Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.N1CCCCC1>ClCCl.[OH-].[Na+]>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1
Reactant: Cc1cccc(S)c1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1cccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 1.3 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.4 mmol of 3-methylbenzenethiol, and 1.4 mmol of piperidine in 25 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid which was dissolved in 2 N NaOH, washed with ether, acidified to pH 2, and extracted with ethyl acetate. The extract was washed with water, dried over MgSO4, and concentrated to give a solid (m.p. 58-60° C.). 1H NMR (DMSO-d6) δ 2.07 (s, 3 H), 3.77 (s, 2 H), 6.06 (m, 1 H), 6.45 (s, 1 H), 6.78 (m, 2 H), 7.25-7.47 (m, 10 H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].O>CN1C(=O)CCC1>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1nc(Cl)ncc1C(N)=O
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(N[C@H]2CC[C@H](O)CC2)ncc1C(N)=O
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(tert-butylamino)-2-chloropyrimidine-5-carboxamide (0.5 g), trans-4-aminocyclohexanol hydrochloride (0.40 g), Na2CO3 (0.28 g) in NMP (3.5 mL) was heated at 85° C. and held for 6 h. The mixture was cooled to 35° C., and water (10 mL) was added. After 30 minutes, the batch was cooled to 25° C. and held for 1 h. The suspension was filtered, washed with water (2.5 mL) and dried in a vacuum oven at 40° C. with a nitrogen bleed for 24 h to give 4-(tert-butylamino)-2-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxamide as a white solid (0.6 g, 89%). 1H NMR (DMSO-d6) δ 9.17 (broads, 1H), 8.32 (s, 1H), 7.01 (broads, 1H), 4.52 (d, J=4.5 Hz, 1H), 3.70-3.25 (m, 2H), 1.84 (m, 4H), 1.41 (s, 9H), 1.33-1.16 (m, 4H).
Reaction SMILES: C[NH+]1CCOCC1.[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:12]([C:28]#[N:29])=[C:11]([SH:30])[N:10]=1.Br[CH2:32][C:33]([NH2:35])=[O:34].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[C:12]([C:28]#[N:29])=[C:11]([S:30][CH2:32][C:33]([NH2:35])=[O:34])[N:10]=1
Reactant: NC(=O)CBr
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCC(=O)[O-])cc1
Agent: C[NH+]1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCC(N)=O)c(C#N)c1-c1ccc(OCC(=O)O)cc1

Procedure:
135 mg (0.316 mmol) of 2-[4-(2-amino-3,5-dicyano-6-sulfanyl-4-pyridinyl)-phenoxy]acetic acid N-methylmorpholinium salt together with 103.3 mg (0.474 mmol) of bromoacetamide and 106.1 mg (1.263 mmol) of NaHCO3 are stirred in 0.5 ml of DMF overnight. After filtration, the reaction solution is prepurified by preparative HPLC. The isolated fraction is reconcentrated under reduced pressure and the residue is purified by preparative thin-layer chromatography.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[F:1][CH2:2][CH2:3][CH2:4][O:5][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: OCCCF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCF)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
5 g of 3-fluoro-propanol (64.03 mmol) and 18 ml of triethylamine (129.32 mmol) were dissolved in 50 ml of dichloromethane. At 0-5° C., 12.9 g toluene-4-sulfonylchloride (67.66 mmol) were added and the reaction mixture stirred at room temperature for 18 h. Standard work-up yielded 13.7 g of toluene-4-sulfonic acid 3-fluoro-propyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C(O)(=O)C.O.[N+:16]([CH:19]([CH:22]=O)[CH:20]=O)([O-:18])=[O:17].[Na]>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:10]=[CH:22][C:19]([N+:16]([O-:18])=[O:17])=[CH:20]2
Reactant: COc1ccc(N)cc1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ncc([N+](=O)[O-])cc2c1
Temperature: 4 °C
Yield: 59.6 %

Procedure:
