Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCSCC2)s1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCSCC2)s1)c1ccncc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
Compound 588 (120 mg, 0.408 mmol) was dissolved in DMF (2 mL), and isonicotinic acid (150 mg, 1.22 mmol), EDC hydrochloride (234 mg, 1.22 mmol) and 1-hydroxybenzotriazole monohydrate (187 mg, 1.22 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 589 (106 mg, 65%).
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([CH3:15])[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Brc1cccc(-c2cnn[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc(-c2cccc(Br)c2)n1
Reaction time: 8 h
Yield: 41.8 %

Procedure:
Methyl iodide (323 μl, 5.2 mmol) was added to a stirred mixture of 5-(3-bromophenyl)-1H-[1,2,3]triazole (776 mg, 3.46 mmol) and potassium carbonate (1.19 g, 8.6 mmol) in DMF (20 ml) at room temperature under nitrogen. The reaction mixture was stirred overnight and then concentrated under reduced pressure. Water (50 ml) was added and then the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were concentrated under reduced pressure while dry loading onto silica gel. The residue was purified by column chromatography (silica gel, 50% Et2O/isohexane) to yield first 4-(3-bromophenyl)-2-methyl-2H-[1,2,3]triazole (344 mg, 42%), the solvent polarity was increased to 80% Et2O/isohexanes to yield 5-(3-bromophenyl)-1-methyl-1H-[1,2,3]triazole (15 mg, 2%), and then the solvent polarity was increased to 100% Et2O to yield 4-(3-bromophenyl)-1-methyl-1H-[1,2,3]triazole (147 mg, 18%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of dimethylsulfamoyl chloride (81 μL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (207 mg, 77%). 1H NMR (400 MHZ, CDCL3) δ7.19 (D, 2H), 6.93-6.91 (D, 2H), 4.05 (T, 2H), 3.78-3.76 (M, 2H), 3.59-3.54 (M, 2H), 3.17-3.15 (D, 2H), 2.76-2.70 (M, 12H), 2.15-2.06 (M, 4H), 1.90-1.87 (M, 6H).
Reaction SMILES: O[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(Cl)(Cl)[Cl:13]>CN(C)C=O>[Cl:13][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(O)cn1
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Cl)cn1
Temperature: 0 °C
Yield: 81 %

Procedure:
Methyl 5-hydroxypyrazine-2-carboxylate (673 mg, 4.37 mmol) synthesized in Example (62a) was dissolved in phosphorous oxytrichloride (6.1 mL), and a few drops of N,N-dimethylformamide were added, followed by heating to reflux for 2 hours under nitrogen atmosphere. The reaction solution was poured into ice water, and extraction was carried out three times with chloroform (30 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine (100 mL each), and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure to afford the desired compound (611 mg, yield 81%) as a gray solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.C(N(CCCC)CCCC)CCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To N,N-dimethylacetamide 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.10 g were added 1-bromo-4-(trifluoromethoxy)benzene 0.12 g, tributylamine 0.15 mL and palladium acetate 3.6 mg at room temperature, and it was stirred at 110° C. for 6 hours. Palladium acetate 3.6 mg was added to it, and it was stirred at 130° C. for 6 hours. 1-bromo-4-(trifluoromethoxy)benzene 0.12 g, tributylamine 0.076 mL and (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 6.3 mg were added to it, and it was stirred at 80° C. for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, and the solvent was removed under reduced pressure after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(4-(trifluoromethoxy)phenyl)vinyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH3:26])=[CH:20][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](F)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:18]#[N:19].[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH3:26])=[CH:20][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([N:35]3[CH2:36][CH2:37][CH:32]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:33][CH2:34]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:18]#[N:19]
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 105 °C
Yield: 43.4 %

Procedure:
Following the procedure of Example 11, a mixture of 200.0 mg (0.51 mmol) of 4-(2,4-dichloro-5-methoxyanilino)-7-fluoro-6-methoxy-3-quinolinecarbonitrile and 472.0 mg (3.06 mmol) of 4-(1-pyrrolidinyl)piperidine in 1.0 mL of 1-methyl-2-pyrrolidinone is heated in a sealed tube at 105° C. for 15 hours to yield the crude product. Purification by preparative thin layer chromatography (eluting with 4:1 dichloromethane/methanol) provides 116.5 mg of the pure product as a yellow solid, mp 225-227° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:34][CH3:35])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]([CH3:33])[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:19][CH:18]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].[OH-].[Na+]>CCCCCC.C(O)C.C(O)C.O1CCCC1>[CH2:34]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]([CH3:33])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:19][CH:18]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:35]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: CCC(CC)C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1oc2ccc(F)cc2c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.7 %

