Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C[C:5]1([CH:12]=[CH2:13])[CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6]1)([O-])=O.C(O)(=[O:16])C.N([O-])=O.[Na+].Cl.CN(C)[CH:25]=[O:26]>>[CH:12]([C:5]1([C:25]([OH:26])=[O:16])[CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6]1)=[CH2:13]
Reactant: CN(C)C=O
Reactant: C=CC1(C[N+](=O)[O-])COCCOC1
Reactant: CC(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: C=CC1(C(=O)O)COCCOC1
Temperature: 40 °C
Yield: 40 %

Procedure:
To a stirred solution of 6-nitromethyl-6-vinyl-[1,4]dioxepane (214 mg, 1.14 mmol) in N,N-dimethylformamide (5 mL) under nitrogen was added acetic acid (684 mg, 652 μL, 11.4 mmol) and sodium nitrite (237 mg, 3.43 mmol). The mixture was heated at 40° C. for 23 h and allowed to cool. The mixture was acidified to pH 1 with hydrochloric acid (2 M) and the aqueous layer was extracted with diethyl ether (3×). The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, filtered, evaporated. Residual N,N-dimethylformamide was azeotroped off with toluene to give the title compound (79 mg, 40%) as a yellow gum. The original aqueous layer was saturated with sodium chloride and extracted with diethyl ether (3×) and the combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. Residual N,N-dimethylformamide was azeotroped off with toluene to give the title compound (22 mg, 11%) as a yellow gum. The two gums were finally combined (101 mg, 51%). 1H NMR (300 MHz, CDC3) δ 3.76-3.93 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.35 (d, J=12.7 Hz, 2H), 5.26 (d, J=17.8 Hz, 1H), 5.27 (d, J=10.9 Hz, 1H), 5.79 (dd, J=17.4, 10.9 Hz, 1H). LCMS (m/z) 195.2 [M+Na], Tr=0.96 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:39])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[S:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:39])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])=[CH:34][CH:33]=3)[S:20]([C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c2ccc(O)cc2)cc1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc(N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 43 %

Procedure:
A solution of the product of Step 3 (15.9 mg, 0.023 mmol), potassium carbonate (13.6 mg, 0.098 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (8.5 mg, 0.041 mmol) in dimethylformamide (1.0 ml) was heated at 70° C. overnight. The reaction was diluted with EtOAc and washed with water several times, then brine. Column chromatography in 100% DCM (+0.2% TEA)-1% MeOH/DCM (+0.2% TEA) gave the pure product. Yield=43%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH2:13]([NH:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH2:18][CH:19]=[O:20])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Reactant: C=CCNCCC=O
Solvent: c1ccccc1
Product: C=CCN(CCC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-allylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-allyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:18])[CH2:9][CH2:8][C:7]2[C:10]([CH3:17])=[C:11]([OH:16])[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1.[CH3:19][NH:20][CH3:21].O.[ClH:23]>CN(C)C=O.C(O)(C)C>[ClH:23].[CH3:19][N:20]([CH3:21])[CH2:2][CH2:3][C:4]1([CH3:18])[CH2:9][CH2:8][C:7]2[C:10]([CH3:17])=[C:11]([OH:16])[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1
Reactant: CNC
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCBr)O2
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN(C)C)O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 12.53 g of 3,4-dihydro-2-(2-bromoethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol and liquid gaseous dimethylamine in 50 ml of dimethylformamide is stirred at room temperature for 16 hours. Water is added and the product is extracted with ethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. One equivalent of hydrochloride acid in isopropanol is added and the resulting precipitate is recrystallized twice from isopropanol/water to yield 9.44 g of the title compound, mp 300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH2:18][CH3:19])[CH3:17])[O:12][C:11]1=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]#[CH:29]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9][CH2:29][C:28]#[CH:27])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH2:18][CH3:19])[CH3:17])[O:12][C:11]1=[O:20]
Reactant: C#CCBr
Reactant: CCC(C)=C1OC(=O)N(c2cc(O)c(Br)cc2F)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(N2C(=O)OC(=C(C)CC)C2=O)c(F)cc1Br
Yield: 76.6 %

