Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:16])[CH:11]2[NH2:15])[C:8]=1[C:17]([O-:19])=[O:18])(=[O:4])[CH3:3].[C:20]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]O)=[CH:29][CH:28]=1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:20]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:18][C:17]([C:8]2[N:9]3[CH:12]([S:13][CH2:14][C:7]=2[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]3=[O:16])=[O:19])=[CH:29][CH:28]=1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)Oc1ccc(CO)cc1
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(N)C2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OCc2ccc(OC(=O)C(C)(C)C)cc2)N2C(=O)C(N)C2SC1

Procedure:
To a suspension of 6.6 mM of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt in 35 ml of dimethyl formamide (DMF) is added 2 equivalents of p-pivalyloxybenzyl alcohol followed by cooling to 0° C after which 7.2 mM of dicyclohexylcarbodiimide in 7.5 ml of DMF is added dropwise with stirring. The mixture is stirred at 0° C for one hour and an additional four hours at room temperature. The formed dicyclohexylurea is removed by filtration. The filtrate is diluted with chloroform, washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid p-pivalyloxybenzyl ester.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>CC(C)=O>[CH3:1][S:2][C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C[S-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: CSc1cc(C(F)(F)F)ccc1C#N
Temperature: 32.5 °C
Reaction time: 2.5 h

Procedure:
Sodium thiomethoxide (37 g of a 21% aqueous solution, 0.11M) was added during 2 hours to a solution of 2-chloro-4-trifluoromethylbenzonitrile (20.56 g, 0.099M) in acetone (34 g) with stirring at 30-35° C. After a further 2.5 hours at 30-35° C. and 3 hours at 60° C., a further addition of sodium thiomethoxide (3.4 g of a 21% aqueous solution, 0.01M) was made. The mixture was maintained at 60° C. for 2 hours, cooled and the organic phase evaporated to give 2-methylthio-4-trifluoromethylbenzonitrile (20.3 g), m.p.80° C. The yield of product was 91%, with a purity of 97%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:26]([Cl:25])[CH:27]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2NCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (3.49 g, 10 mmols), 3,4-dichlorobenzyl chloride (2.1 ml, 15 mmols), potassium carbonate (1.38 g. 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with brine, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give an oil of tert-butyl[3-[5-chloro-2-(3,4-dichlorobenzylamino)phenoxy]benzyl]carbamate (3.03 g, 59.8%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=2)O1>>[CH3:39][S:36]([NH:35][C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:34][CH:33]=1)(=[O:38])=[O:37]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NS(C)(=O)=O)cc3)ccn2c1=O

Procedure:
Methyl 8-(4-(methylsulfonamido)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (74 mg, 0.25 mmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-methane-sulfonamide (96 mg, 0.32 mmol). Compound precipitated from solution and was filtered off and dried in vacuum to afford the title compound 27 as a yellow solid (83 mg, 77%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@H:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:5].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=1[F:22])([OH:14])[CH:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of 0.69 g (3.0 mmol) of (R)-1-chloro-3-(tert-butyldimethylsilyloxy)butan-2-one in 5 mL of toluene was cooled to 0° C., and 5.3 mL (3.3 mmol) of a solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise over a period of 15 minutes. After the completion of the dropwise addition, stirring was continued for another 2 hours, and then 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added thereto, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 3). Thereby, the title compound was obtained in a yield of 94% ((2S,3R): (2R,3R)=90:10).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Br:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[Br:11][C:12]1[N:17]=[C:16]([NH:18][CH:5]=[O:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Br)n1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1cccc(Br)n1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
To acetic anhydride (1.5 mL) was added dropwise formic acid (0.73 mL) under ice-cooling, and the mixture was stirred at 55° C. for 45 min. The mixture was allowed to be warmed to room temperature, tetrahydrofuran (20 mL) was added thereto, and a solution of 6-bromopyridin-2-amine (1.00 g) in tetrahydrofuran (10 mL) was added dropwise thereto over 3 min under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and the obtained white solid was subjected to azeotropy with toluene, and washed with hexane to give the title compound (1.1 g).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1>O>[CH3:11][CH:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: CC1CNCCN1
Solvent: O
Product: CC1CN(c2ccc(C(N)=O)cc2)CCN1
Temperature: 100 °C
Yield: 87.9 %

Procedure:
A mixture of 4-fluorobenzamide (Aldrich; 2.432 g), (RS)-2-methylpiperazine (Aldrich; 4.247 g), and water (9 mL) is heated at 100° C. for 7 days. The mixture is then cooled to 41° C. and water is added. The solid is collected, washed with water and toluene and dried under reduced pressure to give 3.37 g of (RS)-4-(3-methylpiperazin-1-yl)benzamide; 1H NMR (CDCl3, CD3OD) δ 1.17, 2.48, 2.82, 2.94-3.15, 3.04, 3.68, 6.89, 7.73.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:26](=NOC)[C:27]#[N:28])=[C:20]([F:38])[CH:19]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][C:42]=1[NH:50][NH2:51]>>[CH2:33]([C:32]1[C:25]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:10]3[CH:11]=[C:12]([CH2:15][CH2:16][CH3:17])[CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:19][C:20]=2[F:38])=[C:26]([C:27]#[N:28])[N:50]([C:42]2[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[CH:45]=[CH:46][C:41]=2[Cl:40])[N:51]=1)[CH2:34][CH2:35][CH3:36]
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCCC(=O)C(Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(C)(C)C)cc1F)C(C#N)=NOC
Agent: Cl
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C#N)c1Cc1ccc(-c2cc(CCC)ccc2S(N)(=O)=O)cc1F

