Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][C@H:5]([O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[CH2:19]([OH:22])[C:20]#[CH:21]>C(N(CC)CC)C.[Cu]I>[CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][C@H:5]([O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([C:21]#[C:20][CH2:19][OH:22])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCC(CC)C[C@@H](C)OC(=O)c1ccc(I)cc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCC(CC)C[C@@H](C)OC(=O)c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A schlenk tube was charged with 62.5 mg of dichlorobistriphenylphosphine palladium (II) complex and 45.5 mg of copper (I) iodide, and an atmosphere in the system was replaced with nitrogen. 31.9 Grams of p-iodobenzoic acid-(R)-3-ethyl-1-methylpentyl ester and 7.50 g of 2-propyn-1-ol were dissolved in 100 mL of dry triethylamine, and the mixture was charged into the above schlenk tube and stirred at room temperature for 1 day.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([O:19][CH3:20])=[CH:9][C:3]=1[C:4](OCC)=[O:5].[CH:21]([NH2:23])=O>C(O)C>[CH3:20][O:19][C:10]1[CH:9]=[C:3]2[C:2](=[CH:12][C:11]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:1]=[CH:21][NH:23][C:4]2=[O:5]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(OC)c(OCC(F)(F)F)cc1N
Solvent: CCO
Product: COc1cc2c(=O)[nH]cnc2cc1OCC(F)(F)F
Temperature: 175 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A mixture of ethyl 2-amino-4-(2,2,2-trifluoroethoxy)-5-methoxybenzoate (20.2 g, 69.1 mmol) and formamide (50 ml) was heated at 175° C. for 6 hours. The mixture was allowed to cool to ambient temperature, ethanol (150 ml) was added and the reaction allowed to stand for 18 hours. Collection of the solid which had precipitated by suction filtration, followed by washing with ethanol (2×50 ml) and drying in vacuo, yielded 6-methoxy-7-(2,2,2-trifluoroethoxy)-3,4-dihydroquinazolin-4-one (15.8 g, 84% yield) as a pale brown crystalline solid:
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:25]2[C:24](=[O:26])[C:23]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]3[C:21]2=[O:31])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCCCCOc1ccccc1-c1ccccc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCOc1ccccc1-c1ccccc1

Procedure:
A solution of 1-(2-biphenyloxy)-6-chlorohexane 8.0 g) and potassium phtalimide (5.6 g) in dimethylformamide (100) ml) was heated at reflux temperature for 3 hours. The solution was cooled and poured into water, and the product was extracted out with ethyl acetate. The extract was dried and evaporated to afford N-[6-(biphenyloxy)hexyl]phthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([N:27]([CH2:38][CH3:39])[CH2:28][CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH2:38][CH3:39])[CH2:25][CH3:26])=[CH:37][CH:36]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 9.1 %

Procedure:
A mixture of 2.55 g (6.6 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 7 g (34 mmol) of 4-[2-(diethylamino)ethoxy]-aniline was heated at 180° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using firstly 5% methanol in dichloromethane and then dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 150 ml of dichloromethane. The solution was washed with 100 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give 1.18 g (35%) of crude product. Purification by crystallisation from cyclohexane/ethyl acetate gave 310 mg (9%) of pure 3-(2,6-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 123-124° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:6][CH2:7]1
Reactant: Cc1ccc(C=O)cc1F
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc(C)c(F)c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 206 mg of 3-fluoro-4-methylbenzaldehyde, 100 mg of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 15 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.44 g of 1-(2-(4-(3-fluoro-4-methylbenzylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:24]([O:26][CH2:27][CH2:28][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:2][CH2:3]1)(=[O:25])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCN1CCN(CCCOc2cccc3c2CCC(=O)N3)CC1

