Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([F:8])([F:7])[CH2:5][OH:6])=[N+:2]=[N-:3].Br[C:10](F)(F)[C:11](OCC)=[O:12].[N-]=[N+]=[N-].[Na+]>>[N:1]([C:4]([F:8])([F:7])[C:5]([O:12][CH2:11][CH3:10])=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(F)(F)CO
Reactant: CCOC(=O)C(F)(F)Br
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCOC(=O)C(F)(F)N=[N+]=[N-]

Procedure:
2-Azido-2,2-difluoroethanol is useful in the preparation of energetic placizers for explosives and propellants. Ethyl 2-bromo-2,2-difluoroacetate reacts with sodium azide to produce ethyl 2-azido-2,2-difluoroacetate which then reacts with sodium borohydride in water to produce the 2-azido-2,2-difluoroethanol.
Reaction SMILES: [CH3:1][Si:2]([O:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9])([CH3:4])[CH3:3].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][Si:2]([O:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH2:9][Br:11])([CH3:4])[CH3:3]
Reactant: C/C=C/C(=O)O[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)OC(=O)/C=C/CBr
Temperature: 77 °C
Yield: 64.7 %

Procedure:
A stirred mixture of trimethylsilylcrotonate (131 g, 0.828 mol), N-bromosuccinimide (206 g, 1.16 mol), benzoyl peroxide (3.41 g, 0.141 mol) and carbon tetrachloride (1 L) is warmed to reflux (77° C.) under visible light for 5 hours. The mixture is cooled to room temperature and the precipitated solid is removed by filtration. The filtrate is concentrated to a residue, which is distilled under reduced pressure. The product fractions are collected at 93–106° C. (9–15 mmHg) to give 127 g of the title compound (65%). GC-MS purity is 83–89%, 1HNMR is consistent with expected structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][O:14][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:10]=[CH:9]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(-n2cnc(CO)c2)c(F)c1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Reaction time: 0.5 h

Procedure:
3-Fluoro-4-(4-hydroxymethylimidazol-1-yl)nitrobenzene (26.7 g) and imidazole (15.3 g) were suspended in dry N,N-dimethylformnamide (190 ml) and stirred under argon on an ice-bath. t-Butyldimethylsilylchloride (25.5 g) was added in one portion, and stirring continued at ice temperature for 30 minutes, then at ambient temperature overnight. Solvent was evaporated in vacuo at 30° C., the residue diluted with water (200 ml) and extracted into ethyl acetate (700 ml). After washing with water (2×300 ml), brine, and drying over magnesium sulfate, solvent was evaporated (finally on high vacuum) to give an oil which solidified (39.2 g). This was used in the next stage with no further purification.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([CH3:33])[CH2:10][N:11]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13].[CH:34]1[C:43]2[C:38](=[CH:39][C:40]([S:44](Cl)(=[O:46])=[O:45])=[CH:41][CH:42]=2)[CH:37]=[CH:36][N:35]=1>ClCCl>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][N:11]([CH2:10][C@H:9]([NH:8][S:44]([C:40]1[CH:39]=[C:38]2[C:43](=[CH:42][CH:41]=1)[CH:34]=[N:35][CH:36]=[CH:37]2)(=[O:45])=[O:46])[CH3:33])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:13])=[O:14]
Reactant: O=S(=O)(Cl)c1ccc2cnccc2c1
Reactant: C[C@@H](N)CN(CCc1ccccc1Cl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CN(CCc1ccccc1Cl)S(=O)(=O)c1ccccc1[N+](=O)[O-])NS(=O)(=O)c1ccc2cnccc2c1
Reaction time: 6 h
Yield: 73 %

