Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]3=[O:22])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:23].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]3=[O:22])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:23]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1F
Solvent: CSC
Solvent: CC(=O)Cl
Product: O=C1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1F
Temperature: 40 °C
Reaction time: 96 h
Yield: 49 %

Procedure:
To the mixture of (R)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-alcohol (0.726 mmol), freshly fused zinc chloride (2.17 mmol), dimethyl sulphide (3.2 mmol), acetyl chloride (2.17 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. To this reaction mixture extracted with the ethyl acetate water mixture and organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel afforded title compound in 49% yield.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:33][CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24]1>CN(C)C=O.O>[CH2:29]([O:28][C:26]([CH:25]1[CH2:31][CH2:32][CH2:33][N:23]([CH:16]2[CH2:17][N:14]([CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15]2)[CH2:24]1)=[O:27])[CH3:30]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)C1CCCNC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C1
Temperature: 110 °C

Procedure:
Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (A. G. Anderson, Jr. and R. Lok, J. Org. Chem., 1972, 37, 3953)(2.22 g, 7 mmol) and ethyl nipecotate (1.0 g, 6.37 mmol) were dissolved in dimethylformamide (3 mL) and heated at 110° C. for 1 hr. The mixture was cooled to ambient temperature, diluted with water and extracted with dichloromethane (3×15 mL). The extract was dried over anhydrous magnesium sulfate and the solvent removed under vacuum to give an impure sample of 1-(1-benzhydryl-azetidin-3-yl)-piperidine-3-carboxylic acid ethyl ester (2.91 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:19]([F:30])=[CH:18][N:17]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]2[C:19]([F:30])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=4[CH:14]=3)[N:21]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)cc1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)cc4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 5-amino-2-methoxycarbonylbenzofuran with 2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gave N4-(4-chlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine. 1HNMR (DMSO-d6): δ 10.28 (bs, 1H), 10.18 (bs, 1H), 8.25 (d, 1H, J=4.5 Hz), 7.96 (bs, 1H), 7.84 (m, 1H), 7.67 (m, 3H), 7.57 (m, 1H), 7.37 (bd, 2H, J=9.0 Hz), 3.88 (s, 3H); LCMS: purity: 96%; MS (m/e): 413 (MH+).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11][OH:12].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH2:15]([O:14][CH2:13][C@@H:10]([NH:9][C:24](=[O:25])[CH2:23][Cl:22])[CH2:11][OH:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@@H](CO)COCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@@H](CO)COCc1ccccc1
Temperature: 0 °C

Procedure:
Add triethylamine (7.0 mL, 50.6 mmol) to a RT slurry of (S)-2-amino-3-benzyloxy-propan-1-ol hydrochloride (5 g, 23.0 mmol) in CH2Cl2 (75 mL). Stir until all the solid dissolves and then cool to 0° C. Add chloroacetylchloride (2.0 mL, 25.3 mmol). Stir 1 h and add more TEA (960 μL, 6.9 mmol) and chloroacetylchloride (549 μL, 6.9 mmol) to consume all the starting amine with continued stirring for 2 h. Pour into a separatory funnel containing 1 N HCl (200 mL) and extract with CH2Cl2 (2×250 mL). Wash the combined organic extracts with brine (200 mL), dry over Na2SO4, and concentrate to give crude N—((S)-1-benzyloxymethyl-2-hydroxy-ethyl)-2-chloro-acetamide. Dissolve this intermediate in THF (75 mL), cool to 0° C., and treat with NaH (1.1 g, 27.6 mmol). Stir 6 h at 0° C. to form the NH morpholinone. Add additional NaH 1.1 g (27.6 mmol) followed by MeI (3.6 mL, 57.5 mmol). Stir at 0° C. for 30 min and then pour into a separatory funnel containing 0.1 M HCl (200 mL). Extract with EtOAc (2×250 mL). Wash the combined organic extracts with brine (200 mL), dry over Na2SO4, filter, and concentrate to give the crude methylated product. Purify via silica gel chromatography using a gradient of 0-100% EtOAc/hexanes to yield 1.3 g (24%, 3 steps) of the title compound. MS/ES m/z 236.1 [M+H]+.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:5][CH:4]=1>C(#N)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][S:11](=[O:13])(=[O:12])[NH2:1])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC(CS(=O)(=O)Cl)c1ccc(Cl)cc1
Reactant: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(CS(N)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
Ammonia (1.5 mL, 31.50 mmol) was added to a suspension of tert-butyl 1-(4-chlorophenyl)-2-(chlorosulfonyl)ethylcarbamate (Intermediate 78) (0.542 g, 1.53 mmol) in acetonitrile (10 mL). The mixture was stirred for 16 hours at room temperature. The mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine. The organic solution was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (10% ethyl acetate/DCM to 30% ethyl acetate/DCM). The desired product, tert-butyl 1-(4-chlorophenyl)-2-sulfamoylethylcarbamate (0.351 g, 68.5%), was thus isolated as a colourless solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CN(C)C=O.[Tl+].[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]1[C:27](=[O:28])[N:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:25]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:23]1=[O:24]>CCOCC>[C:35]1([N:25]2[C:23]([O:24][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])=[C:22]([CH2:21][CH2:20][CH2:19][CH3:18])[C:27](=[O:28])[N:26]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Agent: [Tl+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1c(OS(=O)(=O)c2ccc(C)cc2)n(-c2ccccc2)n(-c2ccccc2)c1=O
Reaction time: 8 h
Yield: 33 %

