Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][NH:3][C:4](=[S:7])[NH:5][NH2:6].[C:8]([O:15]CC)(=O)[C:9](OCC)=[O:10]>C(O)C>[SH:7][C:4]1[N:3]([CH3:2])[C:9](=[O:10])[C:8]([OH:15])=[N:6][N:5]=1
Reactant: CNC(=S)NN
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: Cn1c(S)nnc(O)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 22 liter (l.) flask containing 12.5 l. of anhydrous ethanol maintained in a nitrogen atmosphere were slowly added 230 g. of sodium. The mixture was maintained at room temperature overnight, a slow, but constant, stream of nitrogen being admitted to the flask. The mixture then was heated to 50° C., and 1050 g. (10 mole) of 4-methylthiosemicarbazide were added. The temperature of the mixture fell to 40° C. To the mixture were then added 1530 g. of diethyl oxalate through a funnel. Addition was at a rate sufficient for the reaction mixture to attain a temperature of from about 60° C. to about 65° C. The temperature of the resulting mixture rose to 65° C. The mixture was refluxed with stirring for four hours during which time a precipitate formed. The precipitate changed in appearance during the period of reflux. Upon discontinuing heating and stirring, the white solid grandually settled to the bottom of the flask leaving a clear light yellow supernatant liquid. The mixture was allowed to stand overnight. The bulk of the clear supernatant was removed by suction, and the white crystalline product in the form of its sodium salt was removed from the residual mixture by filtration and washed with dry ethanol.
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH2:9])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11]>CC[O-].[Na+]>[NH2:11][C:10]1[N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:7](=[O:8])[NH:9][C:13](=[O:14])[CH:12]=1
Reactant: CC(C)(C)CNC(N)=O
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Product: CC(C)(C)Cn1c(N)cc(=O)[nH]c1=O

Procedure:
N-neopentylurea (13.0 g, 0.1 mol) and ethyl cyanoacetate (10 ml) were heated in 4N NaOEt (100 ml) for 4 hours under reflux. The reaction mixture was evaporated to dryness, the residue treated with water (100 ml) and then acidified with AcOH to pH 4–5 to form a colorless precipitate. Yield: 11.2 g (59%).
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH:8]1[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH2:9]1.Cl.[CH2:17]([OH:20])[CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][O:20][CH:8]1[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH2:9]1
Reactant: OCCO
Reactant: BrC1Cc2ccccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: OCCOC1Cc2ccccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 56.1 g of potassium t-butoxide, 150 ml of ethylene glycol was dropwise added in a stream of nitrogen to dissolve potassium t-butoxide completely. To the solution, 45.3 g of 1-bromobenzocyclobutene (synthesized according to a method of DeCamp et al., J. Org. Chem., 1981, 46, 3918) was dropwise added. After the addition was completed, the mixture was heated to 80° C., and stirred for 8 hours. The mixture was cooled to room temperature, and poured into ice-cold water. After adjusting pH to 6 with hydrochloric acid, an organic phase was extracted with ethyl acetate. After the solvent was distilled away, the residue was purified in a silica gel chromatography to obtain 20.6 g of 1-(2′-hydroxyethoxy)-benzocyclobutene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([CH3:22])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16]OS(C)(=O)=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[C:7]([CH3:8])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:28]2[C:27](=[O:29])[C:26]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]3[C:24]2=[O:34])[N:14]=1)[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOS(C)(=O)=O)cs1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN2C(=O)c3ccccc3C2=O)cs1
Temperature: 85 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
2-Methyl-2-[(4-{2-[(methylsulfonyl)oxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid tert-butyl ester (123 g) synthesized in Example 5 was dissolved in N,N-dimethylformamide (800 mL), potassium phthalimide (59.7 g) was added thereto and the mixture was stirred for 2 hr at 85° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (136 g) as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:23]#[N:24])[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])C>C(O)CCC>[NH2:24][C:23]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Br:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18]
Reactant: C=CCOC(=O)C(C#N)=COCC
Reactant: NNc1c(Cl)cc(Br)cc1Cl
Solvent: CCCCO
Product: C=CCOC(=O)c1cnn(-c2c(Cl)cc(Br)cc2Cl)c1N