Procedure:
20 grams of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril and 3 ml of ethyl 2-bromoacetate and 1.5 ml of triethylamine are mixed with 20 ml of dimethyl formamide at 50°-60° C. for 8 hours under stirring conditions. The reaction mixture is concentrated under reduced pressure and to the viscous residue thus obtained are added 30 ml of 2% sodium hydrogen-carbonate aqueous solution followed by extraction with chloroform. The chloroform layer is washed with water, dried and chloroform is removed by distillation. The residue is purified by silica gel chromatography and recrystallized from isopropanol to obtain 5-{3-[4-(2-acetyloxyethyl)piperazinyl]-propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 131°-132° C.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH:12]([C:20](=[O:22])[CH3:21])C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])ccc(O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To tert-butyl 2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate in dichloromethane from above was added further dichloromethane (123 l) followed by trifluoroacetic acid (158 kg) whilst maintaining the temperature at 25° C. The reaction was stirred for 20 hours. The mixture was distilled, removing 283 kg of distillate. Toluene (176 l) was added and the mixture distilled, removing 208 kg of distillate. Further toluene (176 l) was added and the mixture distilled, removing 133 kg of distillate. To the residue was added 7.4% w/w aqueous sodium hydroxide (˜705 kg) until the mixture was pH 10.5. The aqueous layer was separated and washed with toluene (250 l). The aqueous layer was diluted with water (250 l), heated to 40° C. and acetic acid (191.4 kg) added, reducing the pH from 10.1 to 3.8. The pH was then adjusted to 1 with 20% w/w sulphuric acid (˜315 kg). The mixture was cooled to 0° C. and seeded with 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one. Further water (600 kg) was added and the solid isolated by filtration. The filter cake was washed with water (300 l). The product was dried under vacuum (50 mbar) at 40° C. Yield: 56.0 kg, 74% based on 1,2,3-trifluoro-4-nitrobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21](O)[C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[C:19]([CH:34]([CH3:36])[CH3:35])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:37])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:44])CC)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([CH:21]([F:44])[C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)=[C:19]([CH:34]([CH3:36])[CH3:35])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:37])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Under argon, 159 mg (0.31 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]-methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 58A) are dissolved in 3.1 ml of toluene, 49 μl (0.37 mmol) of diethylaminosulfur trifluoride are slowly added at −78° C. and the mixture is stirred at −78° C. for 2 h. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, and dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase:cyclohexane/ethyl acetate 15:1). This gives 118 mg (74% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(OC)(C)(C)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:1])=[CH:3][CH2:4][CH:5]1[CH2:9][CH:10]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1=CCC(CC=O)C1(C)C
Solvent: COC(C)(C)C
Product: CCOC(=O)C=CCC1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a flame-dried 250 ml round bottom flask campholenic aldehyde (10.0 g, 65.7 mmol) and methyl tertiary-butyl ether (MTBE) (100 ml) were added to give a solution and the flask was slowly cooled to 0° C. in an ice water bath. (Carbethoxymethylene)triphenyl-phosphorane (22.8 g, 66.0 mmol) was slowly added to the solution. The reaction mixture was stirred at 0° C. for 20 min then stirred at room temperature for about 24 h. After the reaction was completed, the reaction mixture was reduced to half its volume in vacuo and 100 ml of hexanes was added. The flask containing the reaction mixture and hexanes was then placed in an ice bath for 30 min. The reaction mixture was then filtered through a plug of filter paper, celite, silica, and sand and washed three times, first with hexanes, then 9:1 and then 1:1 Hexanes/MTBE. The combined eluates were concentrated in vacuo and purifed via flash column chromatography (1:8 Hexanes/Ethyl Acetate (AcOEt)) to give ethyl 4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enoate (13.1 g, 89%) as an oil. The NMR data is indicated below.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:18]O>>[Cl:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:18])=[O:13]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)cc(O)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc(O)c1O
Temperature: 25 °C

Procedure:
A mixture of methanol (60 ml) and sulfuric acid (5.2 ml) was stirred at room temperature. 5-Chloro-2,3-dihydroxybenzoic acid (0.11 mol) was added. The reaction mixture was stirred and refluxed for 20 hours, and then poured out onto ice. The precipitate was filtered off, washed with water, and dried, yielding 18.48 g of methyl 5-chloro-2,3-dihydroxybenzoate (intermediate 9; mp: 102° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncccc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncccc2F)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
0.63 g of 5-(4-chlorophenyl)-4-(3-fluoro-2-pyridyl)-6-methyl-2H-pyridazin-3-one and 7.2 g of phosphorus oxychloride were mixed. The mixture was stirred for 1.5 hours on an oil bath of 120° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.64 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.51 g of 3-chloro-5-(4-chlorophenyl)-4-(3-fluoro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (16) of the present invention.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:34])[CH:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=O>C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[Cl:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:34])[CH:14]=[C:7]2[O:9][CH3:10]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: COc1cc(=O)[nH]c2ccc(Cl)cc12
Yield: 67.4 %

