Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:10]3[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[C:10]3[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2nc(CC3CCCC3)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2nc(CC3CCCC3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1OC

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclopentylmethyl-5,6-dimethoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:11]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)(=[O:28])=[O:27])[CH2:12][C:13]([N:15]([CH2:24][CH3:25])[CH2:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:40]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:11]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)(=[O:28])=[O:27])[CH2:12][C:13]([N:15]([CH2:24][CH3:25])[CH2:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=1)=[S:40]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCN(Cc1cncc(C)n1)C(=O)CN(c1cc(N(C)C)ccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Solvent: Cc1ccccc1
Product: CCN(Cc1cncc(C)n1)C(=S)CN(c1cc(N(C)C)ccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 2-[(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy-benzenesulfonyl)-amino]-N-ethyl-N-(6-methyl-pyrazin-2-ylmethyl)-acetamide (20 mg) in dry toluene (0.2 mL) was added in one portion phosphorus pentasulfide (10 mg). The reaction mixture was stirred at 80° C. under nitrogen for 3 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure and the residue was purified by FC (EA/n-heptane: 8/2 to EA) to give 12 mg (57%) of the title compound as a foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].N1C=CC([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]2)=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:26][CH:25]([CH:22]1[CH2:21][CH2:20][NH:19][CH2:24][CH2:23]1)[C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1)=[O:12])([O-:3])=[O:2]
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(Nc1ccccc1[N+](=O)[O-])OC(c1ccncc1)C1CCNCC1
Yield: 197.1 %

Procedure:
A solution of 2-nitrophenyl isocyanate (4.25 g, 25.9 mmol) and 1-(4-pyridyl)piperidine-4-methanol (4.13 g, 21.5 mmol) in methylene chloride (100 mL) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 5% methanol/1% triethylamine/94% chloroform) to yield 7.55 g (96%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Br)cc1)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 91.7 %

Procedure:
In a 250 mL flask equipped with a nitrogen inlet, overhead stirring assembly, and reflux condenser were placed 3-nitrobenzoyl chloride (28 g, 0.15 mol), bromobenzene (130 g, 0.83 mol), and aluminum chloride (22 g, 0.16 mol). The mixture was heated for 3 h at 100° C., then cooled to room temperature and stirred for an additional 16 h. The mixture was poured into 1 L of acidic (HCl) ice water, and the organics were extracted using methylene chloride, dried over magnesium sulfate, and the solvents were removed under reduced pressure to yield a yellow powder. Recrystallization from acetone afforded 42.1 g (90% yield) of white crystals: m.p. 104°-105° C.
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:19][C:18]1[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=1)#[CH:3]
Reactant: Nc1ccc(F)cc1
Reactant: O=C([O-])OCC=Cc1ccccc1
Product: C#CC(Nc1ccc(F)cc1)c1ccccc1
Reaction time: 12 h
Yield: 97 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and p-fluoroaniline (0.130 g, 1.17 mmol). The reaction was conducted at room temperature for 12 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 95/5. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.214 g, 96%). HPLC analysis indicated the enantiomeric excess of the product was 94% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=22.5 (major), 29.4 (minor) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.48-7.41 (m, 4H), 7.39-7.34 (m, 1H), 6.96-6.89 (m, 2H), 6.63-6.56 (m, 2H), 6.11 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.36 (dt, J=17.2, 1.2 Hz, 1H), 5.31 (dt, J=10.0, 1.2 Hz, 1H), 4.95 (d, J=5.6 Hz, 1H), 4.02 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 155.76 (d. J=234 Hz), 143.44 (d, J=2.3 Hz), 141.61, 128.71, 127.45, 127.03, 116.03, 115.44 (d, J=22.1 Hz), 114.30 (d, J=8.4 Hz), 61.36. Anal. Calcd for C15H14NF: C, 79.27; H, 6.21; N, 6.16; F, 8.36. Found: C, 79.16; H, 6.24; N, 6.24; F, 8.46.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[Cl:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>>[Cl:21][C:22]1[N:23]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:4]=3[N:3]=2)[CH:24]=[CH:25][N:26]=1
Reactant: Clc1ncc[nH]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Cl)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 185, with Intermediate B instead of Intermediate C and 2-chloro-1H-imidazole instead of 2-(3,5-dichlorophenyl)-1H-imidazole. LCMS: 361.2 m/z (M+H)+; ret. Time 10.06 min (Analytical Method C).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([S:41](Cl)(=[O:43])=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:41]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:43])=[O:42])=[C:3]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:4]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1cccc2ccccc12)c1ccccc1