Procedure:
0.3 mL of triethylamine and 280 mg of (R)—N-(2-aminopropyl)-N-(2-chlorophenethyl)-2-nitrobenzenesulfonamide prepared in Reference Example 6 were added with stirring at room temperature to a dichloromethane solution of isoquinoline-6-sulfonyl chloride prepared in Reference Example 1, and the mixture was then stirred for 6 hours. The reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 300 mg of the title compound (73%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:6]([CH2:31][CH:32]=[CH2:33])[C:5]=1[O:34][CH3:35])=[O:3].[OH-].[Li+]>CO>[NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:6]([CH2:31][CH:32]=[CH2:33])[C:5]=1[O:34][CH3:35])=[O:3]
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(N)=O)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)O)c2CCC)ccc(C(N)=O)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound of Example 55 (100 mg, 0,195 mmol) and 390 μl of 1M lithium hydroxide (0.3896 mmol) were added to 2.0 ml of methanol, and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum, 5.0 ml of water was added to the residue, and the mixture was acidified with 10% hydrochloric acid. The mixture was filtered, and the white solid which was recovered was dried in a 40° C. oven overnight to give the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine (0.28 g, 0.871 mmol) in methylene chloride (10 mL) was added triethylamine (0.363 mL, 0.26 mmol.) and methanesulfonyl chloride (0.071 g, 0.915 mmol) The mixture was stirred at room temperature for two hours, and was then quenched by addition of water. The mixture was extracted with methylene chloride, and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc 1:1) gave 0.296 g of N-[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-methanesulfonamide as a foam. MS (M+H)=400.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[OH:24].[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]2[O:24][CH3:25]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a stirring solution of 6-(1-benzofuran-2-yl)-4-hydroxy-2-(trifluoromethyl)-quinoline (1.33 g, 4.04 mmol) in DMF (40 mL) at room temperature was added K2CO3 (0.670 g, 4.85 mmol) followed by methyl iodide (0.276 mL, 4.44 mmol) drop-wise. The reaction mixture was stirred for 4 hours then concentrated and the residue was diluted with EtOAc (200 mL). The organic layer was washed with H2O (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified on a Biotage Flash 40 apparatus (5-15% EtOAc:petroleum ether) to afford the product (0.930 g) as a solid. Mass spectrum (+ESI, [M+H]+) m/z 344. 1H NMR (500 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.46 (d, 1H, J=9.1 Hz), 8.19 (d, 1H, J=9.1 Hz), 7.68-7.79 (m, 3H), 7.48 (s, 1H), 7.40 (t, 1H, J=7.8 Hz), 7.32 (t, 1H, J=7.8 Hz), and 4.26 ppm (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[C:11]([OH:19])=[C:10]([C:20](OCC)=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:39][NH2:40])(=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[C:11]([OH:19])=[C:10]([C:20]([NH:40][NH:39][C:26](=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:21])[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(Cc2ccccc2)c1=O
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(Cc2ccccc2)c1=O

Procedure:
Reagents: Comp 41 (0.56 mmols, 0.20 g); dodecanoyl hydrazine (0.62 mmols, 0.133 g). Yield: 0.25 g (85%), white solid, m.p.=167° C.-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1.C1C(=O)N([Br:41])C(=O)C1>>[Br:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Yield: 61 %

Procedure:
Following General Procedure I, (R)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethyl(methyl)carbamate (400 mg, 0.86 mmol) was reacted with NBS (184 mg, 1.03 mmol) to afford the desired product (285 mg, 61%) as a yellow solid: ESI MS m/z 543 [C26H30BrN2O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([O:19]CC)=O)=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.O.[NH2:23][NH2:24]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([NH:23][NH2:24])=[O:19])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(O)ccc1-c1cc(OC)ccc1F
Solvent: CCO
Solvent: O
Product: COc1ccc(F)c(-c2ccc(O)cc2C(=O)NN)c1
Temperature: 95 °C
Reaction time: 46 h

Procedure:
To a solution of ethyl 2′-fluoro-4-hydroxy-5′-methoxy-[1,1′-biphenyl]-2-carboxylate (1.37 g) in ethanol (15 mL) was added hydrazine monohydrate (4.47 mL), and the mixture was stirred at 95° C. for 46 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane and then methanol/ethyl acetate) to give the title compound (1.05 g) as a white amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1

Procedure:
7-Acetoxyisoflavone was prepared from 7-hydroxyisoflavone (2.6 g, 10.9 mmol), acetic anhydride (16 ml) and pyridine (3.0 ml) as described for 4′,7-diacetoxydaidzein. Yield: (2.5 g, 82%) m.p. 133° C. 1H NMR (CDCl3): δ 2.36 (s, 3H, OCOCH3), 7.18 (dd, 1H, J 2.2 Hz 8.6 Hz, H6), 7.31 (d, 1H, J 2.2 Hz H8), 7.39-7.57 (m, 5H, ArH), 8.00 (s, 1H, H2), 8.33 (d, 1H, J 8.6 Hz, H5). Mass spectrum: m/z 280 (M, 28%); 237-(98); 238 (57).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:1]=[C:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: N#Cc1c(N)cccc1CCC1CCCCC1
Product: CCOC(=O)Cc1nc2cccc(CCC3CCCCC3)c2c(N)c1C(=O)OCC