p-Anisidine hydrochloride (35.0 g, 219.4 mmol) was weighed into a dry 300 mL three-necked round-bottomed flask, equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, a solid addition funnel and a thermometer. Glacial acetic acid (150 mL) was added to the solid, with vigorous stirring to maintain a homogeneous suspension. To this suspension was added sodium nitromalonaldehyde monohydrate (12.0 g, 76.4 mmol) and the mixture stirred for 1.0 h at 25° C. A short-path distillation head was placed on the flask and approximately 120 mL of acetic acid/water removed under reduced pressure at 40° C. To the residue (imine 13) was added glacial acetic acid (40 mL) and sulfolane (75 mL). The resulting solution was flushed with argon to :remove air and the flask immersed in an oil bath preheated to 195° C. The mixture was vigorously stirred while acetic acid was removed by distillation. When the temperature reached 184°-185° C. the mixture was stirred for a further 15 min at 185° C. and then poured (while still at ca. 180° C.) onto crushed ice (750 g). The resulting solution was allowed to stand in a refrigerator (overnight) until precipitation was complete. The dark brown solid precipitate was filtered and transferred to a round-bottomed flask (500 mL) containing 2M hydrochloric acid (250 mL). The mixture was heated at reflux for 50-60 min and the boiling; solution filtered through a preheated Buchner funnel to remove an insoluble brown gum. The hot filtrate was cooled to ca. 4° C. and extracted with chloroform (4×50 mL). The combined extracts were dried (MgSO4) and the chloroform removed on a rotatory evaporator to give the crude 3-nitro-6-methoxyquinoline 14 (9.3 g, brown solid).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:29](B1OC(C)(C)C(C)(C)O1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[CH2:29]([C:14]1[N:15]=[C:11]([C:10]2[C:2]([CH3:1])=[N:3][N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=23)[S:12][C:13]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1Cc1ccccc1
Yield: 41.9 %

Procedure:
Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (450 mg, 1.1 mmol) produced in Example 15(i), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 4.6 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (70 mg, 0.086 mmol), cesium carbonate (670 mg, 2.1 mmol), water (5 mL) and 1,2-dimethoxyethane (30 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (174 mg, 43%) was obtained as a brown solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[C:9]([O:18][CH3:19])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([O:18][CH3:19])[CH:8]=1
Reactant: C1CCNC1
Reactant: COc1cc(Br)ccc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(Br)ccc1NC(=O)CN1CCCC1
Temperature: 80 °C
Yield: 99.3 %

Procedure:
Add pyrrolidine (7.5 mL, 90 mmol) to a mixture of N-(4-bromo-2-methoxy-phenyl)-2-chloro-acetamide (5.0 g, 18 mmol) and potassium carbonate (4.96 g, 36 mmol) in acetonitrile (180 mL). Heat the mixture at 80° C. for 4 h. Cool the mixture to RT and filter with CH2Cl2 (300 mL). Wash the filtrate with brine (400 mL), back extract the aqueous twice with CH2Cl2 (300 mL). Wash the combined organic layer with water (250 mL). Dry the organic portion over Na2SO4, filter, and concentrate. Dry the resulting solid on house vacuum overnight to give 5.6 g (99%) of the title compound. LC-ES/MS m/z (81Br) 314.0 [M+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].O>CN(C=O)C>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cccc(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 3-tert-butyltoluene (0.5 mL, 2.9 mmol) in carbon tetrachloride (20 mL). Add NBS (530 mg, 3 mmol) and irradiate the reaction mixture with a 250 watt sun-lamp with simultaneous heating to reflux for 1 h. Cool to ambient temperature, filter, and concentrate filtrate to dryness to give crude 1-bromomethyl-3-tert-butylbenzene. Dissolve crude 1-bromomethyl-3-tert-butylbenzene (600 mg) in anhydrous DMF. Add portion wise sodium azide (260 mg, 4 mmol) and stir at room temperature for 2 h. Pour the mixture into water (250 mL), extract with EtOAc (3×50 mL), wash combined organic extracts with brine, dry over MgSO4, filter and evaporate solvent to give crude 1-azidomethyl-3-tert-butylbenzene, that was used without further purification. Dissolve crude 1-azidomethyl-3-tert-butylbenzene in methanol containing 10% Pd/C (75 mg) at 5° C., and stir the resulting slurry under 1 atm H2 for 1 h. Filtrate, concentrate in vacuo and purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1 and 1:1), EtOAc, methanol and 2M ammonia in methanol to give the title compound (255 mg, 53% overall). MS (ES+) m/z: 164 (M+H)+.
