Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:11][CH2:10][CH2:9][C:8]#[C:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: NCCC#Cc1ccccn1
Product: O=S(=O)(NCCC#Cc1ccccn1)c1ccccc1Cl
Yield: 31818.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 184, from 4-(pyridin-2-yl)but-3-yn-1-amine (16 mg, 0.11 mmol) and 2-chlorobenzene-1-sulfonyl chloride (30 mg, 0.14 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 11.2 mg (35 mmol, 32%) of 2-chloro-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as a brown oil.
Reaction SMILES: C(OCC[CH:6]([C:31]([OH:33])=[O:32])[N:7]([CH2:18][P:19]([S:26][CH2:27][CH2:28][CH2:29][CH3:30])([S:21][CH2:22][CH2:23][CH2:24][CH3:25])=[S:20])[C:8](OCC1C=CC=CC=1)=O)C.Br.[CH2:35]([O:37][CH2:38]C)[CH3:36]>C(O)(=O)C>[CH2:35]([O:37][CH2:38][CH2:8][N:7]([CH2:18][P:19]([S:21][CH2:22][CH2:23][CH2:24][CH3:25])([S:26][CH2:27][CH2:28][CH2:29][CH3:30])=[S:20])[CH2:6][C:31]([OH:33])=[O:32])[CH3:36]
Reactant: CCOCC
Reactant: CCCCSP(=S)(CN(C(=O)OCc1ccccc1)C(CCOCC)C(=O)O)SCCCC
Agent: Br
Solvent: CC(=O)O
Product: CCCCSP(=S)(CN(CCOCC)CC(=O)O)SCCCC
Reaction time: 6 h

Procedure:
2-Ethoxyethyl-N-[bis(butylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (9.2 g., 0.017 mole) was dissolved in 30 ml. of 35% hydrobromic acid in acetic acid. The reaction was stirred for approximately 6 hours. Diethyl ether was added which precipitated a viscous oil. The oil was washed three additional times with diethyl ether and then dissolved in benzene. The benzene solution was treated with excess propylene oxide. The propylene oxide treated solution was concentrated in vacuo and the residue chromatographed on silica gel employing diethyl ether as an eluant to yield 2-ethoxyethyl-N-[bis(butylthio)phosphinothioylmethyl]glycine as an oil, ND25 =1.5490, which gave the following analysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][CH:22]([CH2:24][CH2:25][CH:26](Br)[CH3:27])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:26]([CH3:27])[CH2:25][CH2:24][CH:22]([Br:21])[CH3:23])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(Br)CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(Br)CCC(C)Oc1ccc2[nH]cc(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
To a solution of 3-[2-(t-butyloxycarbonylamino)ethyl]-5-hydroxy-1H-indole (1.34 g, 4.86 mmol) in acetonitrile (50 mL) were added 2,5-dibromohexane (2.4 g, 9.72 mmol) and potassium carbonate (1.3 g, 9.72 mmol) and the resulting mixture was stirred at reflux for 60 hours. After cooling to room temperature, the solution was poured into ethyl acetate (40 mL), washed with water (40 mL), dried over sodium sulfate and evaporated to dryness. Column chromatography on silica gel using hexane/ethyl acetate (4:1, 2:1 and 1:1) provided the title compound as a syrup (0.65 g, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:12][CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[N:12]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1nc2cc[nH]c2cc1F
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2nc(C#N)c(F)cc21
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a solution of 6-fluoro-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (758 mg, 4.71 mmol) in THF (20 mL) was added NaH (60% in mineral oil, 452 mg, 9.42 mmol). After stirring for 30 min, SEM-Cl (1527 mg, 9.42 mmol) was added, followed by stirring at RT for 16 h. The reaction mixture was quenched by adding sat'd aq.NH4Cl and extracted with EtOAc (100 mL×2). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a petroleum ether:EtOAc gradient (10:1-0:10) to afford 1096 mg (80%) of 6-fluoro-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile. MS (ESI): m/z=292.1[M+1]+.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:5]>COCCO.O1CCCC1>[CH2:4]([O:6][C:7]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:21])[CH3:5]
Reactant: CCOC(=O)C(=O)CN1CCCc2ccccc21
Agent: [Cl-]
Agent: [Mg+2]
Solvent: COCCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(cccc13)CCC2
Reaction time: 5 h
Yield: 47.5 %