Procedure:
Prepared as in Example 2a from 2-amino-6-(2-cyclohexylethyl)benzonitrile (Example 113b) and diethyl 3-oxopentanedioate as an orange solid (33%). 1H NMR (400 MHz, DMSO-d6) δ 0.87-0.96 (m, 2H), 1.14-1.22 (m, 7H), 1.27-1.32 (m, 4H), 1.47-1.52 (m, 2H), 1.61-1.68 (m, 4H), 1.74-1.77 (m, 2H), 3.21-3.25 (m, 2H), 4.03 (s, 2H), 4.09 (q, J=8.0 Hz, 2H), 4.27 (q, J=8.0 Hz, 2H), 7.27 (t, J=4.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.63 (brs, 2H). MS 413 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([CH:9]=1)[NH2:8])#[N:2].[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([N:8]=[C:16]=[S:17])[CH:9]=1)#[N:2]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ccc(N2CCOCC2)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)c(N=C=S)c1

Procedure:
Reaction of 5-cyano-2-morpholinoaniline (2 g) with thiophosgene (1.15 ml) in dioxan (2 ml) and water (25 ml) at 0° C. for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 5-cyano-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([S:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:17]=2[CH:25]=[O:26])=[C:7]([C:12]=1[O:13][CH3:14])[C:8]([O:10]C)=[O:9])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+]>CO>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([S:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:17]=2[CH2:25][OH:26])=[C:7]([C:12]=1[O:13][CH3:14])[C:8]([OH:10])=[O:9])=[O:2]
Reactant: COC(=O)c1c(Sc2c(C=O)cc(C)cc2OC)ccc(C=O)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)cc(CO)c1Sc1ccc(C=O)c(OC)c1C(=O)O

Procedure:
302 mg (0.8 mol) of the compound from Example 17 are dissolved in 4.6 ml of methanol and stirred at 25° C. with 36 mg of p-toluenesulphonic acid for 1 h. After addition of 0.45 g of potassium hydroxide, the mixture is heated under reflux overnight. It is concentrated in vacuo, and the residue is adjusted to pH=3 using dilute hydrochloric and washed with ethyl acetate. The organic phase is dried using sodium sulphate and concentrated in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])[CH3:2].C1N2CN3CN(C2)CN1C3.[C:21](O)(=[O:23])C>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])[CH:21]=[O:23])[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1cccc(C)c1O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CCc1cc(C=O)cc(C)c1O
Temperature: 25 °C

Procedure:
A solution of 2-ethyl-6-methyl-phenol (8.40 g, 61.7 mmol) and hexamethylene tetraamine (12.97 g, 92.5 mmol) in acetic acid (60 mL) and water (14 mL) is heated to 115° C. The water is distilled off at 117° C. and collected with a Dean-Stark apparatus. Then the water separator is replaced by a reflux condenser and the mixture is refluxed for 3 h. The mixture is cooled to rt, diluted with water (100 mL) and extracted with EA. The org. extract is washed with sat. aq. NaHCO3, dried over MgSO4 and evaporated. The remaining solid is dissolved in EA and treated with heptane to initialize crystallisation. The solid material is collected and dried to give 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (3.13 g) as a colourless crystalline powder, 1H NMR (CDCl3): δ 9.83 (s, 1H), 7.58-7.53 (m, 2H), 5.30 (s br, 1H), 2.69 (q, J=7.6 Hz, 2H), 2.32 (s, 3H), 1.28 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].Cl.Cl.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:15]=[CH:14][C:13]=1[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH2:30][CH:29]1[C:41]([NH2:43])=[O:42])=[O:27].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH2:21][CH2:20]2)[CH:15]=[CH:14][C:13]=1[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH2:30][CH:29]1[C:41]([NH2:43])=[O:42])=[O:27]
Reactant: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCC(Oc2ccc(CC(=O)N3CCN(c4ccccc4C)CC3C(N)=O)c(OC)c2)CC1
Reaction time: 18 h