Procedure:
The reaction of 3-[[2'-(N-t-butylsulfamoyl)-3-fluoro-5'-n-propylbiphenyl-4-yl]methyl]-2-methoxyimino-4-oxooctanenitrile (from Step C) with 2-chloro-5-nitrophenylhydrazine hydrochloride according to the procedure of Example 1, Step G, yields the title compound.
Reaction SMILES: [N:1]([C@@H:4]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].Cl[C:19](=[CH2:22])[C:20]#[N:21]>O>[C:20]([C:19]1[N:3]=[N:2][N:1]([C@@H:4]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:22]=1)#[N:21]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N=[N+]=[N-]
Reactant: C=C(Cl)C#N
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)n1cc(C#N)nn1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
A mixture of ethyl 2-azido-4-phenyl-(2S)-butyrate (2.33 g) and 2-chloroacrylonitrile (1.75 g) in water (25 ml) is stirred at about 80° C. for 23 hours. After cooling, the product is extracted with toluene and purified by column chromatography (30 g of silica gel 60; eluent toluene). The purified product is obtained as a yellowish oil (yield 1.84 g; 65% of theory) and characterized by 1H-NMR spectrum (CDCl3). δ value: 1.29 (*H; t; J=7 Hz); 2.40-2.67 (4H, m); 4.20 (2H, q, J=7 Hz); 5.39 (1H, m); 7.10 (2H, dxd, J1=6.6 Hz, J2≦1.5 Hz); 7.24 (1H, txt, J1=6.6 Hz, J2≦1.5 Hz); 7.31 (2h, m); 8.21 (1H, s).
Reaction SMILES: [C:1]1([CH:11]=[C:12]2[CH2:17][C:16](=[O:18])[O:15][C:13]2=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:1]1([CH:11]=[C:12]([CH2:17][C:16](=[O:18])[NH:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Solvent: ClCCl
Product: O=C(CC(=Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
In 60 ml of dichloromethane were dissolved 3.00 g of the succinic anhydride and 1.52 g of phenethylamine, and the mixture was stirred for 2 hours at room temperature. The precipitated crystals were collected by filtration to obtain 4.02 g of 2-(1-naphthylmethylene)-3-(phenethylcarbamoyl)propionic acid as colorless crystals.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:17]>O>[Br:9][C:5]1[C:4]([CH3:10])=[N:3][C:2]([F:17])=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)nc(C)c1Br
Temperature: 90 °C
Yield: 36 %

Procedure:
To a suspension of 2-amino-5-bromo-4,6-dimethylpyridine (4.02 g, 20.0 mmol) in HBF4 (48% in water, 15 mL) cooled in an ice bath was added a solution of NaNO2 (1.73 g, 25.0 mmol) in water (5 mL). The reaction mixture turned clear, and 10 min later a precipitate was formed. The precipitate was collected by filtration, dried under vacuum and added to hot heptane (100 mL) pre-heated at 90° C. After heated at 90° C. for 2 h the mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to afford 3-bromo-2,4-dimethyl-6-fluoropyridine as a pale yellow solid (1.45 g, 36%). 1H NMR (CDCl3): δ 2.43 (s, 3H), 2.61 (s, 3H), 6.66 (d, 1H, J=3.0 Hz). 19F NMR (CDCl3): δ 3.24.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[F:23])[C:16]([O:18]C)=O)(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>C1COCC1>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[CH:20]=[CH:21][C:22]([F:23])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:11])[CH:14]=2)=[O:18])[CH:38]=[CH:37][N:36]=1
Reactant: COC(=O)c1ccc(F)c(NS(=O)(=O)c2cc(F)ccc2F)c1
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)n1)c1ccc(F)c(NS(=O)(=O)c2cc(F)ccc2F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of methyl 3-(2,5-difluorophenylsulfonamido)-4-fluorobenzoate (40 g, 116 mmol) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 406 mmol, 406 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (17.8 g, 139 mmol) in THF (50 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (300 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound of Step B (31 g, 60.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.72-13.77 (br, 1H), 8.57-8.61 (m, 0.4H), 8.38-8.42 (m, 1H), 8.13-8.19 (m, 0.4H), 7.97-8.02 (m, 1H), 7.78-7.82 (m, 0.4H), 7.57-7.63 (m, 1H), 7.52-7.57 (1.4H), 7.02-7.30 (m, 4.2H), 6.91-6.93 (m, 1H), 5.93 (s, 1H), 4.40 (s, 1H). MS (ES+): 442 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C(O)(=O)C>O>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:18]([CH2:17][C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[O:14][CH3:13])[C:5]2=[O:7]
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: COc1ccc(CN)c(OC)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)c(OC)c1
Temperature: 80 °C
Yield: 72.7 %

