Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]([C:15]([OH:17])=[O:16])([CH3:14])[CH3:13])[CH:7]=1.O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]([C:15]([OH:17])=[O:16])([CH3:13])[CH3:14])[CH:7]=1.[C:21]1(=[O:26])[NH:20][C:24](=[O:25])[CH2:23][CH2:22]1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(C)c(OCCCC(C)(C)C(=O)O)c1
Solvent: C1COCCO1
Product: O=C1CCC(=O)N1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To Gemfibrozil (GEM) (5.0 g, 20.0 mmol) in 30 mL dioxane was added N-hydroxysuccinimide (2.3 g, 20.0 mmol) in 20 mL dioxane and dicyclohexylcarbodiimide (4.5 g, 22.0 mmol) in 50 mL dioxane. The reaction was stirred overnight and the insoluble dicyclohexylurea removed by filtration. The solvent was removed by rotary evaporation and the residue dissolved in 15-20 mL of CH2Cl2. Hexane was added dropwise until crystal formation was seen and the mixture was chilled to 4° C. overnight. Approximately 3 mL of additional n-hexane was added and the mixture chilled to −20° C. overnight. The activated ester formed small planer crystals and was harvested, washed with hexane and dried in vacuum (5.8 g, 80%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7](=[O:9])[CH3:8])[CH2:2]1.C(N(CC)CC)C.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:7]([CH:3]1[O:4][CH2:5][CH2:6][N:1]([C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:2]1)(=[O:9])[CH3:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)C1CNCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a solution of 1-(morpholin-2-yl)ethanone (3.9 g, 30.0 mmol) in DCM (60 mL) was added triethylamine (1.0 g, 10 mmol) to adjust pH 9. Then benzyl carbonochloridate (5.6 g, 33.0 mmol) and triethylamine (3.0 g, 30.0 mmol) were added and the mixture was stirred at room temperature for 16 hr. The reaction solution was added 1120 (20 mL) and extracted by DCM (100 mL*3). The organic layer was concentrated and purified by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=20/1-15/1-10/1) to give benzyl 2-acetylmorpholine-4-carboxylate (5.0 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([N+:19]([O-])=O)=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].O.C([O-])([O-])=O.[Na+].[Na+]>CCO.CC(O)=O.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11]
Reactant: CC(Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
To a suspension of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (10 g, 30 mmol) in EtOH/AcOH (200/250 mL) was added iron powder (16.75 g, 300 mmol) in one portion. The mixture was then refluxed for 75 min. The reaction mixture was allowed to cool to room temperature. The precipitate was collected by filtration. The filtrate was concentrated by evaporator and in vacuo to give black residue. The black residue was combined with the collected solid. Water (300 mL) was added and the aqueous mixture was neutralized with Na2CO3, then extracted with ether (3×200 mL). The combined ethereal solution was washed with saturated NaHCO3 (2×60 mL), H2O (60 mL) and brine (60 mL), dried over anhydrous Na2SO4, concentrated by evaporator in vacuo to afford 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (8.67 g, 96%) as an off-white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[S:7][C:8]([S:15]([CH3:17])=O)=[CH:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.C(Cl)Cl>[CH2:1]([NH:3][C:4]([C:6]1[S:7][C:8]([S:15][CH3:17])=[CH:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2]
Reactant: CCNC(=O)c1sc(S(C)=O)cc1[Si](C)(C)C
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCNC(=O)c1sc(SC)cc1[Si](C)(C)C
Temperature: 0 °C
Yield: 88.2 %

Procedure:
To a solution of the compound of Example 260 (0.6 g) and Nal (0.8 g) in 10 mL acetone was added slowly 0.4 mL trifluoroacetic anhydride at 0° C. and the mixture was stirred at 0° C. for an additional hour. Then CH2Cl2 and aq sat sodium meta-bisulfite were added. The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue with 10% ethyl acetate-hexane gave 0.5 g of the title compound as a white solid. m.p. 58-61° C.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].[C:27]12[C:35](=[O:36])[O:34][C:32](=[O:33])[C:28]=1[CH2:29][CH2:30][CH2:31]2.O.Cl>CN(C)C=O.C(O)C>[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:35]([C:27]2[CH2:31][CH2:30][CH2:29][C:28]=2[C:32]([OH:34])=[O:33])=[O:36])[N:5]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: O=C1OC(=O)C2=C1CCC2
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.4 %