Procedure:
To an acetonitrile solution (25 ml) of 3-(2'-fluoro-4'-bromo-5'-hydroxyphenyl)-5-(sec-butylidene)-1,3-oxazolidine-2,4-dione (0.26 g, 0.82 mmol) was added potassium carbonate (0.11 g) and the mixture was heated at reflux for 1 hour. After the addition of propargyl bromide (0.1 g, 0.83 mmol), the reaction mixture was further refluxed for 1 hour. 3-(2'-fluoro-4'-bromo-5'-propargyloxyphenyl)-5-(sec-butylidene)-1,3-oxazolidine-2,4-dione (0.24 g, 77% yield) was obtained by an operation similar to that of Example 1.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:9](=O)[C:8]=2[CH:7]=[CH:6]1)(=[O:4])=[O:3].[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:9]1[CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]1=2)[C:21]([NH2:23])=[NH:22]
Reactant: CS(=O)(=O)n1ccc2c1CC(c1ccccc1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)n1ccc2c1CC(c1ccccc1)CC2=NNC(=N)N
Yield: 77.7 %

Procedure:
A mixture of 1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.40 g), aminoguanidine hydrochloride (0.17 g), concentrated hydrochloric acid (0.069 ml), water (0.069 ml) and ethanol (40 ml) was refluxed for 20 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water, dried and recrystallized from ethanol to give 4-guanidinoimino-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 12) (0.41 g) as colorless crystals.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](OC(=O)C)(=O)[CH3:12].C(=O)(O)[O-].[Na+]>>[CH3:11][C:12]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2ccccc2c(=O)o1

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compounds (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 2,5-dihydroxy benzaldehyde (30c, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4c) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [Cl-].[Li+].[C:3](=[C:6]([CH2:24][CH2:25]Cl)[CH2:7][C:8]1(C(OC)=O)[CH:13]([CH3:14])[CH2:12][C:11]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:10][C:9]1=[O:19])([CH3:5])[CH3:4].O>CN(C)P(=O)(N(C)C)N(C)C>[C:3](=[C:6]1[CH2:24][CH2:25][C:8]2([CH:13]([CH3:14])[CH2:12][C:11]([O:15][CH:16]([CH3:17])[CH3:18])=[CH:10][C:9]2=[O:19])[CH2:7]1)([CH3:4])[CH3:5]
Reactant: COC(=O)C1(CC(CCCl)=C(C)C)C(=O)C=C(OC(C)C)CC1C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C)=C1CCC2(C1)C(=O)C=C(OC(C)C)CC2C
Temperature: 130 °C
Yield: 81.9 %