Procedure:
20.5 parts by weight of 2,6-dichloro-4-bromophenylhydrazine and 14.5 parts by weight of allyl ethoxymethylene-2-cyanoacetate in 100 parts by volume of n-butanol were refluxed for 4 hours. The butanol was evaporated off, the oily residue was dissolved in 150 parts by volume of ether, and dry halogen chloride gas was passed in, with ice-cooling. The hydrochloride which had precipitated was stirred with saturated sodium bicarbonate solution, and the precipitate was filtered off with suction and dried under reduced pressure to give 24.8 parts by weight of allyl 5-amino-1-(2,6-dichloro-4-bromophenyl)-pyrazole-4-carboxylate of melting point 85° C. (active ingredient No.6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Cl[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=2)[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=3)[CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc2cc(CCl)ccc2c1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1ccc2cc(CN3C(=O)CCCC3c3c(OC)cccc3OC)ccc2c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(chloromethyl)-6-methoxynaphthalene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.80 min.; [M+H]+: 406.18 g/mol.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O.O>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[C:9]([CH3:36])=[N:8][C:7]([N:39]5[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:12][CH:11]=4)[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:30])([F:29])[F:31])=[CH:23][CH:24]=1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N2CCCCC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 7 h
Yield: 167.4 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (102.1 mg, 0.172 mmol) in N,N-dimethylformamide (1.5 mL) was added piperidine (85.0 μL, 0.858 mmol). The reaction mixture was stirred, at 80° C. for 7 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (78.7 mg, 0.288 mmol, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([Br:22])[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2].[CH:25]1([CH2:28]O)[CH2:27][CH2:26]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:28][CH:25]3[CH2:27][CH2:26]3)[CH:18]=[C:17]([Br:22])[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(Br)c2)cc1C
Reactant: OCC1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC3CC3)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (1.0 g; 2.43 mmol), cyclopropylcarbinol (175 mg; 2.43 mmol) and tributylphosphine (1.07 mL; 4.38 mmol) was dissolved in THF (100 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (1.1 g; 4.38 mmol) dissolved in THF (20 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was filtered, evaporated to dryness and purified by flash chromatography (ethyl acetate:heptane 1:9→2:3). Yield: 980 mg; 86%; HPLC-MS: m/z: 465.0 (M)+; Rt: 2.74 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:11])[CH2:9]O.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12>>[O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[CH2:11][N:35]1[C:31](=[O:41])[C:32]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:33]2[C:34]1=[O:36]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](CO)CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@H](CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O

Procedure:
Thereafter, (25R)-16-oxo-26-hydroxycholesterol (9) is converted to (25R)-16-oxo-26-hydroxycholesterol-26-tosylate (8) directly or indirectly by solvolysis of a (25R)-16-oxo-26-hydroxycholesterol-3β,26--ditosylate (7). Intermediate (8) is then subjected to displacement reaction with a phthalimide salt to form (25R)-16-oxo-26-phthalimidocholesterol (5). The reaction conditions and reagents for effecting all these conversions are the same as described above.
Reaction SMILES: [OH-].[Na+].[CH3:3][SH:4].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8]>CO.O1CCCC1>[CH3:3][S:4][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: CS
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSCC(=O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To 11.3 g (141 mmole) of 50% aqueous sodium hydroxide dissolved in 50 ml of methanol and cooled to -20° C. was added 7.7 g (160 mmole) of gaseous methyl mercaptan. To this solution was added 30.5 g (130 mmole) of 2-bromo-4'-chloroacetophenone dissolved in 40 g of tetrahydrofuran. After warming to room temperature and stirring for 30 minutes the mixture was concentrated in vacuo, partitioned between hexanes and water, dried over anhydrous magnesium sulfate, filtered, and reconcentrated in vacuo to yield 25.3 g of 2-methylthio-4'-chloroacetophenone, an oil.
Reaction SMILES: [CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].[CH3:11][SiH:12]([N:14](Cl)[C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13]>C1COCC1>[CH3:11][SiH:12]([N:14]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13]
Reactant: C[SiH](C)N(Cl)C(C)(C)C
Reactant: c1ccc2[cH-]ccc2c1
Agent: [Li+]
Solvent: C1CCOC1
Product: C[SiH](C)N(C1C=Cc2ccccc21)C(C)(C)C
Reaction time: 6.5 h
Yield: 73.6 %

Procedure:
Lithium indenide (1.73 g, 0.014 moles) in THF (50 mL) was added drop wise to a solution of dimethylsilyl(t-butylamino)chloride (3.53 g, 0.021 moles) in THF (75 mL). This mixture was allowed to stir for 6.5 hrs. And the volatile materials were removed. The residue was extracted and filtered using hexane. Removal of the hexane resulted in the isolation of the desired product as an oil (2.53 g, 74.3% yield).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][O:13][C:14]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[OH:17][CH:16]([C:15]1[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:14]=1[O:13][CH3:12])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(OC)c(OC)c1OC
Reaction time: 0.17 h