Procedure:
In 30 ml of N,N-dimethylformamide, 3.63 g of 5-ethyl-2-imino-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3,4-thiadiazoline was dissolved, followed by the addition of 1.44 g of 1-cyclopentene-1,2-dicarboxylic anhydride. The resulting mixture was stirred at room temperature for 6 hours. To the reaction mixture, 200 ml of water and 5 ml of hydrochloric acid were added. The powders so precipitated were collected by filtration. The powders so obtained were suspended in 100 ml of ethanol and the resulting suspension was heated under reflux for 20 minutes. The powders were collected by filtration, washed successively with ethanol and diethyl ether and then dried, whereby 4.53 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH:7]=[CH:8][N+:9]([O-])=O)=[CH:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[O:3][C:4]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C=C[N+](=O)[O-])o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(CCN)o1

Procedure:
In close analogy to the procedure described above, 2-Methyl-5-(2-nitro-vinyl)-furan is reacted with lithium aluminium hydride to provide the title compound.
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.Cl.[CH3:10][O:11][C:12](=[O:18])[C@H:13]([CH:15]([CH3:17])[CH3:16])[NH2:14]>O1CCOCC1>[N-:14]=[C:5]=[O:4].[CH3:10][O:11][C:12](=[O:18])[C@H:13]([CH:15]([CH3:17])[CH3:16])[NH2:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
Trichloromethyl chloroformate (1.08 mL) was added to a stirred suspension of L-valine methyl ester hydrochloride (3.0 g, 17.9 mmol) in 10 mL dry dioxane. The mixture was refluxed for 1.5 h, concentrated, and the residue flash distilled (bath temperature 100°-125° C., 0.5 mm vacuum) to afford 1.0 g of L-valine methyl ester isocyanate. A solution of 0.55 g (3.5 mmol) of L-valine methyl ester isocyanate in 7.5 mL dry toluene was treated with 4M HCl in dioxane (79 mL, 0.315 mmol) at RT and stirred for 5 min. The resulting mixture was treated with 1.0 g solid K2HPO4 for 5 min, followed by the addition of Compound 104b (0.464 g, 3.15 mmol). The mixture was refluxed for 9 h, diluted with EtOAc and washed with sat. NaHCO3 followed by brine. The organic phase was dried (MgSO4), concentrated, and the crude product purified by flash chromatography (silica gel/hexane to EtOAc-hexane 1:9 to 1:4, stepwise gradient) to afford 0.51 g (53%) of Compound 104c as a yellow gummy solid.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH:9]([O:12][C:13](=[O:16])[CH2:14][NH2:15])([CH3:11])[CH3:10].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH:9]([O:12][C:13](=[O:16])[CH2:14][NH2:15])([CH3:11])[CH3:10]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CC(C)OC(=O)CN
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of glycine isopropyl ester and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is redissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give glycine isopropyl ester isocyanate.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[C:9]1([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C>O1CCOCC1>[N-:18]=[C:4]=[O:3].[C:9]1([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: NCC(=O)Oc1ccccc1
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of glycine phenyl ester and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give glycine phenyl ester isocyanate.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH3:14]>C(O)C>[C:2]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:14]
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Reactant: N
Solvent: CCO
Product: N#Cc1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.2 Grams of a 2-(trichloromethyl)benzimidazole compound [compound (101)] of the formula (XI) in which X is H and Z is OCF2CFHO was dissolved in 30 ml of ethanol. The resulting solution was added by drops to 4 ml of a 25% aqueous ammonia at 5° C. After stirring for 1 hour at 5° to 15° C., the reaction solution was poured into an ice/conc. hydrochloric acid mixture and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 2.83 g of a 2-cyanobenzimidazole compound [compound (i)] of the formula (II) in which X is H and Z is OCF2CFHO.
Reaction SMILES: N#N.[SH:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[SiH4].[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCCCCC.C(N(CC)CC)C>[C:18]([S:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: CCCCCCCC(=O)Cl
Agent: N#N
Agent: [SiH4]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Yield: 86.8 %