Procedure:
N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 1-naphthalenesulfonylchloride (54 mg, 0.239 mmol) according to general method 3 to give 40 mg of a purple solid. MS (posES-FIA) m/z=Found: 523.2; Calcd 523.14; 1H NMR δ 8.83-8.59 (m, 1H), 8.10 (d, 1H), 8.02-7.97 (m, 1H), 7.90 (d, 1H), 7.74-7.38 (m, 8H), 6.69-6.65 (m, 1H), 6.39-6.34 (m, 2H), 3.35-3.14 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[C:17](Cl)(=[O:23])[O:18][CH2:19][CH2:20][O:21][CH3:22]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:23])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Reactant: COCCOC(=O)Cl
Solvent: CCOC(C)=O
Product: COCCOC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 10.00 g (35.44 mmol) of 3-bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine dissolved in 120 mL of EtOAc, at 0° C. was added 5.40 g (38.99 mmol) of 2-methoxyethyl carbonochloridate, followed by 9.86 mL (70.88 mmol) of TEA. After 5 minutes, the ice bath was removed, and the reaction mixture stirred at RT. After 5 hr, LCMS showed that the reaction was complete. It was diluted with EtOAc, quenched with brine, and the organic layer dried over MgSO4. It was concentrated and purified on the ISCO with a 330 g column eluting with 0-9% MeOH/DCM to obtain the desired product, 12.63 g (93%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.42 (s, 3 H) 3.62-3.69 (m, 6 H) 3.73-3.82 (m, 4 H) 4.26-4.35 (m, 2 H) 6.36 (d, J=7.83 Hz, 1 H) 7.86 (s, 1 H) 8.27 (d, J=7.83 Hz, 1 H). LRMS (ESI) m/e 384 [(M+H)+, (doublet), calcd for C14H18BrN5O3 383].
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.C1COCC1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>>[OH:22][CH2:21][CH:20]([NH:19][C:14](=[O:15])[O:16][CH2:17][CH3:18])[CH2:23][OH:24]
Reactant: NC(CO)CO
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)NC(CO)CO
Reaction time: 4 h
Yield: 54.5 %

Procedure:
In a 1 liter round bottom flask with magnetic stir bar, serinol (10.0 g) and Na2CO3 (25.0 g) were dissolved in the mixture of DI water (250 mL) and THF (150 mL). The reaction mixture was allowed to cool in ice. Ethyl chloroformate (10.5 mL) was added drop-wise and the reaction was allowed to proceed in ice for 4 hours, followed by about 16 hours at room temperature. Another 100 mL of DI water was added to the reaction mixture and the product was extracted into ethyl acetate (20×100 mL). The crude product (11.6 g) was further purified by flash column chromatography, using silica as the packing material and CH3OH:CHCl3 (1:9) mixture as the eluent. The final product was a transparent viscous oil that was crystallized in the presence of trace ethyl acetate (1 to 2 mL) along with vigorous scratching using a spatula. The crystallized product was washed with cold ethyl acetate:hexanes (1:1) mixture (1×100 mL), and dried under vacuum to result in white crystalline solid (8.9 g, 54.5%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:20])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:12]O)=[CH:9][C:4]=2[O:3][CH2:2]1.[ClH:21].[H][H]>C(O)C.O.[Pd]>[ClH:21].[ClH:21].[NH2:12][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:20]
Reactant: [H][H]
Reactant: O=C(C(=NO)c1ccccn1)c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(C(=O)c1ccc2c(c1)OCO2)c1ccccn1
Yield: 59 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-2-pyridin-2-yl-ethane-1,2-dione 2-oxime (2 g, 7.75 mmol) was dissolved in ethanol (100 ml) and hydrochloric acid (2 ml of a 36% solution in water) was added. Palladium on charcoal catalyst (0.5 g) was added and the reaction mixture was stirred under a positive pressure of hydrogen for 1.5 hours. The catalyst was removed by filtration through Kieselguhr and the resulting filtrate evaporated to dryness under reduced pressure. Trituration under anhydrous diethyl ether gave the title compound as a pale yellow solid (1.5 g, 59%); m/z (API) 257 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[C:17]2[Cl:23].N1C=CC=CC=1>O>[Cl:23][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([NH:13][S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH:15]=2)[NH:19][N:18]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2[nH]nc(Cl)c2c1)c1ccc(Cl)c(Cl)c1
Yield: 4.7 %