Procedure:
Then, p-Toluenesulfonyl chloride (0.95 g, 5.0 mmole) was allowed to react with a dimethylformamide (20 ml) suspension of the Thallium (I) salt of phenylbutazone. Within a few minutes the solvent because pink and a yellow solid, instead of the white Thallium (I) salt of phenylbutazone, was observed suspended in the pink solution. The suspension was stirred overnight in a tightly sealed flask, then it was diluted with 100 ml of ether and filtered. The filtrate was concentrated in vacuo to remove the ether and the dimethylformamide was evaporated under a stream of nitrogen. The residue from the evaporation was suspended in dichloromethane and filtered. Analysis of the filtrate by TLC showed that it contained only one major component. The dichloromethane was evaporated in vacuo and the residue was crystallized from ether to give 0.76 g (mp 112°-121° C., 33% yield) of yellow crystals which contained only one component by TLC analysis. Recrystallization of the yellow crystals gave analytically pure crystals, mp 125°-127° C. with spectral properties identical to the crystals, mp 112°-121° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]1([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21]1)=[O:18])=[CH:10][CH:9]=2)#[CH:4].[CH2:28](Br)[C:29]#[CH:30].O>C1COCC1>[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]1([CH2:24][O:25][CH2:30][C:29]#[CH:28])[CH2:23][CH2:22][CH2:21]1)=[O:18])=[CH:10][CH:9]=2)#[CH:4]
Reactant: C#CCBr
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(CO)CCC3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCC1(NC(=O)C(Oc2ccc3ncc(C#C)cc3c2)SC)CCC1
Temperature: 25 °C
Yield: 15.5 %

Procedure:
NaH (172 mg, 60% in oil) was added to a solution of 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-cyclobutyl)-2-methylsulfanyl-acetamide (850 mg) in THF (50 ml), at room temperature, under nitrogen atmosphere. The mixture was stirred until gas evolution ceased (30 min). Propargyl bromide (638 mg, 80% toluene solution) was added and the mixture was stirred at 40° C. during 3 hours, and then after cooling to room temperature poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/CH2Cl2, 1/1/1) to give 2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-N-(1-prop-2-ynyloxymethyl-cyclobutyl)-acet-amide (146 mg) as slightly brown oil. 1H NMR (CDCl3) δ ppm: 8.82 (1H, d); 8.18 (1H, d); 8.03 (1H, d); 7.44 (1H, dd); 7.21 (1H, d); 6.88 (1H, br s); 5.62 (1H, s); 4.14 (2H, s); 3.84-3.74 (2H, dd, AB system); 3.28 (1H, s); 2.49-2.13 (4H, m); 2.42 (1H, s); 2.19 (3H, s); 2.01-1.79 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[NH:15][C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[N:12]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:15]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[N:12]=3)=[N:9][N:8]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc2nc(-c3n[nH]c4ncc(Br)cc34)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(-c3nn(COCC[Si](C)(C)C)c4ncc(Br)cc34)n(COCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-bromo-3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine Compound 19c (HOAc salt, 50 mg, 0.145 mmol) was added to a suspension of NaH (60% in mineral oil, 23 mg, 0.581 mmol) in DMF (5 mL). The mixture was stirred at r.t. for 5 mins, then SEMCl (97 mg, 0.581 mmol) was added. The mixture was stirred at r.t. for 12 hrs, then diluted with AcOEt (60 mL) and washed with water. The solvent was evaporated to dryness and the residue was purified by chromatography to provide 5-bromo-3-[6-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 20a (60 mg, 78% yield) as a sticky oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:35][C@H:36]1[NH:40][C:39](=[O:41])[CH2:38][CH2:37]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:35][C@H:36]2[NH:40][C:39](=[O:41])[CH2:38][CH2:37]2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: O=C1CC[C@@H](CO)N1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OC[C@@H]4CCC(=O)N4)c3)cc2)cccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
The product from Example 61F (88 mg, 0.2 mmole), (S)-5-(hydroxymethyl)-2-pyrrolidinone (58 mg, 0.5 mmole), di-tert-butyl azodicarboxylate (69 mg, 0.3 mmole), and triphenylphosphine (77 mg, 0.3 mmole) were dissolved in tetrahydrofuran (1.5 mL) in a capped test-tube and shaked at room temperature overnight. Ethyl acetate (2 mL) was added to dilute the reaction mixture. Then, the diluted organic solution was washed with water (2 mL) and saturated sodium chloride solution (2 mL), dried in vaccuo, and purified by HPLC to give the pure intermediate.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:18][C:19]([F:28])([F:29])[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:13]2[N:12]=[C:11]([C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)[CH:16]=[N:15][CH:14]=2)=[CH:26][CH:27]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Yield: 20.4 %