Procedure:
A solution of 3.4 ml (40 mmol) of methyl propiolate in 30 ml of tetrahydrofuran was treated at -78° under argon with 25 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 7.85 g (40 mmol) of 2,3,4-trimethoxybenzaldehyde in 40 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was brought to room temperature, stirred for 15 minutes and treated with 60 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(2,3,4 -trimethoxyphenyl)-2-butynoate as a red oil.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C(O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]([N+:1]#[C-:2])=[CH:11][N:12]([CH3:14])[CH3:13])[CH3:8]
Reactant: COC(OC)N(C)C
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CCO
Product: [C-]#[N+]C(=CN(C)C)C(=O)OCC

Procedure:
4-carboalkoxythiazoles are prepared essentially according to the procedure of Schollkopf, U., Porsch, P., Lau, H. Liebigs Ann. Chem. 1444 (1979). Thus, according to Method 55 and 56, reaction of ethyl isocyanoacetate with N,N-dimethylformamide dimethyl acetal in a suitable alcoholic solvent such as ethanol at room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester. A solution of this compound in a suitable solvent such as tetrahydrofuran is treated with gaseous hydrogen sulfide in the presence of a suitable tertiary amine base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole.
Reaction SMILES: O.[NH2:2]N.C[N:5](/[CH:7]=[N:8]/[C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([I:17])[CH:11]=1)C>C(O)(=O)C>[I:17][C:12]1[CH:11]=[C:10]([C:9]2[NH:8][CH:7]=[N:5][N:2]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(C(=O)/N=C/N(C)C)cc1I
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2nnc[nH]2)cc1I
Temperature: 90 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Hydrazine monohydrate (0.30 g, 6.0 mmol) was added to a stirred solution of (E)-N-((dimethylamino)methylene)-3-iodo-4-methylbenzamide (preparation 48b, 1.20 g, 3.8 mmol) in acetic acid (6 mL) and the mixture was stirred and heated to 90° C. After 2 hours, the mixture was concentrated in vacuo and water and 2N aqueous sodium hydroxide solution were added to the residue. The solid that formed was filtered, washed with water and dried in vacuo to give the title compound (0.98 g, 91%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:16][N:14]1[CH:15]=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:26][C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)[CH:8]=2)[N:12]=[CH:13]1
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4)c3s2)c1
Temperature: 190 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 224 (950 mg, 3.81 mmol), 4-nitrophenol (795 mg, 5.72 mmol), K2CO3 (1.05 g, 7.62 mmol) and Ph2O (5 mL) was stirred at 190° C. for 2 h in a sealed tube, cooled and treated with additional amount of 4-nitrophenol (795 mg, 5.72 mmol). The mixture was stirred for another hour at the same conditions, cooled to room temperature and diluted with DCM. The DCM solution was extracted with 2N HCl; the aqueous phase was collected, basified with concentrated ammonium hydroxide solution (pH˜11) and extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 225 (860 mg, 64% yield) as an orange solid. MS (m/z): 353.1 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.[N+](C1C=C(S(O[CH2:46][C@H:47]2[CH2:49][O:48]2)(=O)=O)C=CC=1)([O-])=O>>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH3:20])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH2:46][C@H:47]4[CH2:49][O:48]4)[CH3:21])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H]2CO2)c1=O

Procedure:
Prepared from N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)pyrazinyl]-4-methyl-benzamide (Example 252j) and (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate, using a similar method to that described in Example 299a.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[N:26]([CH2:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]2[N:39]=[C:38]([C@@H:40]3[CH2:44][CH2:43][CH2:42][NH:41]3)[NH:37][C:36]=2[CH:45]=1)=[O:31])=[N+:27]=[N-:28].Cl.[CH3:47][N:48]([CH3:59])[C@H:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:50](O)=[O:51].CCN(C(C)C)C(C)C>CN(C)C=O>[N:26]([CH2:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]2[N:39]=[C:38]([C@@H:40]3[CH2:44][CH2:43][CH2:42][N:41]3[C:50](=[O:51])[C@H:49]([N:48]([CH3:47])[CH3:59])[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[NH:37][C:36]=2[CH:45]=1)=[O:31])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NCC(=O)c1ccc2nc([C@@H]3CCCN3)[nH]c2c1
Reactant: CN(C)[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@@H](C(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CN=[N+]=[N-])cc2[nH]1)c1ccccc1
Reaction time: 6 h
Yield: 50.1 %