Procedure:
Into a 12-liter, three-necked round bottom flask equipped with mechanical stirrer, addition funnel, thermocouple, heating mantle, N2 inlet, and temperature controller were charged 1,021 grams of 3-mercaptopropyltriethoxysilane (SILQUEST® A-1891 silane from OSi Specialties, Inc., a subsidiary of Crompton Corp. of Greenwich, Connecticut), 433 grams of triethylamine, and 3,000 ml hexane. The solution was cooled in an ice bath, and 693 grams of octanoyl chloride were added over a two hour period via the addition funnel. After addition of the acid chloride was complete, the mixture was filtered two times, first through a 0.1 μm filter and then through a 0.01 μm filter, using a pressure filter, to remove the salt. The solvent was removed under vacuum. The remaining yellow liquid was vacuum distilled to yield 1,349 grams of octanoylthiopropyltriethoxysilane as a clear, very light yellow liquid. The yield was 87 percent.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1)=[NH:4].[ClH:17]>>[ClH:17].[CH3:1][N:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[NH:4]
Reactant: CCOC(=O)c1ccc(C(=N)N(C)C)cc1
Agent: Cl
Product: CN(C)C(=N)c1ccc(C(=O)O)cc1

Procedure:
Ethyl 4-(N,N-dimethylamidino)benzoate and 6 N hydrochloric acid were heated under reflux for 6 hours and then the solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pt](=O)=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:12][C:13](=[O:15])[CH3:14])[C:4]=2[N:3]=1
Reactant: CC(=O)Nc1cccc2ccc(C)nc12
Agent: O=[Pt]=O
Product: CC(=O)NC1CCCc2ccc(C)nc21
Temperature: 60 °C
Yield: 66 %

Procedure:
To a 3-neck, 500 mL round bottom flask containing a stir bar was added 2-methyl-8-acetamidoquinoline (5.69 g, 28.4 mmol) and platinum(IV) oxide (322 mg, 5 mol %). The flask was equipped with two Teflon cannulae: one for purging of the reaction flask with nitrogen gas and introduction of hydrogen, and the other leading to a flask connected to a bubbler. Trifluoroacetic acid (100 mL) was added to the reaction flask under an atmosphere of nitrogen. The stirred reaction mixture was flushed with nitrogen gas and warmed to 60° C. Hydrogen gas was bubbled through the stirred reaction for 3 h. The progress of the reaction was monitored by GC and/or TLC. The reaction mixture was cooled to room temperature, purged with nitrogen gas and the catalyst was filtered through a pad of Celite and washed with CH2Cl2 (100 mL). The solvent was removed in vacuo and the residue was basified with saturated NaOH (pH>14). The mixture was then extracted with CHCl3 (3×250 mL). The organic extracts were dried (MgSO4), filtered and concentrated. The crude material was purified by flash chromatography using 10% MeOH in EtOAc to provide the product (3.83 g, 66%) as a white solid. 1H NMR δ 1.57-1.66 (m, 1H), 1.77-1.86 (m, 2H), 2.02 (s, 3H), 2.44 (s, 3H), 2.43-2.57 (m, 1H), 2.68-2.73 (m, 2H), 4.67-4.74 (m, 1H), 6.79 (br s, 1H), 6.92 (d, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz); 13C NMR δ 21.6, 25.4, 25.8, 29.6, 31.0, 53.0, 123.4, 131.4, 139.2, 155.9, 157.2, 172.2; ES-MS m/z: 227 (M+Na+).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:9]([CH3:19])[C:8]2=[O:20].S(Cl)([Cl:23])=O>>[Cl:23][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:9]([CH3:19])[C:8]2=[O:20]
Reactant: Cc1c(-c2ccccc2)oc2c(CO)cccc2c1=O
Reactant: O=S(Cl)Cl
Product: Cc1c(-c2ccccc2)oc2c(CCl)cccc2c1=O

Procedure:
8-Hydroxymethyl-3-methylflavone was treated with thionyl chloride to give 8-chloromethyl-3-methylflavone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[CH2:12]([O:19][C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Yield: 73.1 %