Procedure:
Using Method K, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 4-(trifluoromethoxy)aniline (51 mg, 0.29 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 80° C. for 12 hours. The same workup as for Method K and a combination of column chromatography and preparative TLC furnished 19 mg of title compound. Yield: 20.4%. 1H NMR (250 MHz, DMSO-d6) δ 2.10 (s, 3 H), 7.34-7.47 (m, 3 H), 7.60 (d, 1 H, 7.9 Hz), 7.74 (d, 1 H, 7.8 Hz), 8.00 (d, 2 H, 9.1 Hz), 8.21 (s, 1 H), 8.51 (bs, 2 H), 9.82 (s, 1 H), 10.10 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.09, 117.01, 119.09, 119.87, 120.94, 121.68, 129.15, 130.40, 133.52, 136.73, 139.92, 141.96, 141.99, 147.66, 151.00, 168.45; m/z 389.3 [(M+H)+, calcd for C19H15F3N4O2 388.1].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].O.[OH-].[Na+:20].[S:21]([O-:24])([O-:23])=[O:22].[Na+].[Na+]>C(O)CC>[Na+:20].[S:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O-:17])=[O:16])([OH:24])(=[O:23])=[O:22]
Reactant: O=S([O-])[O-]
Reactant: O=C(O)CCCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: O=C([O-])CCCCCCCCCCCCCS(=O)(=O)O

Procedure:
Above prepared 14-bromo-tetradecanoic acid (8.34 g, 26.0 mmol) was dissolved in n-propanol (10 mL), water (25 mL) and 1M aqueous solution of sodium hydroxide (32 mL) and sodium sulfite (5.00 g, 39.7 mmol) was added. Reaction mixture was heated to reflux for 22 hrs. After cooling down white precipitate was filtered off. Conc. hydrochloric acid was added to give acidic pH and precipitate was centrifuged and decantated two times with water (2×50 ml). After lyophilization 14-sulfo-tetradecanoic acid sodium salt was obtained as a white solid.
Reaction SMILES: [C:1](=[S:9])([S-:8])[S:2][CH2:3][CH2:4][O:5][CH2:6][CH3:7].[K+].[CH2:11]([S:13][CH:14]1[N:17]([CH:18](Cl)[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C:16](=[O:33])[CH2:15]1)[CH3:12]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH2:11]([S:13][CH:14]1[N:17]([CH:18]([S:9][C:1]([S:2][CH2:3][CH2:4][O:5][CH2:6][CH3:7])=[S:8])[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C:16](=[O:33])[CH2:15]1)[CH3:12]
Reactant: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOCCSC(=S)[S-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: CCOCCSC(=S)SC(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SCC
Reaction time: 1 h
Yield: 30.9 %

Procedure:
A solution of 3.58 g potassium 2-ethoxyethyl trithiocarbonate and 3.7 g benzyltriethylammonium chloride in 100 ml methylene chloride was cooled to 0° C. under a nitrogen atmosphere and a solution of 5.3 g of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-chloroacetate in 50 ml methylene chloride was added dropwise. The reaction mixture was stirred for 1 hour, then washed with three 50 ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. (8.6 g). The crude product was chromatographed on silica gel eluting with 5% ethyl acetate in chloroform to yield 2.3 g of the title compound as an oil. The IR spectrum of a chloroform solution of the title compound had an absorption at 5.65 micron; and the NMR spectrum in deuterochloroform showed peeks at 1.2(m,6H);2.34-3.77(c,10H);4.7,4.98(m,1H); 5.26(s,2H); 6.62,6.86(s,1H); 7.43(m,2H); and 8.16(m,2H). ppm.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N:18]3[CH:22]=NC=N3)=[N:13][C:12]2=[O:23])[CH2:8][C@@H:7]1[N:24]=[N+:25]=[N-:26])(=[O:3])[CH3:2].[CH2:27](N)[CH2:28]C>CC#N>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14]([NH:18][CH2:22][CH2:27][CH3:28])=[N:13][C:12]2=[O:23])[CH2:8][C@@H:7]1[N:24]=[N+:25]=[N-:26])(=[O:3])[CH3:2]
Reactant: CCCN
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(-n3cncn3)nc2=O)C[C@@H]1N=[N+]=[N-]
Solvent: CC#N
Product: CCCNc1nc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](COC(C)=O)O2)cc1C