Procedure:
Ethyl 3-{[(4-{[2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl]amino}phenyl)carbonyl](methyl)amino}propanoate (9.18 g) obtained in Example A71(5) was dissolved in hexane-ethanol (1:1, volume ratio), subjected to HPLC using CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), and eluted with hexane-ethanol (1:1, volume ratio) as a mobile phase at room temperature and at a flow rate 60 mL/min. The resulting fraction containing an optically active form having a longer retention time was concentrated to give an amorphous form (4.67 g, 99.9% ee). The obtained amorphous form (4.67 g) was dissolved in ethanol (20 mL) and tetrahydrofuran (20 mL), 1N aqueous sodium hydroxide solution (19.4 mL) was added, and the mixture was stirred at room temperature for 20 min. The solvent was evaporated under reduced pressure. Water (30 mL) was added, and the mixture was neutralized with 1N hydrochloric acid under ice-cooling and stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (4.21 g, 96%, 99.9% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH3:14].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH2:14][Br:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2ccccc2)ccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
3.90 g (19.2 mmol) of 4-chloro-3-methylbiphenyl was dissolved in 100 ml of carbon tetrachloride and to this solution was added 632 mg (3.85 mmol) of 2,2′-azobisisobutylonitrile, and the mixture was stirred at room temperature for 15 minutes. To this solution was added 3.43 g (19.2 mmol) of N-bromosuccinimide, and the mixture was stirred for 3.5 hours while heating under reflux. To the reaction solution was further added 632 mg (3.85 mmol) of 2,2′-azobisisobutyronitrile and 300 mg (1.69 mmol) of N-bromosuccinimide, and the mixture was stirred for 2 hours under reflux with heating. The reaction mixture was filtrated, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane) to obtain 4.69 g of 2-chloro-5-phenylbenzyl bromide in the form of colorless transparent oil.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:22])(=O)[CH2:2][CH3:3].[CH2:23]([O:25][NH2:26])[CH3:24]>CO>[CH2:23]([O:25][NH:26][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:22])[CH2:2][CH3:3])[CH3:24]
Reactant: CCON
Reactant: CCC(=O)C1C(=O)CC(CCSc2ccc(Cl)cc2)CC1=O
Solvent: CO
Product: CCONC(CC)=C1C(=O)CC(CCSc2ccc(Cl)cc2)CC1=O
Yield: 55.5 %

Procedure:
1.6 g of 2-propionyl-5-[2-(4-chlorophenylthio)ethyl]cyclohexane-1,3-dione was allowed to react with 0.8 g of ethoxyamine at room temperature for 16 hours in 60 ml of methanol. After completion of the reaction, the resulting reaction solution was treated as in Example 1 to obtain oily product. Purification of the oily product by column chromatography gave 1 g of the desired compound as colorless oily material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH2:9][CH2:8][C:7](=[O:10])[C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[H+].[B-](F)(F)(F)F>>[CH3:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:6]1[C:7](=[O:10])[CH2:8][CH2:9][CH:5]1[CH2:4][C:3]([O:2][CH3:1])=[O:16]
Reactant: CCCCCC1=C(CC(=O)OC)CCC1=O
Agent: F[B-](F)(F)F
Agent: [H+]
Product: CCCCCC1C(=O)CCC1CC(=O)OC
Reaction time: 20 h
Yield: 99 %