Procedure:
Add magnesium chloride (27.7 g, 0.29 mol) to 2-methoxyethanol (400 mL) and heat the mixture to reflux. Add a solution of 3-(3,4-Dihydro-2H-quinolin-1-yl)2-oxopropion-ic acid ethyl ester (0.29 mol) in 2-methoxyethanol (100 mL) and tetrahydrofuran (40 mL) slowly to the MgCl2 mixture over 1 hour. Upon completion of addition, stir the mixture for 5 hours at reflux, and then concentrate under reduced pressure. Treat the concentrated crude mixture with 2N hydrochloric acid (500 mL) and extract with dichloromethane (3×400 mL). Combine the organic layers, dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 20% ethyl acetate/hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as an orange solid (31.6 g, 48%).
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22].Cl>C1COCC1>[CH:7]([CH:4]1[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2][CH:3]1[O:10][C:21](=[O:22])[CH2:20][Br:19])([CH3:8])[CH3:9]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(OC(=O)CBr)C1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of (−) Menthol (2.75 mmoles) in anhydrous THF (5 ml), Et3N (2.75 mmoles) is added under stirring. The solution temperature is lowered to 0° C. and bromo-acetylbromide (2.5 mmoles) added. The solution temperature is then allowed to raise to room temperature and the reaction mixture is stirred for 2 hours. An HCl 1N (2 ml) aqueous solution is added and the organic phase is extracted with ethyl acetate (3×5 ml). The pooled organic phases are washed with a saturated aqueous NaCl solution (1×15 ml), dehydrated on Na2SO4 and filtered. The solvent is evaporated under a reduced pressure and the crude product is purified by flash chromatography in n-hexane/ethyl acetate 97/3 volume/volume. 388 mg of 2-isopropyl-5-methyl-cyclohexyl ester of the bromo acetic acid (51% yield) are recovered.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2].[NH2:18][CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:18][CH2:19][CH:20]2[O:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21]2)=[O:11])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.4 %

Procedure:
To a stirred mixture of 4-acetylamino-5-chloro-2-ethoxybenzoic acid (2.0 g), 2-aminomethyl-4-(4-fluorobenzyl)morpholine (1.6 g), and dichloromethane (20 ml) is added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 g), and the resulting mixture is stirred at 25° C. for 1.5 hours. The reaction mixture is washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue is recrystallized from ethanol to give the title compound (2.1 g), mp 161°-163° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C@H:8]1[N:11]([Si](C(C)(C)C)(C)C)[C:10](=[O:19])[C@@H:9]1[C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH3:21])[CH3:7])=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]([C@H:8]1[NH:11][C:10](=[O:19])[C@@H:9]1[C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[CH3:21])[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C

Procedure:
A solution of (3S,4S)-4-(1-ethoxycarbonylethyl)-3-(1-(R)-t-butyldimethylsilyloxyethyl)-1-t-butyldimethylsilyl-2-azetidinone (46.3 g) in dry tetrahydrofuran (60 ml) was treated with a 1 M tetrahydrofuran solution of tetra-n-butylammonium fluoride (96 ml) at room temperature for 45 minutes. The reaction mixture was diluted with ethyl acetate (250 ml) and washed with brine (60 ml). The washing was extracted with ethyl acetate (50 ml). The extract and the ethyl acetate layer were combined together, washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave and oily residue, which was purified by silica gel chromatography to yield (3S,4S)-4-(1-ethoxycarbonylethyl)-3-(1-(R)-t-butyl-dimethylsilyloxyethyl)-2-azetidinone.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:14][CH:13]([OH:15])[CH2:12][CH2:11][CH:7]1[C:8]([OH:10])=[O:9])=[O:5].[SH:16][CH2:17][CH2:18]C(N1CCC[C@H]1C(O)=O)=O>>[CH2:17]([S:16][S:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:14][CH:13]([OH:15])[CH2:12][CH2:11][CH:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:18]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Reactant: O=C(O)C1CCC(O)CN1C(=O)CCS
Product: CCSSCCC(=O)N1CC(O)CCC1C(=O)O

