Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:20])([F:19])[S:15]([NH2:18])(=[O:17])=[O:16].C(N(CC)CC)C.[OH-].[Na+].[Na]>O.C(#N)C>[F:13][C:14]([F:20])([F:19])[S:15]([NH:18][S:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:11])=[O:10])(=[O:17])=[O:16]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1Br
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(NS(=O)(=O)C(F)(F)F)c1cc(Br)ccc1Br
Temperature: 25 °C
Yield: 87 %

Procedure:
Inside a glove box, a 100 mL round-bottom flask equipped with a reflux condenser, stirring bar, and septum was charged with 2,5-dibromo-benzene-sulfonyl chloride (16.35 g, 50 mmoles), trifluoromethanesulfonamide (7.27 g, 50 mmoles), and acetonitrile (50 mL). Triethylamine (14 mL, 100 mmoles) was added slowly by syringe. The solution was heated to a reflux overnight. The solution was cooled to room temperature and poured into an aqueous solution of sodium hydroxide (4.0 g, 100 mmoles) in 100 mL water. The solvents were evaporated on a rotary evaporator and the solids were dried under vacuum. The solids were recrystallized by dissolving in dioxane at a reflux, treating with decolorizing carbon, filtering the solution, and concentrating the solution at a reflux to 130 mL to induce crystallization. The white crystals were collected by vacuum filtration, washed with dioxane, and dried under vacuum. The recrystallization was repeated to give 19.45 g (83% yield) of N-trifluoromethanesulfonyl-2,5-dibromo-benzene-sulfonamide, sodium salt. The salt was dried overnight in a vacuum oven at 150° C. under a nitrogen purge.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH2:6][NH:7][CH3:8])C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[S:18])[CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:8][N:7]1[CH2:6][C:5](=[O:4])[N:16]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[C:17]1=[S:18]
Reactant: S=C=Nc1cccnc1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(c2cccnc2)C1=S
Yield: 39.6 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), pyridin-3-yl-isothiocyanate (6.8 g), triethyl amine (10.1 g) and chloroform (200 mL) was heated at reflux for 3.5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (300 mL) and washed with water (2×200 mL). The organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated. Crystallization from ethyl acetate afforded the title compound (4.1 g) as an off-white solid, m.p. 149°-151° C. Anal. Calcd. for C9H9N3O S: C, 52.16; H, 4.38; N, 20.28. Found: C, 52.16; H, 4.05; N, 20.06. Mass spectrum (EI, M.+) m/z 207.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=O)[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[F:22][C:23]1[CH:24]=C(N)[CH:26]=[CH:27][C:28]=1[N:29]1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:57][N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]([C:19](=[O:21])[NH:29][C:28]3[CH:27]=[CH:26][C:57]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[CH:24][C:23]=3[F:22])[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: CCOC(=O)c1ccc(-c2cc(C(=O)O)ccc2Cl)cc1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc(C(=O)Nc3ccc(N4CCOCC4)cc3F)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
A mixture of 6-chloro-biphenyl-3,4′-dicarboxylic acid 4′-ethyl ester (213 mg), 3-fluoro-4-morpholin-4-yl-phenylamine (179 mg), EDAC (174 mg), HOBT (123 mg) and N-methylmorpholine (200 μl) in DMF (3 ml) was stirred at room temperature. After 11 h, water (30 ml) was added and the resulting suspension filtered. The residue was then purified by chromatography. Elution with 1:1 ethyl acetate:petrol gave a brown oil (235 mg).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:31])[NH:10][CH:11]([CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[C:12]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:24][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:31])[CH2:25][C:26]3[N:27]=[CH:28][NH:29][CH:30]=3)[S:16][C:17]=2[CH:23]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)NC(Cc1c[nH]cn1)C(=O)Nc1nc2ccc(F)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(F)cc2s1)[C@H](Cc1c[nH]cn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 76.7 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 18e (153 mg, 0.32 mmol); LiOH (7.7 mg, 0.32 mmol); THF/MeOH/H2O (3.5 mL: 1.5 mL: 1.5 mL); yielded 31a as a white solid (103 mg, 71.5%). 1H NMR (DMSO-d6, 400 MHz): δ 14.55 (bs, 1H); 14.36 (bs, 1H); 9.18-9.02 (m, 1H): 7.93-7.91 (m, 1H); 7.79-7.75 (m, 1H); 7.44 (s, 1H); 7.31-7.29 (t, 1H); 4.96-4.91 (q, 1H); 3.72-3.71 (d, 1H, J=1.62 Hz); 3.51-3.50 (d, 1H, J=1.62 Hz); 3.29-3.16 (m, 2H). %). 13C NMR (DMSO-d6, 100 MHz): 169.50, 168.51, 165.84, 165.84, 159.82, 157.53, 157.44, 145.02, 133.67, 132.68, 132.57, 128.56, 121.63, 117.01, 114.40, 114.16, 108.27, 108.00, 52.67, 52.19, 51.34, 26.20. ESI-HRMS (m/z): [M+H+] calcd. for C17H14FN5O5S: 420.0773, observed: 420.0777.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23]Br>C1(C)C=CC=CC=1>[Br-:20].[Br:20][CH2:21][CH2:22][CH2:23][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C