Procedure:
In a glove box under argon and at room temperature, 38 mg of [(COD)Ru(2-methylallyl)2 ] (0.12 mmole) and 36 mg (0.12 mmole) of (-)-Me-DuPHOS were dissolved in 5.38 g (24 mmole) of methyl-3-oxo-2-pentyl-1-cyclopentene-acetate in a glass beaker adapted for use in an autoclave which was equipped with a stirrer. Thereafter, 39 mg of HBF4 etherate (0.24 mmole; 32.7 μl, syringe) were gently added under stirring. After stirring for 4 h, 3.4 ml of this catalytic solution (containing about 0.075 mmole of catalyst) were transferred to another beaker, and another 8.38 g (37.4 mmole) of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate (total amount about 53 mmole) were added to this. Working as previously described, the substrate was hydrogenated at a H2 pressure of 5×106Pa. The reaction was allowed to proceed for 20 h at room temperature. The autoclave was degassed, opened, and the catalyst was precipitated using pentane, filtered and the filtrate concentrated to obtain the desired Hedione®. The thus obtained product (yield 99% based on the above mentioned substrate) showed the following isomer ratios: cis/trans=97/3: (+)-cis/(-)-cis=80/20, 60% e.e.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:29](B(O)O)([CH3:31])=[CH2:30].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:3]4[C:2]([C:29]([CH3:31])=[CH2:30])=[CH:7][CH:6]=[CH:5][N:4]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: C=C(C)B(O)O
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(C)c1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 150 °C

Procedure:
3-Bromo-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (0.25 g, 0.58 mmol) and isopropenylboronic acid pincaol ester (available from Aldrich, 0.12 ml, 0.64 mmol) were placed in a microwave vial and dissolved in 1,4-dioxane (4 ml). Pd(PPh3)4 (66 mg, 0.06 mmol) and Na2CO3 (0.58 ml, 1.16 mmol, 2 M aqueous solution) were added and the mixture was heated at 150° C. for 10 mins under microwave irradiation. The reaction mixture was filtered through Celite, washing with ethyl acetate. The organic mixture was washed with water (10 ml) and brine (10 ml), dried over MgSO4, filtered and the solvent was removed in vacuo. The resulting orange solid was purified by mass-directed automated preparative HPLC (Method B) to give the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([CH:7]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2)=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cccc(CC(=O)Cl)c1
Product: COc1cccc(CC(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)c1
Yield: 66 %

Procedure:
tert-Butyl 3-(2-(3-methoxyphenyl)acetyl)-4-oxopiperidine-1-carboxylate (388 mg, 66%) was synthesised from tert-butyl 4-oxopiperidine-1-carboxylate and 2-(3-methoxy-phenyl)acetyl chloride according to the general procedure for the preparation of diketones.
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[CH:25])[C:22]34O[C:17]3([CH:18]([O:27][Si](C(C)(C)C)(C)C)[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[CH:14][C:13]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[CH:25])[C:22]3[CH2:21][CH2:20][CH2:19][C:18](=[O:27])[C:17]=3[C:16]3[CH:15]=[CH:14][C:13]([O:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:12][C:11]2=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2cc(OC(=O)C(C)(C)C)ccc2C23OC12CCCC3O[Si](C)(C)C(C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C#CC1C2=C(C(=O)CCC2)c2ccc(OC(=O)C(C)(C)C)cc2N1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
To a solution of Compound 228 (7.0 g, 12.16 mmol) in wet CHCl3 (100 mL) was added BF3.OEt2 (7.48 mL, 60.82 mmol). The mixture was stirred at 25° C. (1. 5 hours) until TLC indicated complete conversion of Compound 228. Silica gel (10.0 g) was added to the reaction mixture followed by stirring at 25° C. for another 12 hours. Silica gel was filtered off through Celite and washed with ethyl ether (100 mL). The solvent was removed in vacuo, and the residue was purified by flash column chromatography (silica gel, 10 percent ethyl ether in benzene) to provide Compound 229 (3.91 g, 73 percent). A more polar component (about 1.0 g) was also isolated which could not be converted to Compound 229 in the presence of silica gel for prolonging reaction time. Compound 229: white solid; mp 140°-142° C.; Rf =0.44 (silica, 10 percent ethyl ether in benzene); IR (CHCl3) νmax 3305, 2977, 1737 (shoulder), 1720, 1705, 1684, 1607, 1577, 1495, 1382, 1306, 1201, 1178, 1122 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J=8.7 Hz, 1 H, H1), 7.43-7.35 (m, 3 H, H4 and aromatic), 7.28-7.16 (m, 3 H, aromatic), 6.98 (dd, J=8.7, 2.4 Hz, 1 H, H2), 5.86 (d, J=2.4 Hz, 1 H, H6), 2.87-2.51 (m, 4 H, H7 and H9 ), 2.26 (d, J=2.4 Hz, 1 H, acetylenic), 2.24-2.08 (m, 2 H, H8), 1.33 (s, 9 H, COC(CH3)3); MS (FAB+) m/e (rel intensity) 444 (M+H, 82), 350 (15), 266 (20), 238 (15); HRMS for C27H26NO5 (M+H), calcd 444.1811, found 444.1842.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][C:21]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:24])[C:22]#[CH:23]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I.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>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[N:5]=[C:6]([C:23]#[C:22][C:21]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:24])[CH3:20])[CH:7]=[CH:8][C:9]=2[C:10](=[O:16])[C:11]=1[C:12](=[O:13])[NH:14][CH3:15]
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(C)OCC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COC(C)(C)C#Cc1ccc2c(=O)c(C(=O)NC)c(N)n(CC)c2n1
Temperature: 90 °C
Yield: 82.4 %