Procedure:
2-Chloroethanesulfonyl chloride (0.035 ml, 54.6 mg, 0.33 mmol) in methylene chloride (3 ml) was cooled in an ice bath under nitrogen. A solution of 1-(2-methoxy-4-(4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)-piperazine-2-carboxamide dihydrochloride (149 mg, 0.28 mmol) and diisopropylethylamine (0.243 ml, 0.18 g, 1.4 mmol) in methylene chloride (3 ml) was added dropwise and the mixture was stirred in the cold for 18 hours. The mixture was concentrated in vacuo and the residue chromatographed on silica gel eluted with 3% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo to give 1-(2-methoxy-4-(1-ethenylsulfonyl-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]=[N+]=[N-])=[CH:25][C:24]=1[Cl:33]>O1CCCC1.O>[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][C:24]=1[Cl:33]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CN)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Add triphenylphosphine (30.3 g, 115 mmol) to crude 4-azidomethyl-2-chloro-benzoic acid methyl ester (5.8 g, 25.7 mmol) in tetrahydrofuran (152 mL) and water (4.6 mL). Stir the reaction mixture at room temperature overnight. Concentrate the reaction mixture and partition the residue between 1N hydrochloric acid and ethyl acetate. Separate the organic layer and wash the organic layer with water. Combine the aqueous layers, wash with ethyl acetate, and then neutralize with 1N sodium hydroxide. Extract the resulting aqueous mixture with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the crude title compound (2.2 g, 11.0 mmol). MS (m/z): 200 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH3:31])[N:17]=[C:18]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[N:19]=1.C(N(CC)CC)C.C(N=C=NC(C)C)(C)C>C(Cl)(Cl)Cl>[CH3:31][C:16]1[CH:15]=[C:14]([CH3:13])[N:19]=[C:18]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[N:17]=1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: COc1ccccc1CC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(C)cc(C)n2)cc1
Yield: 40 %

Procedure:
2-Methoxyphenylacetic acid (33 mg, 0.20 mmol) and sulfamethazine (55 mg, 0.20 mmol) were dissolved in 4 ml of chloroform. Triethylamine (70 μl, 0.55 mmol) and diisopropylcarbodiimide (50 μl, 0.20 mmol) were added to the reaction mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness, washed with water and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) to obtain white crystals with the yield of 40%. 1H NMR (CDCl3, 500 MHz): 8.04 (2H, m), 7.54 (2H, m), 7.30 (2H, m), 6.98 (2H, m), 6.60 (1H, s), 3.95 (3H, s), 3.72 (2H, s), 2.33 (6H, s); MS (ESI+): m/z 449 (M+Na)+, 427 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N-:13]=[N+:14]=[N-:15].[Na+].O>CS(C)=O>[N:13]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCCCl)c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCC(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of 4-chloro-1-phenylbutan-1-one (26.4 mL, 164 mmol) in DMSO (200 mL) was added sodium azide (12.8 g, 197 mmol). The solution was warmed to 55° C. and stirred for 16 hours. The cooled mixture was then treated with water and extracted with ether. The combined organics were washed with water and brine, then dried over MgSO4 and concentrated to provide the product as an orange oil (30.7 g, 99%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([OH:22])=O)[CH2:3]1.Cl.[CH3:24][N:25]([CH2:39][C@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27].C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([N:42]2[CH2:43][CH2:44][C@H:40]([CH2:39][N:25]([CH3:24])[C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])[CH2:41]2)=[O:22])[CH2:3]1
Reactant: CN(C[C@H]1CCNC1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@H]1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.1 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)proline (4.65 g) in anhydrous dimethylformamide (60 ml), (3S)-3-[N-methyl-N-(4-nitrobenzyloxycarbonyl)aminomethyl]pyrrolidine hydrochloride (4.95 g), diisopropylethylamine (5.23 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.03 g) and 1-hydroxybenzotriazole (2.23 g) were added. The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to chromatography through a silica gel column. From the fractions eluted with ethyl acetate/methanol=9/1, (2S,4R)-4-hydroxy-2-[(3S)-3-[N-methyl-N-(4-nitrobenzyloxycarbonyl)aminomethyl]pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8.70 g) was obtained as a powder.