Procedure:
N-(3-Chloro-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide can be obtained in the following way: a solution of 1.1 g of 3,4-dichlorobenzenesulfonyl chloride is added dropwise to a solution, cooled to 0° C. of 0.75 g of 5-amino-3-chloro-1H-indazole and of 14 ml of pyridine. After reacting for 10 minutes at a temperature in the region of 0° C. and 2 hours 30 minutes at a temperature in the region of 20° C., 50 ml of distilled water are added to the reaction medium. The medium is extracted with 50 ml and 25 ml of ethyl acetate. The organic phase is subsequently dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture as eluent. The yellow oil thus obtained is again purified by chromatography on a silica column with dichloromethane as eluent. 0.08 g of N-(3-chloro-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide is thus obtained in the form of a thick white oil (analysis C13H8Cl3N3O2S % calculated C, 41.46; H, 2.14; Cl, 28.24; N, 11.16; O, 8.50; S, 8.51. % found C, 41.43; H, 2.58; N, 10.81; S, 7.84).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17](F)[CH:18]=2)[NH:13][C:12](=[O:24])[C:11]1=[O:25])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:18]=2)[NH:13][C:12](=[O:24])[C:11]1=[O:25])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21)OCC
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc21)OCC
Yield: 181.8 %

Procedure:
140 mg of (6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is heated with 129 mg of morpholine for 1.5 hours to 120° C. bath temperature. After concentration by evaporation in a vacuum, the residue is chromatographed on silica gel with toluene:glacial acetic acid:water=10:10:1. After concentration by evaporation of the corresponding fractions, 300 mg of (7-morpholino-6-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=1[C:30]([F:33])([F:32])[F:31]>O1CCCC1.CN(C)C=O.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:18][C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=2[C:30]([F:31])([F:33])[F:32])[C:10]1=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CN2CC[C@H](NC(=O)OC(C)(C)C)C2=O)c(C(F)(F)F)c1

Procedure:
669 mg of (S)-3-(t-butoxycarbonylamino)pyrrolidin-2-one (J. Med. Chem., 1999, 42, 3557-3571) was dissolved in 30 ml of tetrahydrofuran/N,N-dimethylformamide (9:1) and the mixture was stirred under ice cooling. 60% sodium hydride was added thereto and the mixture was stirred for 20 minutes. A solution (3 ml) of ethyl 4-(bromomethyl)-3-trifluoromethylbenzoate (Reference Example 2 (step 2)) in tetrahydrofuran was added dropwise, followed by stirring at room temperature for 6 hours after removing an ice bath. The reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate twice, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 867 mg of the objective compound as pale yellow crystals.
Reaction SMILES: C(=O)=O.CC(C)=O.[Cl:8][C:9]1[CH:37]=[CH:36][C:12]2[N:13]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:14](=[O:26])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:11]=2[CH:10]=1.CC([O-])(C)C.[K+].[Br:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48]Br>C1COCC1>[Br:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48][CH:15]1[C:14](=[O:26])[N:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:12]2[CH:36]=[CH:37][C:9]([Cl:8])=[CH:10][C:11]=2[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:16]1
Reactant: COc1ccc(CN2C(=O)CN=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Reactant: BrCc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(CN2C(=O)C(Cc3cccc(Br)c3)N=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Yield: 84.5 %