Procedure:
1-(5-O-Acetyl-3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-4-(1,2,4-triazol-1-yl)-2-(1H)-pyrimidinone (0.5 g, 1.4 mMol) was dissolved in dry CH3CN (50 mL) and treated with n-propylamine (0.6 mL, 7 mMol) at ambient temperature for 48 hours. The reaction was evaporated to an oil and chromatographed on silica gel eluted with 20:1 CHCl3/MeOH (v/v). The appropriate fractions were combined and evaporated to give the title compound as a solid: mp=138°-140° C.; UV(nm): at pH 1 λmax=285,217(ε=14900,12200), λmin=246(ε=2500); at pH 13 λmax=274(ε=12500), λmin=250(ε=9000), λsh=236(ε=10000); H NMR(DMSO-d6) δ7.32(s,1H,H6), 7.24-7.18(m,1H,--NH--), 6.13(t,1H,H1',J=6.44 Hz), 4.45-4.40(m,1 H,H3'), 4.23-4.21(m,2H,--NH--CH2--), 4.00-3.92(m,1H,H4'), 3.26-3.19(m,2H,H5'), 2.33-2.26(m,2H,H2'), 2.05(s,3H,acetyl), 1.85(s,3H,5-CH3), 1.57-1.46(m,2H,--CH2--CH3), 0.88-0.81(t,3H,--CH2--CH3).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].[CH2:16]([Mg]Br)[CH3:17].Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]([CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH2:16][CH3:17])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Reactant: CC[Mg]Br
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCC(c1cc(C(C)(C)O)on1)C(C#N)C#N
Reaction time: 1 h

Procedure:
1.02 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.05 g of copper(I) iodide was added and ml of a 3 M solution of ethylmagnesium bromide in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.40 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]propyl}malononitrile.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][C:4]=2[C:5]2[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:18][CH:15]1[CH2:14][C:4]2[C:5]3[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]=3[CH:11]=[C:2]([Br:1])[C:3]=2[CH2:17][CH2:16]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1[nH]c2cc(Br)c3c(c2[nH]c1=O)CC(O)CC3
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Br)c3c(c2[nH]c1=O)CC(OCc1ccccc1)CC3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-9-hydroxy-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (0.1 g, 0.32 mmol) and sodium hydride (16 mg, 0.4 mmol) in dimethylformamide (1 mL) was stirred at 0° C. for 30 min, and then treated with benzyl bromide (70 mg, 0.4 mmol). The reaction mixture was stirred for 48 h and warmed to room temperature during that time. The solvent was removed by rotoevaporation, the residue triturated in ethyl acetate, and the solid collected by filtration and dried. CI MS m/e (M+1) 402, 404. H-NMR (200 MH2, dmso): 1H, s, 12.05; 1H, s, 11.95; 5H, m, 7.4-7.2; 1H, s, 7.05; 2H, s, 5.4; 1H, s, 4.75; 1H, m, 3.9; +ring protons.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].O>C(Cl)Cl>[F:1][CH2:2][CH2:3][CH2:4][O:5][S:7]([CH3:6])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCF
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCCF
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.6 %

Procedure:
A solution of 3-fluoro-propan-1-ol (31.2 g, 400 mmol) in 300 mL of CH2Cl2 was treated with methanesulfonyl chloride (55 g, 38 mL, 480 mmol, 1.2 equiv) at 0° C. The resulting reaction mixture was gradually warmed to room temperature and stirred for 1-2 hours. When 1H NMR showed the reaction was complete, the reaction mixture was treated with H2O (100 mL), and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with H2O (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the desired methanesulfonic acid 3-fluoro-propyl ester (57.2 g, 91% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])c(C(=O)Cl)c1

Procedure:
A mixture of 5-methyl-2-nitrobenzoic acid (3.6 g, 19.87 mmol) and thionyl chloride (18 mL) was stirred under reflux for 20 hours then concentrated under reduced pressure to give 5-methyl-2-nitrobenzoyl chloride (3.77 g) which was used without further purification.