Procedure:
To a stirred solution of triphenylphosphine (511 g, 1.85 mol; assay: 95.0%) in toluene (800 g), 1,3-dibromopropane (371 g, 1.82 mol; assay: 99.0%) was added slowly within 1 hour at <5° C. After complete addition the solution was heated to reflux for 17 hours whereupon a suspension was obtained which was then cooled to room temperature. The product was filtered off at 20° C., washed with toluene (2×800 g) and dried under vacuum (21 h, 60° C.) to give 3-bromopropyltriphenylphosphonium bromide (Olo-IM3) as a white, crystalline solid (yield: 757 g, 1.63 mol, 89.6%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]#[N:22])=[CH:16][C:15]=1[O:30][CH3:31].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1.CCOC(C)=O>[CH2:36]([O:35][C:33](=[O:34])[C:20]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:21]#[N:22])[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[C:15]([O:30][CH3:31])[CH:16]=1)[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(C(C#N)Cc2ccccc2)ccc1F
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C#N)(Cc1ccccc1)c1ccc(F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a −78° C. cooled solution of diisopropylamine (5.11 ml, 35.8 mmol) in THF was added n-butyllithium (22.40 ml, 35.8 mmol) and stirred for 1 h while the reaction mixture was allowed to warm up <−40° C. 2-(4-Fluoro-3-methoxyphenyl)-3-phenylpropanenitrile (6.1 g, 23.89 mmol) dissolved in THF was added followed by ethyl chloroformate (3.42 ml, 35.8 mmol). The reaction mixture was stirred over night and was allowed to heat up to room temperature. Evaporated solvents and redissolved in EtOAc, washed with 10% citric acid, water and brine and the combined organic layers were dried over MgSO4, filtered and evaporated to obtain 7.2 g of a yellow oil, that was purified by flash chromatography on 330 g SiO2 using 20% EtOAc in cyclohexene to obtain 18.26 g of the desired product as a pale yellow oil.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[NH:2]1[CH2:3][CH2:4][CH:5]([CH:8]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=3)[CH2:6][CH2:7]1
Reactant: CN1CCC(C(=O)c2ncccc2CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc2c(c1)CCc1cccnc1C2C1CCNCC1
Yield: 97.6 %

Procedure:
To a mixture of 5.0 g (16.2 mmole) of (1-methyl-4-piperidinyl)[3-(2-phenylethyl)-2-pyridinyl]methanone (which can be prepared in the same manner as described in Preparative Example 1, Steps A-D) in 70 mL of methanol was added portionwise 0.8 g (21.1 mmole) of sodium borohydride. The next day the solution was concentrated in vacuo to give a slurry which was dissolved in water and extracted with CHCl3. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to provide a liquid which was distilled (bp 190°-195° C. 1 mm Hg) to give 4.4 gms of the title compound as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[C:18]=[O:19]>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:18]([NH:17][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[O:19])=[CH:11][CH:10]=2)[O:5]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C

Procedure:
Intermediate 19 was prepared in analogy to GP 3 by reaction of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 1-isocyanato-3-trifluoromethylbenzene.
Reaction SMILES: I[CH2:2][CH3:3].FC(F)(F)C(O)=O.[NH:11]1[CH2:15][CH2:14][C@@H:13]([CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:2]([N:11]1[CH2:15][CH2:14][C@@H:13]([CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1)[CH3:3]
Reactant: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 31.4 %

Procedure:
Iodoethane (4.1 g) was added to a cooled mixture of benzyl N—((R)-pyrrolidin-3-ylmethyl)carbamate trifluoroacetate salt (Intermediate 171, 7.6 g) and potassium carbonate (12.2 g) in DMF (10 mL) while maintaining the temperature at 0° C. The mixture was then stirred at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give benzyl N—((S)-1-ethylpyrrolidin-3-ylmethyl)carbamate (1.8 g) as a colourless oil, which was used without further characterisation.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:19])[C:14]=1[CH2:15][N:16]=[N+]=[N-])=[CH:11][CH:10]=[C:9]([Cl:20])[CH:8]=2)=[O:4].Cl>[Pt](=O)=O.C(Cl)Cl.C(OCC)(=O)C>[ClH:20].[CH3:1][N:2]([CH3:27])[C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:19])[C:14]=1[CH2:15][NH2:16])=[CH:11][CH:10]=[C:9]([Cl:20])[CH:8]=2)=[O:4]
Reactant: CN(C)C(=O)c1c(CN=[N+]=[N-])c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 147.1 %