Procedure:
By substituting 1-(3-mercaptopropanoyl)-5-hydroxy-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 97, 1-[3-(ethyldithio)propanoyl]-5-hydroxy-L-pipecolic acid is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][Mg]Cl>C1COCC1>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)([OH:29])[CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2cccc(F)c2)C1
Reactant: COCCCC[Mg]Cl
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1Oc1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of (3R)-1-(tert-butoxycarbonyl)-3-((3-fluorophenoxy)benzoyl)piperidine (0.95 g, 2.37 mmol) in THF (3 mL) at −20° C. was added 1.45 M 4-methoxybutyl magnesium chloride in THF (3.3 mL, 4.76 mmol) dropwise. The resulting solution was warmed to rt slowly, and the completion of reaction was confirmed by LC-MS (˜20 min). The reaction was quenched with satd aq NH4Cl (4 mL) and extracted with Et2O (4×5 mL). The combined organic layers were washed with water and brine, and the solvent was removed in vacuo to give a crude product which was purified by flash column chromatography to afford (R)-tert-butyl 3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (0.50 g, 43%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1([C:26]2[NH:27][C:28]3[C:33]([C:34]=2[CH3:35])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:17][C:16]([N:23]([CH3:25])[CH3:24])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]1.C(N(CC)CC)C.[CH:43]1([S:48](Cl)(=[O:50])=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]1.[OH-].[Na+]>ClCCl>[CH2:19]([C:16]1([N:23]([CH3:25])[CH3:24])[CH2:17][CH2:18][C:13]([C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][CH2:2][NH:1][S:48]([CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)(=[O:50])=[O:49])=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:26]2[NH:27][C:28]3[C:33]([C:34]=2[CH3:35])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14][CH2:15]1)[CH2:20][CH2:21][CH3:22]
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCN)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCNS(=O)(=O)C2CCCC2)CC1

Procedure:
4-(3-(2-aminoethyl)-1H-indol-2-yl)-1-butyl-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexylamine (120 mg, 0.255 mmol, mixture of the two possible diastereoisomers in a ratio of approx. 30:70) mixed in dichloromethane (5 ml) with triethylamine (0.12 ml, 0.863 mmol) and cyclopentane sulphonyl chloride (65 mg, 0.385 mmol). After a reaction time of 24 h at 25° C. the reaction mixture was mixed with 1N sodium hydroxide solution (10 ml) and extracted with dichloromethane (3×15 ml). The combined organic phases were dried with Na2SO4 and then filtered. The volatile constituents of the filtrate were completely removed in a vacuum. The residue (yellow foam, 173 mg) was purified by column chromatography [silica gel 60 (25 g); ethyl acetate/methanol 4:1 (250 ml), methanol/30% ammonia 9:1 (100 ml)]. The product was obtained as a beige-coloured solid with a yield of 39 mg (25%) (melting point 111-115° C., AS 11227, mixture of the two possible diastereoisomers in a ratio of approx. 30:70).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.C(O)C.[OH-].[Ba+2:37].[OH-]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ba:37]
Reactant: [Ba+2]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: [Ba]
Temperature: 62.5 °C
Reaction time: 18 h

Procedure:
Raltegravir (100 gm), ethanol (600 ml), acetonitrile (400 ml) and barium hydroxide (42 gm) were added at 25 to 30° C. The contents were heated to 60 to 65° C. to obtain a solution. The solution was cooled to 25 to 30° C. and stirred for 18 hours at 25 to 30° C. The solid obtained was collected by filtration and dried to obtain 108 gm of raltegravir barium.
Reaction SMILES: [CH3:1][CH:2]([C:15]1([O:21][CH2:20]1)[C:16]([O:18]C)=[S:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O-]CC.[Na+].O>C(O)C>[CH3:1][CH:2]([C:15]1([O:21][CH2:20]1)[C:16]([OH:18])=[S:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCC(C)C1(C(=S)OC)CO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCC(C)C1(C(O)=S)CO1
Reaction time: 0.25 h

