Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12]>N1C=CC=CC=1>[C:11](=[O:12])([O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CC1(C)OC[C@@H](COC(=O)Oc2ccc([N+](=O)[O-])cc2)O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(4S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethanol (362 mg, 2.74 mM) was dissolved in pyridine (9 ml), stirred at ambient temperature, and treated in portions with 4-nitrophenyl chloroformate (552 mg, 2.74 mM). After 6 hours, solvent was evaporated, the residue redissolved in ethyl acetate (15 ml), washed with water (15 ml), sodium bicarbonate solution (15 ml), brine (15 ml), and dried (magnesium sulfate). Removal of the solvent gave the product as an oil sufficiently pure for further use (858 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:26])([C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:5][OH:6].Cl[CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1>CN(C)C=O>[F:3][C:4]([F:26])([C:7]([F:24])([F:25])[C:8]([F:22])([F:23])[C:9]([F:20])([F:21])[C:10]([F:18])([F:19])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:5][O:6][CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC1(CCl)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dispersion of 50 weight percent sodium hydride (4.0 g, 83 mmol) in mineral oil was washed with hexanes and suspended in 200 milliliters of dimethylformamide. A solution of 30 grams of 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol (75 mmol) in 50 milliliters of dimethylformamide was added over a period of 3 hours, and the resulting mixture was stirred at room temperature for one hour. Next, a solution of 9.3 grams (77 mmol) of 3-chloromethyl-3-methyloxetane in 20 milliliters of dimethylformamide was added and the resulting mixture was heated at 75° C. for 16 hours. The mixture was cooled to room temperature and slowly poured into 1 liter of ice/water and extracted with two volumes of Freon 113. The combined organic extracts were washed twice with water, once with 2 weight percent aqueous hydrochloric acid and once with brine, dried over magnesium sulfate, filtered, and evaporated to give 32 grams of crude product. The crude product was distilled under reduced pressure to give 26.5 grams (73%) of analytically pure 3-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctoxymethy)-3-methyloxetane (i.e., 15-FOX), an oil with a boiling point of 68 to 70° C./1.6 mm-Hg. The experimental analyses were: 1H NMR (CDCl3/Freon 113) δ 4.49 and 4.37 (AB, J=5.5 Hz, 4 H), 4.00 (triplet, J=13.2 Hz, 2 H), 3.70 (singlet, 2 H), and 1.32 (singlet, 3 H); 13C NMR δ 21.02, 40.33, 68.77 (triplet, J=146.2 Hz), 78.60, and 79.87 (signals from carbon bearing fluorine are not included due to complex splitting patterns and low peak intensities); 19F NMR δ −81.3 (3 F), −119.9 (2F), −122.6 (2 F), −123.3 (2 F), −123.5 (2 F), −123.9 (2 F) and −126.8 (2 F). The elemental analysis was: Calculated for C13H11F15O2: C, 32.2; H, 2.3; F, 58.9. Found: C, 32.2; H, 2.2; F, 58.3.
Reaction SMILES: [Mg].[CH3:2][C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([CH3:16])[C:10](=[O:15])[CH2:11][C:12]([O-:14])=O)[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:25]O>>[CH3:2][C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([CH3:16])[C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:25])[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CC(=O)[O-])CO1
Reactant: CO
Agent: [Mg]
Product: CC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A suspension of magnesium turnings (100 mg) in methanol was stirred whilst a solution of t-butyl [4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (1.40 g) in methanol was added. The mixture was heated at 60° C. for 1 hour, cooled and evaporated. Toluene was added and the mixture re-evaporated. The residue was redissolved in toluene and a solution of acetyl chloride (300 mg) added. The mixture was stirred at 20° C. for 1 day, then hydrochloric acid (2M) added and the stirring continued for another 1 hour. The organic phase was washed with hydrochloric acid (2M) then with water and dried (magnesium sulphate) 4-Toluene-sulphonic acid (50 mg) was added and the mixture stirred at 80° C. for 1 hour, cooled and washed in turn with saturated sodium bicarbonate solution and water, dried (magnesium sulphate) and evaporated to give 5-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-1,3-oxazin-3-yl)-5-methyl-2,4-hexanedione (Compound 193, 0.15 g) as a brown gum, NMR 1.56(s,6H), 1.91(s,3H), 2.15(s,3H), 3.66 and 3.70(s,1H), 5.25(t,2H), 7.20-7.44(m,5H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[CH3:36][N:37]1[CH:41]=[C:40]([CH2:42][C:43](O)=[O:44])[N:39]=[CH:38]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43](=[O:44])[CH2:42][C:40]4[N:39]=[CH:38][N:37]([CH3:36])[CH:41]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Cn1cnc(CC(=O)O)c1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(CC(=O)N2CCC(c3ccc(NC(=O)c4nc(C#N)c[nH]4)c(C4=CCCCC4)c3)CC2)c1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), according to the procedure in Example 29 using (1-methyl-1H-imidazol-4-yl)-acetic acid. 1H-NMR (400 MHz, CD3OD): δ 8.82 (s, 1H), 8.10 (d, 1H), 8.00 (s, 1H), 7.42 (s, 1H), 7.16 (dd, 1H), 7.06 (d, 1H), 5.80 (m, 1H), 4.66 (m, 1H), 4.12 (m, 1H), 4.04 (m, 2H), 3.92 (s, 3H), 3.28 (m, 1H), 2.82 (m, 2H), 2.26 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C28H31N7O2, 498.2 (M+H), found 498.2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1.O1CCN(C2C=CC(N)=C(N)C=2)CC1.