Procedure:
To a stirred and cooled (dry ice/acetone bath) solution of E2 (6.00 g, 14.2 mmol) in THF (80 mL) was slowly added 1 M KOtBu (21 mL, 21 mmol, 1.5 eq). The resulting deep red mixture was stirred over dry ice/acetone bath ˜10 min followed by the slow addition of a solution of 3-bromobenzyl bromide (5.10 g, 21.4 mmol, 1.5 eq) in THF (15 mL). After stirring another ˜45 min at −78° C., the reaction mixture was quenched with saturated brine and diluted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated (rotovap, then high vacuum). Chromatography over silica gel using 10-30% EtOAc/heptane gave 7.08 g (yield of 84%) of the title product. Noting that when using benzyl chlorides as alkylating agents, tetrabutyl ammonium iodide was added along with the alkylating agent at low temperature. 1H NMR (300 MHz, CDCl3) δ 3.57 (d, 2H), 3.70 (s, 3H), 3.73 (t, 1H), 3.83 (s, 3H), 4.59 (d, 1H), 5.62 (d, 1H), 6.61 (d, 2H), 6.8-6.9 (m, 4H), 7.2-7.45 (m, 8H), 7.63 (fine d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:16][CH2:15][C:14](=[O:17])[CH:13]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCC1CC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (WO 02/081435) (2.0 g, 5.2 mmol) in dry tetrahydrofuran (10 mL) was added dropwise to a cooled solution of 0.5 M lithium hexamethyldisilazide in tetrahydrofuran (11.4 mL) at −78° C. The mixture was stirred at this temperature for 2 hours before adding 2-(trimethylsilyl)ethoxymethyl chloride (1.4 mL, 7.8 mmol) and the solution allowed to warm to rt. over 16 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL), and the organic phase separated, dried (MgSO4) and evaporated to dryness. The product was purified on silica eluting with [9:1] hexane-ethyl acetate to yield 1.2 g of the title compound. 1H NMR CDCl3 7.38 (4H, s), 7.24-7.16 (1H, m), 7.12-7.06 (1H, m), 6.97-6.87 (1H, m), 3.66 (1H, dd, J=9.7 and 3.0 Hz), 3.51-3.45 (3H, m), 3.17-3.15 (1H, m), 3.05-2.98 (1H, m), 2.56-2.49 (2H, m), 241-2.35 (2H, m), 2.23-2.17 (1H, m), 0.91-0.87 (2H, m) and 0.03 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:12]([O:16][C:17]([NH:19][C:20]1[C:21]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:30][N:29]=2)=[O:27])=[CH:22][S:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([O:16][C:17]([NH:19][C:20]1[C:21]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[O:11])=[CH:30][N:29]=2)=[O:27])=[CH:22][S:23][CH:24]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(CNCCCN2CCOCC2)cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(CN(CCCN2CCOCC2)C(=O)Nc2ccc(F)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
3,4-Difluorophenyl isocyanate (15 μL, 0.13 mmol) was added to a solution of N-(4-t-butoxycarbonylaminothiophen-3-yl)-5-[3-(morpholin-4-yl)propylaminomethyl]pyridine-2-carboxylic acid amide (Reference Compound No. 5-12, 43 mg, 0.091 mmol) in dichloromethane (2.0 mL), and then the reaction mixture was stirred at room temperature for 1.5 hours. The reaction solution was purified by silica gel column chromatography (chloroform-methanol) to give 53 mg of the title reference compound as a colorless solid. (Yield 92%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(OC(=O)C)C>[CH3:23][C:22]([NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:21])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1)=[O:24]
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of (S)—N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (10 gm) and ethylacetate (100 ml), acetic anhydride (10 ml) is slowly added at ambient temperature, then stirred at ambient temperature for 1 hour. The separated solid is filtered and dried under reduced pressure at 50° C. to give 9.5 gm of linezolid form III.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1.Br[CH2:21][CH:22]=[CH:23][C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:27][C:26]([CH3:29])([CH3:28])[C:25]#[C:24]/[CH:23]=[CH:22]\[CH2:21][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2]
Reactant: CNCc1cccc(NC(=O)c2ccccc2)c1
Reactant: CC(C)(C)C#CC=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C/C=C\C#CC(C)(C)C)Cc1cccc(NC(=O)c2ccccc2)c1

Procedure:
N-methyl-3-benzoylaminobenzylamine hydrochloride (277 mg) was dissolved in 3 ml of dimethylformamide, and 221 mg of 1-bromo-6,6-dimethyl-2-hepten-4-yne and 552 mg of potassium carbonate were stirred overnight at room temperature. The reaction mixture was diluted with water, and extracted with ethyl ether. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was separated by filtration, and then the solvent was evaporated. The residue was purified by preparative thin-layer chromatography [thin-layer plate: Kieselgel 60F254, Art. 5744 (a product of E. Merck Co.); developing solvent: hexane/ethyl acetate=3/1] to give the following compounds as colorless oils.