Reaction SMILES: C(I)(I)(I)I.[C:6]([C:16]([F:19])([F:18])[F:17])([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])I>>[F:9][C:8]([F:11])([F:10])[C:6]([C:8]([F:11])([F:10])[F:9])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13]
Reactant: FC(F)(F)C(I)(C(F)(F)F)C(F)(F)F
Agent: IC(I)(I)I
Product: FC(F)(F)C(C(F)(F)F)(C(F)(F)F)C(F)(F)F

Procedure:
Perfluoroneopentane is prepared from CI4 employing the apparatus described above. Five grams of carbon tetraiodide were placed in the Vycor container and the reactor was evacuated to 0.1 mm pressure. The Vycor container is located as in the position shown in the FIGURE. Hexafluoroethane was admitted to the reactor at a flow rate of 15 cc/min to maintain a 0.5 to 1 mm pressure during constant pumping. The discharge was initiated at 10 megahertz and 20 watts using a radio frequency generator. After eight hours the products were removed along with fluorocarbons from a -196°C trap downstream from the reactor. The products were separated from fluorocarbons by trap to trap distillation and purified using liquid nitrogen-cooled columns of a gas chromatograph. A 55 percent yield of the white solid CI(CF3)3 was obtained, which had a F19N.M.R. singlet -13.3 ppm from external trifluoroacetic acid. The mass spectrum contained a parent at 346 and a P-19 peak at 327. The infrared spectrum contained peaks at (1270) (960) and (725) cm-1. The elemental analysis was in agreement with the calculated values. The perfluoroneopentane C(CF3)4 was obtained in 25 percent yield and is a white solid melting at 72.5° to 73°C. The mass spectrum of the compound contains a p-19 at 269 while the F19N.M.R. consists of a singlet at -13.92 ppm from external trifluoroacetic acid. The infrared spectrum contains peaks at (9.80) (720) and 1190 cm-1.
Reaction SMILES: CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].F[C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]>O>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[O:22][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
To a 100 ml flask fitted with a magnetic stirrer and drying tube is added dimethyl sulfoxide (50 ml), anhydrous potassium carbonate (3.6 g, 0.026 mole) and 2-chloro-4-trifluoromethylphenol (4.8 L g, 0.024 mole). This mixture is stirred at room temperature overnight. 5-Fluoro-2-nitrobenzamide (4.5 g, 0.024 mole) is added rapidly and the reaction mixture stirred at room temperature for 24 hours. The reaction mixture is poured into water (300 ml) and triturated with carbon tetrachloride (50 ml). The water and carbon tetrachloride insoluble solid is collected by filtration and dried under vacuum to afford 1.2 g of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzamide, mp 139°-43° C. Anal. Calcd. for C14H8ClF3N2O4 : C, 46.62; H, 2.23; Cl, 9.83; N, 7.76. Found: C, 45.77; H, 2.30; Cl, 10.62; N, 7.91.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27]([N:29]([CH3:59])[C:30]([C:32]1[C:33]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[N:34][N:35]2[C:40]([F:41])=[CH:39][C:38]([C:42]3[CH:43]=[C:44]([CH:48]=[CH:49][C:50]=3[CH3:51])[C:45](O)=[O:46])=[CH:37][C:36]=12)=[O:31])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:41][C:40]1[N:35]2[N:34]=[C:33]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[C:32]([C:30]([N:29]([CH3:59])[C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:31])=[C:36]2[CH:37]=[C:38]([C:42]2[CH:43]=[C:44]([C:45](=[O:46])[NH:12][C:9]3([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=4)[CH2:11][CH2:10]3)[CH:48]=[CH:49][C:50]=2[CH3:51])[CH:39]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2(c3ccccn3)CC2)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
To a solution containing 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (0.011 g, 0.054 mmol), diisopropylethylamine (0.075 mL, 0.43 mmol), 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.028 g, 0.054 mmol) and DMF (0.36 mL) was added HATU (0.041 g, 0.11 mmol) in one portion. The solution was maintained at room temperature for 1 h and concentrated. The resultant residue was purified on silica gel (30-100% ethyl acetate/hexanes, 45 min. gradient) to afford tert-butyl 7-fluoro-2-(4-fluorophenyl)-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a residue. LCMS retention time: 2.428 mM. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 638 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:25][N:26]=[C:27]=[O:28]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:27]([NH:26][CH3:25])=[O:28])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)OC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (200 mg) was dissolved in 2 ml of dry tetrahydrofuran. Methyl isocyanate (0.168 ml) was added thereto. The mixture was refluxed for 10 hours and distilled to remove the solvent. The residue was purified by silica gel chromatography to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-methylaminocarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[N:25]1[CH2:29][CH2:28][S:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C.Cl>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[N:25]2[CH2:29][CH2:28][S:27][CH2:26]2)=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Nn1c(N2CCSC2)nc2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1c(N2CCSC2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.8 %

Procedure:
3,5-Difluorophenylacetic acid (0.152 g, 0.88 mmol), 3-Amino-2-thiazolidin-3-yl-3H-quinazolin-4-one (0.146 g, 0.59 mmol) and HATU (0.268 g, 0.71 mmol) were dissolved in dry DMF (2.5 mL), followed by addition of 2,6-lutidine (205 μL, 1.76 mmol). The reaction mixture was stirred at RT for 48 h and then poured into 1 M HCl (20 mL). The formed precipitate was collected by filtration and washed with water and heptane, which after drying gave the title compound (0.180 g, 76%). LC-ESI-HRMS of [M+H]+ shows 403,1047 Da. Calc. 403,104028 Da.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH2:16]1[O:26][C:25]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=2[O:17]1.[Cl-].[NH4+]>O1CCCC1>[OH:22][CH:21]([C:20]1[CH:23]=[CH:24][C:25]2[O:26][CH2:16][O:17][C:18]=2[CH:19]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:4]
Reactant: C#CC(=O)OCC=C(C)C
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)=CCOC(=O)C#CC(O)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A solution of 10 g (72 mmol) of 3-methyl-2-butenyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 47 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 10.9 g (72 mmol) of 3,4-methylenedioxybenzaldehyde in 120 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes then brought to room temperature and treated with 120 ml of saturated ammonium chloride solution. The aqeuous phase was extracted twice with ether; the 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 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 3-methyl-2-butenyl 4-hydroxy-4-[3,4-(methylenedioxy)phenyl]-2-butynoate as a yellow oil.
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S(O[CH2:13][C:14]2([CH3:17])[CH2:16][O:15]2)(=O)=O)=CC=1.[Cl:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([CH2:13][C:14]3([CH3:17])[CH2:16][O:15]3)[C:26]2=[O:30])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CO2)cc1
Reactant: O=C1NCCN1Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CN2CCN(Cc3ccc(Cl)cc3)C2=O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Sodium hydride (99 mg, 2.49 mmol) was added to a solution of 2-methyl-2-oxiranylmethyl toluene-4-sulfonate (500 mg, 2.37 mmol) in DMF (5 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 1 hour. To which a solution of 1-(4-chlorobenzyl)imidazolidin-2-one (633 mg, 2.61 mmol) in DMF (5 ml) was added while cooling in an ice-bath, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether twice. The extracts were combined, washed with water twice and then with brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=3/1) to afford 1-(4-chlorobenzyl)-3-(2-methyl-2-oxiranylmethyl)imidazolidin-2-one (399 mg, 60%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)C=O.Cl.C(N=C=NCCCN(C)C)C>O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:13][CH2:14][O:18][C:16]1=[O:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@H]1CCOC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.7 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-homoserine (9.0 g), 1-hydroxybenzotriazole (HOBt) (5.4 g) and N,N-dimethylformamide (DMF) (50 ml) was provided and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (7.5 g) was added to the mixture under ice-cooling. The whole mixture was stirred at room temperature for 14 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 1% aqueous citric acid, water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in the order mentioned and dried over MgSO4 and the solvent was distilled off, whereby (S)-3-(N-benzyloxycarbonylamino)tetrahydrofuran-2-one (7.0 g, 84.3%) was obtained. This product was recrystallized from dichloromethane-isopropyl ether. Colorless needles, m.p. 129°-130° C. Optical rotation [α]D -0.5° (C=0.52, CHCl3).