[NH2:36][C:37]1[CH:42]=[C:41]([C:43]#[N:44])[CH:40]=[CH:39][C:38]=1[NH:45]C1N=CC(CC(N)=O)=C(NCC2C=C(F)C=C(F)C=2)C=1>>[NH2:45][C:38]1[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:37]=1[NH:36][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1cc(F)cc(F)c1
Reactant: N#Cc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c(N)c1
Agent: Nc1ccc(N2CCOCC2)cc1N
Product: N#Cc1ccc(N)c(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c1

Procedure:
From 6-chloro-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 20) and 4-morpholino-1,2-phenylenediamine in a manner similar to step 1 of Example 365, a mixture of 6-[(2-amino-4-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide and 6-[(2-amino-5-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (1H-NMR integral ratio 1:1) was obtained as a red oil (yield 17%).
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][CH:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=1[C:25](Cl)=[O:26]>CC(C)=O>[CH3:33][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[C:24]=1[C:25]([N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:1][CH2:2][CH2:3][CH:4]2[CH2:13]1)=[O:26]
Reactant: c1ccc2c(c1)NCC1CCCN21
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1cccc(OC)c1C(=O)N1CC2CCCN2c2ccccc21
Reaction time: 3 h
Yield: 79 %

Procedure:
To a stirred solution of the 1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline 1.7 g. (0.009 mole) and 4 ml. of dry triethylamine in 50 ml. of dry acetone was added 2.5 g. (0.01 mole) of 2,6-dimethoxybenzoyl chloride. The reaction mixture was stirred for three hours and filtered, and the acetone was evaporated under vacuo. The residue was washed with water, dried and recrystallized from aqueous ethanol to afford 2.4 g. (79% yield) of the title compound, m.p. 140°-142° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Cl[C:16]1[C:17]2[CH:24]=[CH:23][NH:22][C:18]=2[N:19]=[CH:20][N:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:19]1[C:18]2[NH:22][CH:23]=[CH:24][C:17]=2[C:16]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[N:21][CH:20]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(c2ncnc3[nH]ccc23)C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl piperidin-3-ylcarbamate compound (5.0 g, 25 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.75 g, 25 mmol) in DMF (50 mL) was added DIEA (4.2 mL, 3.1 g, 25 mmol) and the solution was stirred at 100° C. for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate. To a solution of tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate (6.3 g, 20 mmol) in dioxane (50 ml) was added 4.0 N HCl (50 mL, 200 mmol) and stirred at rt. After several hours, the reaction mixture was concentrated in vacuo to give compound 33.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[NH:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:32])[CH:28]=2)[N:23]=1>>[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[NH:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:32][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:28]=2)[N:23]=1
Reactant: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CN(C)S(=O)(=O)Cl
Product: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(NS(=O)(=O)N(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoylchloride and rac-N2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=482.6 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([NH2:10])=[CH:8][N:7]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C1C(C(O)=O)=CN=C(C2C=CC(C(F)(F)F)=CC=2)N=1.[C:44]([O:48][C:49](=[O:64])[C:50]([O:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][C:61](O)=[O:62])[CH:55]=1)([CH3:52])[CH3:51])([CH3:47])([CH3:46])[CH3:45].COC(=O)CC1C=CC=C(O)C=1.BrC(C)(C)C(OC(C)(C)C)=O>>[C:44]([O:48][C:49](=[O:64])[C:50]([O:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][C:61](=[O:62])[NH:10][C:9]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[N:5][C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)=[N:7][CH:8]=2)[CH:55]=1)([CH3:52])[CH3:51])([CH3:46])([CH3:45])[CH3:47]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Reactant: Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: CC(C)(C)OC(=O)C(C)(C)Br