Procedure:
A mixture of 3-hydroxyphthalic anhydride (1.24 g, 7.6 mmol), 2,4-dimethoxybenzylamine (1.14 mL, 7.6 mmol) and acetic acid (5 mL) was heated at 80° C. for 24 hours. The mixture was allowed to cool and diluted with water (20 mL). The white solid was collected by filtration, washed well with water and dried to give the title compound (1.73 g, 73%). 1H NMR (DMSO-d6) 11.00 (1H, s), 7.62 (1H, dd), 7.29 (1H, d), 7.21 (1H, d), 6.90 (1H, d), 6.56 (1H, d), 6.43 (1H, dd), 4.59 (2H, s), 3.79 (3H, s), 3.72 (3H, s). MS: [M−H+] 314.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:5]1([N:4]2[CH2:3][CH2:2][O:1][C:19]2=[O:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCNc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCCN1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under N2, a solution of N-(2-hydroxyethyl)aniline (500 mg, 3.65 mmol) and triethylamine (1 mL, 7.29 mmol) in THF (2 mL) was added slowly to a solution of triphosgene (360 mg, 1.21 mmol) in THF (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for one hour. The reaction was then quenched with a saturated solution of sodium bicarbonate (4 mL) and extracted with methylene chloride (3×4 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (5%-35% EtOAc/CH2Cl2) gave 3-phenyl-1,3-oxazolidin-2-one. LCMS (ES) m/z 164.2 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22]>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(-n2cncn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(-n2cncn2)cc1)C(F)(F)F
Reaction time: 5 h

Procedure:
1.0 g of 4-[1,2,4]triazol-1-yl-phenol was dissolved in 10 ml of dichloromethane, and 1.72 ml of triethylamine was added thereto. 1.56 ml of Tf2O was added to the mixture and stirred for 5 hr. The reaction was terminated by using water, and the resulting mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cccc(Cl)c4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cccc(Cl)c4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-(4-(3-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (186.7 mg, 0.41 mmol, 1.00 equiv) and sodium hydroxide (82 mg, 2.05 mmol, 5.00 equiv) in tetrahydrofuran/MeOH (1:1) (25 mL) was placed in a 50-mL round bottom flask, stirred for 8 h at 50° C. in an oil bath, and then concentrated under vacuum. This resulted in 177.7 mg (95%) of 3-(4-(3-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.[NH2:25][CH:26]([CH2:30][CH3:31])[CH2:27][O:28][CH3:29]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:29][O:28][CH2:27][CH:26]([N:25]1[C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[C:7]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=4[CH3:20])[C:6]=3[N:5]=[C:4]([C:21]3[C:13]([CH3:14])=[CH:12][C:7]([CH3:8])=[CH:6][C:11]=3[CH3:2])[C:3]=2[CH:22]=[CH:23]1)[CH2:30][CH3:31]
Reactant: Cc1cc(C)c(-c2ccnc3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Reactant: CCC(N)COC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(COC)n1ccc2c(-c3c(C)cc(C)cc3C)nc3c(-c4c(C)cc(C)cc4C)ccnc3c21

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-8-mesityl-2-methyl[1,5]naphthyridine (200 mg, 0.557 mmol) in 2-amino-1-methoxybutane (2.0 mL) was stirred at 200° C. for four hours in a sealed tube. After evaporating, the residue was purified by silica gel column chromatography (30-50% ethyl acetate/hexane). Activated manganese dioxide (290 mg, 3.24 mmol) was added to a solution of the resulting product (130 mg, 0.33 mmol) in toluene (20 mL) and the mixture was heated under reflux for one day. After filtering through Celite, the mixture was evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (108 mg) as white crystals.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CN(C)CCN(C)C.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1.CCCCCC>[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH:30]=[O:31])=[CH:12][CH:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccs2)OCCO1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(c2ccc(C=O)s2)OCCO1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of commercially available 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (5.00 g, 28.49 mmol) in THF (145.0 mL) at −78° C. was added dropwise N,N,N′,N′-tetramethyl-ethylendiamine (4.41 mL, 29.06 mmol) followed by n-BuLi (18.14 mL of a 1.6M solution in hexane, 29.06 mmol), maintaining the temperature at −78° C. The reaction mixture was then stirred for 2 h at −78° C. before DMF (6.74 mL, 87.22 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 16 h. The reaction mixture was poured on sat. aq. NaH4Cl (200 mL) and extracted with EA (2×200 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-2-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.87 min; [M+AcCN]+=240.32. The crude material was dissolved, under inert atmosphere (N2) in MeOH (51.2 mL) and treated at 0° C., portionwise, over 20 min, with NaBH4 (1.35 g, 34.19 mmol in five equal portions). The reaction mixture was stirred for 45 min at rt. The reaction mixture was poured on water (90 mL) and the aq. layer was extracted with EA (2×225 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound: TLC:rf (50:50 hept-EA)=0.40. LC-MS-conditions 02: tR=0.73 min; [M+H]+=201.46.