Procedure:
1.15 g (4.10 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide and 1.39 g (8.19 mmol) of ethyl [(1,1-dimethylprop-2-yn-1-yl)oxy]acetate are placed in a mixture of 10 ml of dimethylformamide and 10 ml of triethylamine. Argon is sparged into the reaction mixture for 15 minutes and then 0.031 g (0.16 mmol) of CuI and 0.144 g (0.20 mmol) of bis(triphenylphosphine)palladium(II) dichloride are successively added. The reaction mixture is heated at 90° C. for 15 hours. After returning to ambient temperature, the reaction mixture is poured onto a water/ice mixture. After separating them by settling, the black gum obtained is dissolved in ethyl acetate and then washed with water. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. 1.4 g of a brown oil are obtained, which oil is purified by chromatography on silica (elution with a cyclohexane/ethyl acetate 30:70 to 20:80 gradient) to give 0.72 g of the expected product in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:14]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: CO
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cc(OC)ccc1Br
Yield: 85 %

Procedure:
To a stirred solution of 2-bromo-5-methoxybenzoic acid (Aldrich 384003; 5.0 g, 21.6 mmol) in methanol (80 mL) was added concentrated hydrochloric acid (2 mL) and the mixture was heated under reflux for 18 hours. The resulting solution was cooled, the solvent was removed in vacuo, water (100 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over MgSO4, filtered and evaporated to obtain methyl 2-bromo-5-methoxybenzoate as a light brown oil (4.50 g, 85%); NMR Spectrum δH (300 MHz, CDCl3) 7.53 (1H, d, J 8.8 Hz, 3-H), 7.32 (1H, d, J 3.0 Hz, 6-H), 6.89 (1H, dd, J 3.0, 8.8 Hz, 4-H), 3.94 (3H, s, Ar OCH3) and 3.82 (3H, s, CO2CH3) (data in accordance with published values, see Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127-11142); νmax/cm−1 (thin film) 2951, 1732 (C═O), 1592, 1472, 1433, 1289, 1250, 1227, 1099, 1017, 975, 823, 792 (data in accordance with published values, see Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127-11142); Rf (hexane-ethyl acetate 5:1) 0.58.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:22][C@@H:21]([CH2:23][O:24]C(=O)C)[C@H:16]([O:17]C(=O)C)[C@@H:11]2[O:12]C(=O)C)[C:8]2[CH:28]=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:7]=2[N:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[CH:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:22][C@@H:21]([CH2:23][OH:24])[C@H:16]([OH:17])[C@@H:11]2[OH:12])[C:8]2[CH:28]=[C:29]([Cl:34])[C:30]([Cl:33])=[C:31]([Cl:32])[C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)c(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC(C)Nc1nc2c(Cl)c(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 74.6 %

Procedure:
2-(Isopropylamino)-4,5,6-trichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.00 g, 1.86 mmol), sodium carbonate (0.26 g, 2.45 mmol), water (4 mL), methanol (6 mL) and ethanol (8mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford 0.57 g (75%) of a white powder; m.p. 223-224° C. Anal. Calcd for C15H18Cl3N3O4: C, 43.87; H, 4.42; N, 10.23. Found: C, 43.63; H, 4.55; N, 9.98.