl-phenoxymethyl)-1,2,4-oxadiazole are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])[CH3:2]
Reactant: CCOc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 2-ethoxybenzoic acid (0.75 g, 4.5 mmol) in 23 mL of methylene chloride at 0° C. was treated with oxalyl chloride (0.44 mL, 4.9 mmol) followed by 2 drops of dimethylformamide. The solution was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure to provide 0.83 g of 2-ethoxybenzoyl chloride. To a solution of 4-trifluoromethylthiazol-2-ylamine (0.50 g, 3.0 mmol) in 10 mL THF at 0° C. was added a solution of the fleshly prepared acid chloride in 5 mL of THF and 2 mL of methylene chloride, followed by triethylamine (1.0 mL, 6.6 mmol). The reaction mixture was warmed to 65° C. and stirred 8 hours. The mixture was diluted with ethyl acetate and washed twice with water, then brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 30-50% ethyl acetate/hexanes gradient) afforded 0.47 g (50%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.66 (t, J=6.95 Hz, 3H), 4.38 (q, J=6.89 Hz, 2H), 7.03-7.10 (m, 2H), 7.17 (d, J=7.80 Hz, 1H), 7.42 (s, 1H), 8.29 (dd, J=7.97, 1.86 Hz, 1H) MS (DCI/NH3) m/z 317 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:13][C:11](=[O:12])[CH:10]([CH3:16])[CH2:15][N:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]1=[O:8]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=c1cc(Br)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Cn1ccc(Br)cc1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromo-1H-pyridin-2-one (0.50 g), methyl 2-bromoisobutyrate (0.45 mL), and potassium carbonate (0.68 g) in dimethylformamide (5 mL) was stirred at 60° C. for 3 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 70:30->50:50) to afford the title compound. Yield: 0.53 g (67% of theory); Mass spectrum (ESI+): m/z=274/276 (Br) [M+H]+. Additionally 2-(4-bromo-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester was obtained (Yield: 0.15 g; Mass spectrum (ESI+): m/z=274/276 (Br) [M+H]+)
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[C:25]1(=[O:39])[N:29]([CH2:30][CH2:31][C:32]#[CH:33])[C:28](=[O:34])[C:27]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]12>CN(C)C=O.[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>[C:28]1(=[O:34])[N:29]([CH2:30][CH2:31][C:32]#[C:33][C:2]2[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=2)[C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:25](=[O:39])[C:26]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:27]12
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 78.8 %

Procedure:
5-Iodo-2'-deoxyuridine (354 mg, 1 mmol) was dissolved in 10 mL of dimethylformamide. Cuprous iodide (76 mg, 0.4 mmol), tetrakis (triphenylphosphine) palladium (0) (230 mg, 0.2 mmol), and triethylamine (200 mg, 2.0 mmol) were added. 4-Phthalimidobut-1-yn (300 mg, 1.5 mmol) was added all at once and the reaction kept at 60° C. for three hours. The clear yellow reaction was then evaporated and methylene chloride was added. Scratching of the flask induced crystallization of nearly all of the product which was filtered and recrystallized from 95% ethanol to give 335 mg (78%) of title compound as fine, feathery needles.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[CH2:23][CH2:24][C:25]#[N:26]>>[CH2:11]([O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:25]([NH2:26])[C:24]([CH2:23][C:16]1[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH3:13])=[CH:4]2)[CH3:12]
Reactant: CCOc1ccc(N)c(C=O)c1
Reactant: COc1cccc(OC)c1CCC#N
Product: CCOc1ccc2nc(N)c(Cc3c(OC)cccc3OC)cc2c1

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-ethoxybenzaldehyde and 3-(2,6-dimethoxyphenyl)propionitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:15])[CH3:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:24][C:25]1[N:29]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:37])[N:28]=[CH:27][C:26]=1[CH:38]([CH3:40])[CH3:39].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]2[N:29]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:37])[N:28]=[CH:27][C:26]=2[CH:38]([CH3:40])[CH3:39])=[CH:10][C:9]=1[CH3:15])[CH3:7])[CH3:2]
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CCl
Reactant: CCOC(=O)CC(C)c1ccc(O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of (+/−)-3-(4-Hydroxy-2-methyl-phenyl)-butyric acid ethyl ester (0.366 g, 0.748 mmol) in DMF (4 mL) is added cesium carbonate (1.1 g, 1.5 mmol). After 5 minutes at room temperature, 5-Chloromethyl-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole (0.50 g, 0.748 mmol) is added and the reaction is heated to 50° C. overnight. Upon cooling, water is added followed by 1N HCl. The resulting mixture is extracted two times with ethyl acetate and the organic layers are combined and are washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with 3-5% ethyl acetate/toluene to give the title compound. 1H NMR (CDCl3) δ 1.113-1.163 (m, 6H), 1.26 (d, 6H), 2.399-2.532 (m, 2H), 2.952 (m, 1H), 3.388 (m, 1H), 4.024 (q, 2H), 4.741 (s, 2H), 6.513 (d, 1H), 6.544 (dd, 1H), 6.970 (d, 1H), 7.264 (t, 1H), 7.372 (d, 2H), 7.661 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(O)c(F)c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 40 %

Procedure:
The title compound is prepared from 3-fluoro-4-hydroxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 40% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=326 [M+H]+.