Agent: COC(=O)Cc1cccc(O)c1
Agent: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)Nc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 124C], 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylamine (prepared from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid, see example 133], in analogy to the procedures described in examples 125B] and 125C]) was reacted with 2-(3-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (prepared from (3-hydroxy-phenyl)-acetic acid methyl ester and tert-butyl alpha-bromoisobutyrate, in analogy to the procedure described in example 52A], followed by saponification in analogy the procedure described in example 124A]) to give 2-(3-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl]-methyl}-phenoxy)-2-methyl-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as light yellow amorphous solid.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.Cl.[CH3:11][N:12]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]1[C:20]([NH:22][NH:23][C:24](=[NH:26])[NH2:25])=N>>[NH2:25][C:24]1[NH:26][C:20]([C:13]2[N:12]([CH3:11])[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=2)=[N:22][N:23]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(=N)N
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc(N)[nH]1

Procedure:
In 110 ml. of nitrobenzene, 7.6 g. (0.029 mole) of 2-(1-methyl-5-nitro-2-imidazolecarboximidoyl)-1-amidinohydrazine hydrocloride is stirred at reflux temperature for 23/4 hours, cooled, and the solid collected. This solid is washed with ethyl alcohol, ether, and air-dried to give 6 g. of the title compound, melting point 278°-280° (dec.). The product is purified by removing soluble impurities in a Soxhlet extractor with 95% ethanol. The insoluble products melts at 297°-299° (dec.).
Reaction SMILES: [SH:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=O.[CH2:13]([O:15][C:16]([CH:18]=[C:19]([CH3:31])[CH2:20]P(=O)(OC(C)C)OC(C)C)=[O:17])[CH3:14].CN(C)C=O.[OH-].[Na+]>CCCCCC.O>[SH:1][C:2]([CH3:11])([CH3:12])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=[CH:20][C:19]([CH3:31])=[CH:18][C:16]([O:15][CH2:13][CH3:14])=[O:17]
Reactant: CC(CC=O)CCCC(C)(C)S
Reactant: CCOC(=O)C=C(C)CP(=O)(OC(C)C)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)S
Reaction time: 0.5 h

Procedure:
A mixture of 5 g. of 7-mercapto-3,7-dimethyloctan-1-al 8.5 g. of di-isopropyl 3-ethoxycarbonyl-2-methylprop-2-enyl-phosphonate, and 40 ml. of dimethylformamide, under nitrogen and cooled in an ice-bath, is stirred for 0.5 hours and then ground NaOH (1.165g.) is added. The reaction mixture is stirred at room temperature for 3 hours and then hexane-water (1/1) added. The organic layer is washed with water and brine, dried over calcium sulfate and concentrated. The concentrate is filitered through Florisil using hexane and hexane/ether. The filtrate is concentrated and then distilled to yield ethyl 11-mercapto-3,7,11-trimethyldodeca-2,4 -dienoate (mostly trans-2, trans-4).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].C([Li])CCC.[CH2:33]([S:40]C#N)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.CCCCCC>[CH2:33]([S:40][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#CSCc1ccccc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(SCc2ccccc2)c1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
A solution of 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulphonylpyrazole (3.0 g) in dry tetrahydrofuran (32 ml), stirred under nitrogen at -78° C., was treated with a solution of n-butyllithium in hexane (2.8 ml of a 2.5M solution) over a period of 5 minutes. After 1 hour at -78° C., a solution of benzyl thiocyanate (0.95 g) in tetrahydrofuran (2 ml) was added. The stirred mixture was allowed to warm slowly to room temperature during 16 hours, then poured onto ice/water (50 ml) and extracted with ether (3×50 ml). The combined extracts were dried over anhydrous magnesium sulphate, evaporated in vacuo, and purified by chromatography, eluting with ethyl acetate/hexane (2:98). The product was triturated with hexane to give 5-benzylthio-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulphonylpyrazole (0.25 g), as a white solid, m.p. 117°-119° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][CH2:29][CH:30]2[O:32][CH2:31]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:33]([CH2:31][CH:30]([OH:32])[CH2:29][S:28][CH2:27][C@@H:11]1[CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])=[N+:34]=[N-:35]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC2CO2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(O)CN=[N+]=[N-])N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
A solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-[(2,3-epoxypropyl)thiomethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.59 g), sodium azide (0.52 g) and ammonium chloride (0.43 g) in N,N-dimethylformamide (26 ml) was stirred at 80°-90° C. for 2 hours. The reaction mixture was poured into ice-water (100 ml) and extracted 3 times with ethyl acetate (40 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of n-hexane and ethyl acetate (3:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-[(3-azido-2-hydroxypropyl)thiomethyl]-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.95 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:5][C:6]=1[CH2:7]P(=O)(OCC)OCC.[H-].[Na+].[CH2:28]([O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][C:37]=1[CH3:44])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:28]([O:35][C:36]1[CH:43]=[CH:42][C:39](/[CH:40]=[CH:7]/[C:6]2[S:5][C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[N:3][C:2]=2[CH3:1])=[CH:38][C:37]=1[CH3:44])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOP(=O)(Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C)OCC
Reactant: Cc1cc(C=O)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(/C=C/c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of diethyl {4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methylphosphonate (intermediate 4, 1.4 g) in dry tetrahydrofuran (10 ml) cooled in ice under nitrogen was added sodium hydride (0.12 g, 60% dispersion in mineral oil) and the reaction was stirred for 30 minutes. A solution of 4-benzyloxy-3-methylbenzaldehyde (0.724 g) in dry tetrahydrofuran (10 ml) was added drop-wise, the reaction was allowed to come to room temperature and stirred for 2 hours. The solvent was removed and the residues partitioned between water (50 ml) and chloroform (50 ml). The aqueous phase was extracted with chloroform (20 ml) and the combined organics were washed with water and dried. Removal of solvent gave a solid which was purified by SPE chromatography. Elution with cyclohexane:ethyl acetate (20:1) gave the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([O-:16])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Na+].[N+:18]([O-:36])([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])=[O:19].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[O:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:14]([C:11]1[CH:12]=[N:13][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][CH:10]=1)=[O:16])[N+:18]([O-:36])=[O:19]
Reactant: CN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Reactant: NCCCCCCCCCCCCCCO[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCCCO[N+](=O)[O-])cn2)CC1

Procedure:
To sodium 6-(4-methylpiperazinyl)pyridine-3-carboxylate and 14-aminotetradecyl nitrate was added 150 ml of methylene chloride and then 6.80 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI) and 5.00 g of 1-hydroxybenzotriazole (HOBt) were added at room temperature while stirring and then the mixture was stirred at room temperature for 15 hours. The reaction solution was chromatographed over a silica gel column and the residue was purified by recrystallization to afford the title compound as a colorless crystal.
Reaction SMILES: Cl(O)(=O)(=O)=O.[O:6]=[C:7]1[NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+].C(O[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C>>[O:6]=[C:7]1[NH:11][C@H:10]([C:12]([O:14][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:13])[CH2:9][CH2:8]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
Step (a) Aqueous perchloric acid (70%, 5 mL) was added to a solution of (S)-5-oxopyrrolidine-2-carboxylic acid (20 g, 154.9 mmol) in tert-butyl acetate (260 mL) at ambient temperature. The mixture was stirred at ambient temperature for 18 hrs in a 500 mL round bottom flask sealed with a rubber septum and then poured carefully into sat. sodium bicarbonate (200 mL). The mixture was extracted with ethyl acetate (2×200 mL) and the combined extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product solidified under high vacuum. The solid was treated with a 10:1 hexanes/diethyl ether mixture. The solids were collect by filtration and dried to give (S)-tert-butyl 5-oxopyrrolidine-2-carboxylate (21.65 g, 116.9 mmol, 75.5%), clean as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)(Cl)Cl>[C:19]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:21])[CH3:20]
Reactant: COc1cccc(CCN)c1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cccc(CCNC(C)=O)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-methoxyphenethylamine (56.6 g, 0.37 m) and triethylamine (38.0 g, 0.38 m) in CHCl3 (900 ml) was added acetyl chloride (33.0 g, 0.42 m) dropwise over a period of 30 minutes at 20°-25° C., and then the reaction was stirred overnight. The mixture was extracted with 500 ml ice water, then extracted further with 2×500 ml cold water. The chloroform layer was dried over MgSO4 and concentrated to N-acetyl-3-methoxyphenethylamine as an oil (90 g).