Procedure:
A solution of 6-aminocaproic acid (13.1 g, 0.10 mole) in 2.5 N NaOH (40 ml, 0.10 mole) was cooled to 0° and benzyloxycarbonyl chloride (18.7 g, 0.11 mole) in ether (25 ml and 2.5N NaOH (50 ml, 0.125 mole) were added simultaneously in several portions, with vigorous stirring, over a 1 hr period. The reaction mixture was extracted with ether (3 × 50 ml), cooled in an ice-bath and acidified with 6M HCl. The crystalline product was recrystallized from ether-pet ether to give 19.4 g of product (73.2%); mp 54°-55.5°.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[Ca+2].[C:30](Cl)(Cl)=[S:31]>C(Cl)(Cl)(Cl)Cl.O.C(Cl)Cl.O>[N:13]([C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[C:30]=[S:31]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Reactant: S=C(Cl)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 52, (2.03 g, 5 mmol) and CaCO3 (1 g, 10 mmol) in CCl4/water (10:7.5 mL) is added thiophosgene (0.46 mL, 6 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2Cl2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue that is purified over silica (CH2Cl2) to afford 1.71 g (93% yield) of the desired product. ESI+MS 368 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:22]([O:24]CC)=[O:23])[CH3:21].[I-].[Li+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:22]([OH:24])=[O:23])[CH3:21]
Reactant: CCOC(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(=O)O
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1 g. of N-[4-bromo-3-(1-ethoxycarbonylethyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 5 g. of lithium iodide and 120 ml. of anhydrous N,N-dimethylformamide was heated with stirring in nitrogen gas flow at 140° C. for 1.5 hours and the reaction mixture was cooled to room temperature and 2N-HCl was added and the product was extracted with ether. The extract was concentrated under a reduced pressure and the residue was recrystallized from a mixture of benzene-cyclohexane to obtain 0.72 g. of Compound No. 10 shown in Table 1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:22])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(C(C)C)C(C)C)C.O1CCCC1>[Cu]I>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:16][C:14]([C:7]1[C:8](=[O:13])[N:9]([CH3:12])[C:10]2[C:5]([C:6]=1[OH:22])=[CH:4][CH:3]=[C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=2)=[O:15]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1c(O)c2ccc(C#C[Si](C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
In a sealed tube was combined methyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.75 g, 2.0 mmol), Dichlorobis(triphenylphosphine) palladium(II) (0.14 g, 0.20 mmol), copper(I) iodide (0.077 g, 0.41 mmol), ethynyltrimethylsilane (1.4 ml, 10 mmol), and N-ethyl-N-isopropylpropan-2-amine (2.8 ml, 16 mmol) in tetrahydrofuran (20.0 ml, 2.0 mmol). The tube was flushed with Ar, sealed, and placed in an oil bath at 100° C. for 5 hours. The dark mixture was cooled to rt, filtered and washed with ethyl acetate (2×30 mL). The crude mixture was concentrated, adsorbed onto silica and purified by flash chromatography (15% to 40% EtOAc:Hex gradient) to afford the product as a solid (0.59 g, 75% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:21])[CH3:20]>CO>[C:19]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])(=[O:21])[CH3:20].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Solvent: CO
Product: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30° C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 @ pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm×4.6 mm, 0.5 mL/min., @ 240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).
Reaction SMILES: [Cl-].[CH2:2]([N+:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]([OH:35])(=[O:34])[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:25]([O-:35])(=[O:34])[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27].[CH2:15]([N+:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:14])[CH3:13])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)C(O)c1ccccc1
Agent: CCCCCCCCCC[N+](C)(C)CCCCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C([O-])C(O)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 0.03 mol of didecyldimethylammonium chloride dissolved in 50 mL distilled water was added 0.03 mol of mandelic acid and 0.03 mol of NaOH. The mixture was stirred at 50° C. for 2 h. After cooling to room temperature, 60 mL of chloroform was added. Chloroform phase was washed with distilled water until chloride ions were no longer detected using AgNO3. The obtained mandelate with 96% yield is insoluble in water and was dried in vacuum.