Procedure:
Dry lithium chloride (3.8 g, 0.09 mol) and methyl 1-(2-isopropylidene-4-chlorobutyl)-2-oxo-4-isopropoxy-6-methyl-3-cyclohexene carboxylate (21.3 g, 0.06 mol) were mixed in anhydrous hexamethylphosphoric triamide (120 mL) under nitrogen. The solution was heated at 130° C. for 40 minutes and after cooling was poured into water (300 mL). The mixture was extracted with ether and the extract dried (Na2SO4). Solvent removal gave 15.2 g of crude spiroketones 1 and 2 (glc purity of 93%, spiroketones separated on HPLC). Crystallization from petroleum ether gave 12.9 g of 2-isopropylidene-8-isopropoxy-10-methylspiro[4.5]dec-7-en-6-one isomer 1 exclusively, mp 77°-77.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:17][C:18]([O:20][CH3:21])=[O:19])#[N:5]
Reactant: N#Cc1ccccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To the mixture of 2-hydroxybenzonitrile (40 g, 0.34 mol) and potassium carbonate (51.6 g, 0.374 mol) in 850 mL of acetone was added methyl bromoacetate (51.7 g, 0.34 mol) slowly at room temperature. After being stirred at room temperature overnight, the solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with water then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was recrystallized in methanol to give 40 g of product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:18]1(=[O:30])=[O:29])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Mg]Br>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]([OH:13])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[S:18](=[O:29])(=[O:30])[N:19]([CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:20](=[O:22])[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccccn1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=O)cc2OCc2ccccc2)S1(=O)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C(O)c3ccccn3)cc2OCc2ccccc2)S1(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzaldehyde (Example 81, step B) (75 mg, 0.17 mmol) in anhydrous THF (4 mL) at −78° C. is added dropwise 2-pyridyl magnesium bromide (0.25M in THF, 1.36 mL, 0.34 mmol). The reaction is stirred at −78° C. for 1 h, then is quenched with saturated NH4Cl. The mixture is extracted with EtOAc and the organic phase is dried over MgSO4. The solvent is removed under reduced pressure and the crude material is purified by column chromatography using a gradient of 0-50% EtOAc/hexane to afford the title compound as a colorless oil: (M−H)−=526.
Reaction SMILES: C(N(CC)CC)C.CC[C:10]([C:12](Cl)=[O:13])=O.[NH:15]([C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)[NH2:16].[O:31]1CCO[CH2:33][CH2:32]1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:18]([C:33]([C:32]([O:13][CH2:12][CH3:10])=[O:31])=[N:16][N:15]=3)[N:19]=2)=[CH:24][CH:25]=1
Reactant: C1COCCO1
Reactant: CCC(=O)C(=O)Cl
Reactant: COc1ccc(-c2ccc(NN)nn2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nnc2ccc(-c3ccc(OC)cc3)nn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
2.09 ml (15.0 mmol) of triethylamine and 1.23 ml (11.0 mmol) of ethyloxalyl chloride were added to a dioxane solution (20 ml) of 2.16 g (10.0 mmol) of 3-hydrazino-6-(4-methoxyphenyl)pyridazine, obtained according to the method described in Journal of Medicinal Chemistry, Vol. 30, pp. 239-249 (1987), and the reaction liquid was stirred at 60° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, and acetic acid (10 ml) was added to the resulting residue and stirred at 120° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/4) to obtain 615 mg (yield: 21%) of ethyl 6-(4-methoxyphenyl)[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]1[O:10][CH2:9]1>C(O)C>[CH2:12]([O:11][CH2:7][CH:8]([OH:10])[CH2:9][NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCOCC1CO1
Reactant: COCCCN
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOCC(O)CNCCCOC
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a 2-l flask equipped with a stirrer, a dropping funnel, a nitrogen gas inlet tube and a distillation apparatus, 743.2 g (8.34 mol) of 3-methoxypropylamine (5-a) and 150 ml of ethanol were charged, followed by the dropwise addition of 165.9 g (0.56 mol) of hexadecyl glycidyl ether (4-a) over 3 hours while stirring under heating to 80° C. in a nitrogen atmosphere. After the completion of the dropwise addition, stirring was conducted for further 2 hours at 80° C. From the reaction mixture, ethanol and excessive 3-methoxypropylamine were distilled off by heating under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 196.5 g of the title compound (6-a) were obtained in the form of a white solid (yield: 91% relative to hexadecyl glycidyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[NH2:27][CH:28]([C:34]([CH3:36])=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>ClCCl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]1[O:8][C:34]([CH3:36])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:27]=1
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(C=Cc2ccccc2Cl)oc1C
Temperature: 25 °C