Procedure:
A solution of 3.15 g (0.01 mole) of methyl 2-tetradecylthioglycidate in 50 ml of absolute ethanol is added dropwise to a cooled (0°-5° C.) solution of sodium ethoxide (0.25 g sodium in 12 ml absolute ethanol). The mixture is stirred for 15 minutes while maintaining the temperature below 20° C. and 0.19 g of water is added. Stirring is continued overnight (about 15 hours) at room temperature. The resulting suspension is filtered and the precipitate washed with ether, dried and then stirred for several hours in dilute HCl. The acidic suspension is extracted with ether and the ether layer dried (Na2SO4) and evaporated in vacuo giving the product, 2-tetradecylthioglycidic acid, in good yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:46])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([N:15]([CH3:44])[CH:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([NH:36]C(=O)OC(C)(C)C)[CH:31]=4)=[CH:26][CH:25]=3)[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:14])[C:6]=2[CH:45]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:36][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH:16]([N:15]([CH3:44])[C:13](=[O:14])[CH2:12][N:7]3[C:6]4[CH:45]=[C:2]([Cl:1])[C:3]([Cl:46])=[CH:4][C:5]=4[O:10][CH2:9][C:8]3=[O:11])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:25][CH:26]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(NC(=O)OC(C)(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a solution of 1,1-dimethylethyl {4′-[1-[[(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetyl](methyl)amino]-2-(4-morpholinyl)ethyl]-3-biphenylyl}carbamate (1.55 g, 2.3 mmol) in dichloromethane (8 mL) was added trifluoro acetic acid (8 mL). The resultant mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by using a Gilson preparative HPLC (Phenomenex, 100×50 mm, 10 micron, 90 mL/min, A: acetonitrile, 0.1% TFA B: water, 0.1% TFA, A: 10 to 90% over 15 min, UV detection at 214 nm) to give 0.66 g (50%) of the title compound as tan solid MS (ES) m/e 569.1 [M+H]+
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([OH:19])[C:12]([OH:20])=[N:11]2)=[N+:6]=[N-:7].[K+].[Br-]>>[N:5]([C:8]1[C:9]([N+:1]([O-:4])=[O:2])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([OH:19])[C:12]([OH:20])=[N:11]2)=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=Nc1cc2nc(O)c(O)nc2cc1Cl
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Product: [N-]=[N+]=Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15 ml 89% nitric acid was ice-cooled and then gradually added 1 g (4,2 mmol) 6-azido-7-chloro-2,3-dihydroxyquinoxaline. After stirring at 0° C. for 15 min, the reaction mixture was poured into 100 ml ice-water. The crude product was recrystallized (acetone-methanol-water) to give 0,95 g (80%) 6-azido-7-chloro-2,3-dihydroxy-5-nitroquinooxaline. IR (KBr): 2450 cm-1 (N3). NMR (DMSO-d6) 12.3 (2H, broad s), 7.07 (1H,s).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][CH:12]=[CH:11][C@H:10]1[O:24][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([CH2:15][O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:13][CH:12]=[CH:11][C@H:10]1[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C=CO[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O[C@@H]1C=CO[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4,6-Di-O-benzyl-3-O-tert-butyldimethylsilyl-D-glucal (3 mmol) was dissolved in THF (35 mL). Tetrabutyl fluoride (1M solution in THF) (3.5 mL) was added and the reaction mixture was stirred at room temperature overnight, then water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with water until neutral, and dried over anhydrous sodium sulfate. Solids and solvents were removed and crude product was purified by column chromatography (SilicaGel 60) using hexanes:ethyl acetate as eluents. Pure 4,6-di-O-benzyl-D-glucal (2.61 mmol, yield 87%) was obtained. mp 53° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq., prepared in Synthetic Example 10) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 209 to 210° C./DMF-EtOH.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][C:27](=O)[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(C(F)(F)F)=O>[CH2:17]([N:24]1[C@H:29]([CH3:30])[CH2:28][CH:27]([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1Cc1ccccc1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (400 mg, 1.72 mmol) in THF (15 mL) and TFA (491 uL) was added (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (410 mg, 1.89 mmol) at 0° C. The mixture was stirred at 60° C. for 1 hour under nitrogen atmosphere. Then the mixture was cooled to 0° C. in an ice bath, sodium triacetoxyborohydride (765 mg, 3.43 mmol) was added. The reaction mixture was stirred at 23° C. for 2 hours. Then aq. NaHCO3 was added at 0° C. until pH8-9, and the content was extracted with ethylacetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=3/1) to give the titled compound as a colorless oil. (278 mg, 37% yield). 1H-NMR (400M Hz, CDCl3) δppm; 7.21-7.40 (m, 6H), 6.90 (s, 1H), 3.95 (d, J=14.0 Hz, 1H), 3.90 (s, 3H), 3.60-3.73 (m, 2H), 3.46 (d, J=14.0 Hz, 1H), 3.08-3.12 (m, 1H), 2.98-3.03 (m, 1H), 2.30 (s, 3H), 2.02-2.08 (m, 1H), 1.83-1.88 (m, 1H), 1.52-1.60 (m, 1H), 1.17-1.26 (m, 1H), 1.11 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:26](#[N:29])[CH:27]=[CH2:28]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:27](=[CH2:28])[C:26]#[N:29])=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: C=CC#N
Reactant: COc1ccc(-c2cnc(Cl)c(C=O)c2)cc1
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1cc(-c2ccc(OC)cc2)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.99 g.).