Procedure:
Methyl 5-chloro-2-(2-(triphenyl-λ5-phosphanyliden)-acetylamino)benzoate (3.8 g) was heated at 180° C. for 1 h. The reactant was suspended in chloroform and diisopropyl ether. Solids were collected by filtration and dried to obtain 6-chloro-4-methoxyquinoline-2(1H)-one (1.1 g). (3) A mixture of 6-chloro-4-methoxyquinoline-2(1H)-one (1.1 g), N,N-dimethylaniline (1 mL), and phosphorus oxychloride (4 mL) was stirred at 80° C. to 90° C. for 10 h. The reaction solution was added dropwise to ice water and extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, followed by addition of silica gel. The desiccant and silica gel were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 2,6-dichloro-4-methoxyquinoline (1.2 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.CCOC(C)=O>[CH2:22]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)[CH:13]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(OC)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of methyl6-methoxy-1H-indole-2-carboxylate (Compound 1, 1.0 g, 4.9 mmol) in DMF (10 ml) was added K2CO3 (2.0 g, 14.6 mmol) and benzyl bromide (0.87 ml, 7.3 mmol). The mixture was stirred at room temperature for 40 h and was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by crystallization from Et2O to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:7])#[CH:2]
Reactant: C#Cc1cccc(C(=O)Cl)c1
Reactant: CCNCC
Solvent: ClCCl
Product: C#Cc1cccc(C(=O)N(CC)CC)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 1.49 ml (14.4 mmol) of diethylamine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of diethyl ether, the ether layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=5/1 to 3/1) using silica gel to obtain 1.3 g of 3-ethynyl-N,N-diethylbenzamide which is a desired product as pale yellow liquid. (Yield: 92%)
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([C:16]2[O:22][C@H:21]3[C@H:18]([C:19](=[O:23])[NH:20]3)[N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH:24][CH2:25][C:26](=[O:35])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C([O-])(O)=O.[Na+]>O1CCCC1>[C:16]([NH:17][C@@H:18]1[C@@H:21]([O:24][CH2:25][C:26](=[O:35])[CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[NH:20][C:19]1=[O:23])(=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Reactant: CC(C)(C)OC(=O)CC(=O)CO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
30 ul of boron trifluoride etherate were added to a suspension of 216 mg (1.15 mmols) of (1R, 5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one and 400 mg (2.3 mmols) of freshly prepared tert.-butyl 4-hydroxyacetoacetate in 4 ml of anhydrous tetrahydrofuran at room temperature. After a short time a clear, light yellow solution formed, which was stirred for 0.5 hour at room temperature. It was then poured into dilute NaHCO3 solution. The mixture was extracted with methylene chloride, washed with water and dried over magnesium sulphate. After the solvent had been evaporated off in vacuo and the residue had been chromatographed on 60 g of silica gel (toluene:ethyl acetate 1:3), 128 mg (31%) of tert.-butyl 4-[3(R)-benzoylamino-2-azetidinon-4(R)-yloxy]acetoacetate were obtained as colorless crystals, melting point: 142° C., RF : 0.36 (toluene:ethyl acetate 1:4), [α]D20 =32.24° (0.955 percent in CHCl3).
Reaction SMILES: [CH3:1][NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[NH2:8][C:9]([CH3:50])([CH:47]([CH3:49])[CH3:48])[CH2:10][O:11][C@@H:12]1[C@@:19]2([CH3:44])[C@@H:20]3[CH2:21][CH2:22][C@H:23]4[C:32]([C@@:15]3([CH2:16][O:17][CH2:18]2)[CH2:14][C@H:13]1OC)=[CH:31][CH2:30][C@:29]1([CH3:33])[C@:24]4([CH3:43])[CH2:25][CH2:26][C@@:27]([C@H:38]([CH3:42])[CH:39]([CH3:41])[CH3:40])([CH3:37])[C@H:28]1[C:34]([OH:36])=[O:35]>>[NH2:8][C:9]([CH3:50])([CH:47]([CH3:49])[CH3:48])[CH2:10][O:11][C@@H:12]1[C@@:19]2([CH3:44])[C@@H:20]3[CH2:21][CH2:22][C@H:23]4[C:32]([C@@:15]3([CH2:16][O:17][CH2:18]2)[CH2:14][C@H:13]1[N:5]1[N:6]=[N:7][C:3]([NH:2][CH3:1])=[N:4]1)=[CH:31][CH2:30][C@:29]1([CH3:33])[C@:24]4([CH3:43])[CH2:25][CH2:26][C@@:27]([C@H:38]([CH3:42])[CH:39]([CH3:40])[CH3:41])([CH3:37])[C@H:28]1[C:34]([OH:36])=[O:35]
Reactant: CO[C@@H]1C[C@@]23COC[C@](C)([C@@H]2CC[C@H]2C3=CC[C@@]3(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]23C)[C@H]1OCC(C)(N)C(C)C
Reactant: CNc1nnn[nH]1
Product: CNc1nnn([C@@H]2C[C@@]34COC[C@](C)([C@@H]3CC[C@H]3C4=CC[C@@]4(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]34C)[C@H]2OCC(C)(N)C(C)C)n1

Procedure:
Employing a procedure analogous that described in the preceding Examples, but using N-methyl-1H-tetrazol-5-amine, the title compound was prepared from (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-(2-amino-2,3-dimethylbutoxy)-8-[(1R)-1,2-dimethylpropyl]-14-methoxy-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (prepared as described for Intermediate 6, but as a ˜1:1 mixture of diastereomers).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.Cl.[CH:20]1([N:23]([CH2:29][CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH:20]1[CH2:22][CH2:21]1)[CH2:29][CH3:30])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CCN(CCCCN)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12)C1CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine, N1-cyclopropyl-N1-ethylbutane-1,4-diamine HCl salt (Step 2) and diisopropyethylamine (4 eq), the title compound was obtained; MS (Found M+1=398).