Procedure:
To a solution of J.31 (1.8 g, 4.86 mmol) in ethyl acetate (5 mL) was added HCl/dioxane (10 mL of 4N), and the reaction was stirred 4 hr. The solvents were removed in vacuo, and the HCl salt was exposed to high vacuum for 18 h to give (S)-2-azido-1-(2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone.2HCl a yellow solid. HATU (1.94 g, 5.10 mmol) was added to the HCl salt of (S)-2-azido-1-(2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone (1.8 g, 4.86 mmol), (R)-2-(dimethylamino)-2-phenylacetic acid HCl salt (1.05 g, 4.86 mmol), and Hunig's base (3.4 mL, 19.4 mmol) in dimethylformamide (50 mL) while being rapidly stirred 6 h. The solvent was removed in vacuo and the reside was partitioned into two lots and separately pre-absorbed onto SiO2 (dichloromethane), and subjected to flash chromatography on a 40 M Biotage silica gel column pre-equilibrated 2% B, and eluted with 2% B (150 mL); Segment 2: 2-40% B (1200 mL); Segment 3: 40-80% (600 mL). A=dichloromethane; B=25% methanol/dichloromethane to give J.31a (R)-1-((S)-2-(6-(2-azidoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-(dimethylamino)-2-phenylethanone (combined lots: 1.05 g (50%)) as a yellow foam. 1H NMR (500 MHz, DMSO-d6) δ: 8.16 (s, 1H), 7.82 (dd, J=8.8, 1.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.60-7.56 (m, 5H), 5.51 (s, 1H), 5.22 (dd, J=8.2, 2.8, 1H), 4.95 (m, 2H), 4.09-4.05 (m, 1H), 3.17-3.12 (m, 1H), 2.90/2.84 (br. s, 6H), 2.23-2.19 (m, 1H), 2.21-1.89 (m, 3H). LC (D-Cond. 1): RT=1.5 min; LC/MS: Anal. Calcd. for [M+H]+ C23H26N7O2: 432.22; found: 431.93. HRMS: Anal. Calcd. for [M+H]+ C23H26N7O2: 432.2148; found: 432.2127.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]#[N:24])=[CH:18][C:17]=1[NH:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]#[N:24])=[CH:18][C:17]=1[NH:25][C:26](=[O:27])[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCOC(=O)Nc1cc(C#N)cc(C)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOC(=O)Nc1cc(C#N)cc(C)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl t-butoxycarbonyl(4-cyano-2-(((heptyloxy)carbonyl)amino)-6-methylphenyl)carbamate (416 mg, 0.85 mmol) obtained in Step 3 was dissolved in CH2Cl2 (3.0 mL), added with TFA (1.95 mL, 30 eq, 25.5 mmol) and stirred at room temperature for 2 hours. Subsequently, the mixture thus obtained was added with sat. NaHCO3 and extracted with CH2Cl2. The organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure to obtain the title compound in a white solid (245 mg, yield: 99%).
Reaction SMILES: Cl[C:2]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([Cl:28])[C:22]([F:29])=[CH:21][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C@@H:14]([CH3:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[C:17]([O:16][CH2:15][C@@H:14]([N:13]1[C:2]2[C:3](=[CH:21][C:22]([F:29])=[C:23]([Cl:28])[C:24]=2[N+:25]([O-:27])=[O:26])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]1)[CH3:20])(=[O:19])[CH3:18]
Reactant: CCOC(=O)C(=CN[C@@H](C)COC(C)=O)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn([C@@H](C)COC(C)=O)c2c([N+](=O)[O-])c(Cl)c(F)cc2c1=O
Reaction time: 4 h
Yield: 93.7 %

Procedure:
45.69 g of (+) ethyl 2-(2,4-dichloro-3-nitro-5-fluorobenzoyl)-3-[(1-acetoxyprop-2(S)-yl)amino]acrylate was dissolved in 270 ml of acetonitrile under heating to 65˜70° C. 32.25 g (1.5 eq.) of K3PO4 was added in portions to the reaction mixture, which was then stirred at the same temperature for 4 hours. The reaction mixture was filtered under a reduced pressure and washed with 500 ml of dichloromethane. The filtrate was concentrated under a reduced pressure. The resulting residue was dissolved in 300 ml of dichloromethane and then washed with water. The organic layer was concentrated under a reduced pressure to give 45.4 g of (−) ethyl N-(acetoxy-prop-2(S)-yl )-6-fluoro-7-chloro-8-nitro-4-quinolone-3-carboxylate (Yield: 93.7%).