Procedure:
To a suspension of o-chlorocinnamic acid (9.1 g) in dichloromethane (200 ml) was added triethylamine (21 ml) for dissolution. With cooling with ice-sodium chloride and stirring, ethyl chlorocarbonate (5.0 ml) was added dropwise to the above-obtained solution, and the mixture was further stirred for 10 minutes. To the resulting mixed acid anhydride solution was added portionwise ethyl 2-aminoacetoacetate hydrochloride (9.05 g) and the mixture was stirred under cooling for 20 minutes and at room temperature for 40 minutes. The reaction mixture was washed with diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate and water in that order and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was dissolved in toluene (100 ml). Phosphorus oxychloride (14 ml) was added and the mixture was refluxed for an hour. The solvent and phosphorus oxychloride were distilled off under reduced pressure, and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was treated with isopropyl ether to give ethyl 2-(2- chlorostyryl)-5-methyl-4-oxazolecarboxylate as crystals; yield 6.4 g (44.1%). Recrystallization from ethanol gave yellow prisms melting at 99°-100° C.
Reaction SMILES: [OH-:1].[K+].C([N:11]1[CH2:24][CH2:23][C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:14]=2[CH2:13][CH2:12]1)(=O)C1C=CC=CC=1.Cl.[OH2:33]>C1COCC1>[C:26]([OH:33])(=[O:1])[C:27]([OH:29])=[O:28].[CH:20]1[C:21]2[C:22]3[CH2:23][CH2:24][NH:11][CH2:12][CH2:13][C:14]=3[N:15]3[C:16]=2[C:17]([C:27](=[O:28])[CH2:26][CH2:25]3)=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCn1c2c(c3ccccc31)CCN(C(=O)c1ccccc1)CC2
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C(=O)O
Product: O=C1CCn2c3c(c4cccc1c42)CCNCC3
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
A solution of potassium hydroxide (0.80 g, 14.3 mmol) in H2O (20 mL) was added to a solution of ethyl 3-(3-benzoyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanoate (4.25 g, 10.9 mmol) in THF (30 mL). The reaction mixture was heated at 60° C. for 1 h, then cooled to room temperature, acidified with 10% aqueous HCl, and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, decanted, and concentrated under reduced pressure to give 3.73 g of crude acid. The crude acid (2.00 g, 5.52 mmol) was then added to neat PPA (18.6 g) stirring at 100° C. under N2. After 1.5 h, the reaction was cooled to room temperature, quenched with ice and 10% aqueous NaOH, and then extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with EtOAc/hexanes (gradient 1:1 to 2:1) to give 0.81 g (43%) of the title compound as a yellow solid (mp 177.5-181° C.). 1H NMR (d-DMSO) δ 7.75, 7.46, 7.09, 4.45-4.24, 3.93, 3.61, 3.34, 3.17, 3.11-2.80; IR (drift) 1676, 1628, 1587, 1493, 1483, 1466, 1428, 1357, 1324, 1295, 1276, 1266, 1191, 754, 706 cm1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28](Cl)=[O:29]>ClCCl.CN(C)C=O>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:28]([C:24]2[S:25][CH:26]=[CH:27][C:23]=2[Cl:22])=[O:29])[CH:11]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: COC(=O)c1ccc(Cl)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1NC(=O)c1sccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-amino-4-chlorobenzoate (200 mg, 1.1 mmol) and diisopropylethylamine (285 μL, 1.6 mmol) were dissolved in a solution of dichloromethane (4 mL) and dimethylformamide (2 mL). 3-Chlorothiophene-2-carbonyl chloride (235 mg, 1.3 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was re-dissolved in 25 mL of ethyl acetate. The reaction mixture was washed one time each with 10 mL portions of water, 0.1 M NaOH, and saturated aqueous NaCl. The organic layer was dried with MgSO4 and 90 mg of solid was precipitated by the addition of hexanes. The material was used without further purification. MS (EI) for C13H9Cl2NO3S: 330 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[C:12](C(N)=O)[CH:11]=1)([CH3:9])[O:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[C:21](N1C=CN=C1)([N:23]1C=C[N:25]=[CH:24]1)=[O:22].N12CCCN=C1CCCCC2.Cl.[OH2:45]>O1CCCC1>[F:19][C:2]([F:20])([F:1])[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:24]2[NH:25][O:45][C:21](=[O:22])[N:23]=2)[CH:11]=1)([CH3:9])[O:4][Si:5]([CH3:7])([CH3:6])[CH3:8]
Reactant: O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(O[Si](C)(C)C)(c1ccnc(C(N)=O)c1)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(O[Si](C)(C)C)(c1ccnc(-c2nc(=O)o[nH]2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4 ml of tetrahydrofuran were added 0.5 g of 4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridine-2-carboxamide=oxime and 0.42 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Thereafter, 0.4 g of 1,8-diazabicyclo[5,4,0]undec-7-ene was added at 0° C., and the mixture was stirred at room temperature for 4 hours. To the reaction solution were added water and 10% HCl, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.43 g of 3-{4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridin-2-yl}-1,2,4-oxadiazol-5-one (present compound (61)).