Procedure:
In a 50 mL round-bottomed flask, 3-azidomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide (0.40 g, 1.05 mmol), platinum (IV) oxide (0.05 g, 0.204 mmol) and 4N HCl (0.1 mL) were added to 1:1 CH2Cl2/ethyl acetate (10 mL). The reaction was charged with 1 atm H2 using a balloon and stirred at room temperature for 4 hr. The catalyst was filtered off and washed with methanol. The filtrate was evaporated to afford 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide hydrochloride salt (0.303 g, 74% yield). The intermediate was used in the next step without further purification. MS calcd. for C19H18ClN3O2 [(M+H)+] 356, obsd 356.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.[C-]#[N:26].[Na+]>CCO>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[NH:26][CH:22]=[N:23][CH:24]=1
Reactant: O=CCc1cccc(Cl)c1F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: Fc1c(Cl)cccc1Cc1cnc[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 930.7 %

Procedure:
The preparation of Intermediate B3 followed the procedure by Horne et al. Heterocycles, 1994, 39, 139 incorporated herein by reference. A solution of (3-chloro-2-fluoro-phenyl)-acetaldehyde (Intermediate B2) (0.30 g, 4.57 mmol) in EtOH (7 mL) was treated with tosylmethyl isocyanide (TosMIC) (0.33 mg, 7.18 mmol) and NaCN (˜10 mg, cat.). The resulting mixture was allowed to stir at rt for 20 minutes. The solvent was removed in vacuo and the residue was dissolved in ˜7M NH3 in MeOH (35 mL) and transferred to a re-sealable tube. This mixture was heated in a re-sealable tube at 90-100° C. for 12 h. Thereafter the mixture was concentrated and purified by chromatography on SiO2 with 5% MeOH (sat. w/NH3):CH2Cl2 to give 5-(3-chloro-2-fluoro-benzyl)-1H-imidazole 0.4 g (31%) as an amber oil. The fumaric acid salt of the latter compound was formed in methanol and tetrahydrofuran. The solvent was removed and the salt was re-solvated in methanol:tetrahydrofuran and titurated with 20% ether-hexane. The solid was collected on a glass frit and dried under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>ClCCl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([NH:1][C:25](=[O:26])[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=2)[CH:12]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc2c(c(-c3cccnc3)c1)OCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c(c(-c3cccnc3)c1)OCC2)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
5-Amino-2,3-dihydro-7-(pyrid-3-yl)benzofuran (D64) (0.13 g, 0.00062 mole) was dissolved in dichloromethane (10 ml) and cooled to 0° C. under argon. Triethylamine (0.09 ml, 0.00068 mole) was added, followed dropwise by phenyl chloroformate (0.08 ml, 0.00065 mole) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was washed with deionised water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.20 g, 97%) as a cream solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3]
Reactant: N#Cc1c(OCC2CCNC2)cccc1[N+](=O)[O-]
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(COc2cccc([N+](=O)[O-])c2C#N)C1

Procedure:
Prepared as in Example 165b from 2-nitro-6-(pyrrolidin-3-ylmethoxy)benzonitrile hydrochloride (Example 181d) and propionyl chloride in 51% as a yellow solid. MS 304 (MH+).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:8]=[CH:9][C:3]=2[O:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>ClCCl.CO>[CH3:31][CH:30]([CH2:29][NH:33][C:14](/[CH:13]=[CH:12]/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1)=[O:16])[CH3:32]
Reactant: CC(C)CN
Reactant: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)CNC(=O)/C=C/C=C/c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
A mixture of piperinic acid (350 mg, 0.0016 mole, 1 eq) and triethylamine (0.4 ml, 0.0032 mole, 2 eq) in dichloromethane (50 ml) was stirred for 15 min at 0° C. To this mixture methanesulfonyl chloride (0.18 ml, 0.0024 mole, 1.5 eq) was added and stirred for further 30 min at 0° C. Isobutylamine (0.23 ml, 0.0024 mole, 1.5 eq) was added to the mixture and stirred for 1 h at 0° C. and 2 h at room temperature. Dichloromethane (50 ml) was added to the mixture which was then washed with 5% HCl (3×100 ml), saturated aqueous NaHCO3 (3×100 ml) and water (3×100 ml). The organic fraction was dried over anhydrous sodium sulphate, filtered and rotary evaporated to yield a yellowish solid residue. Recrystallisation from methanol yielded colourless needles of piperlonguminine (120 mg, 32% yield)2. The reaction is presumed to proceed through a mesylate ester intermediate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11](=[O:21])[CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11](=[O:21])[CH:12]([P:13]([O:15][CH2:16][CH3:17])([O:18][CH2:19][CH3:20])=[O:14])[CH2:25][CH:26]2[CH2:28][CH2:27]2)=[CH:22][CH:23]=1
Reactant: BrCC1CC1
Reactant: CCOP(=O)(CC(=O)OCc1ccc(OC)cc1)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(CC1CC1)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a suspension of 60% sodium hydride in mineral oil (0.840 g, 21.0 mmol) in DMF (100 mL) was added a solution of 2-(diethoxyphosphoryl)acetic acid 4-methoxybenzyl ester (6.04 g, 19.1 mmol) from Step A in DMF (10 mL). The reaction mixture was stirred for 30 min at room temperature. Bromomethylcyclopropane (2.4 mL, 24.8 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with diethyl ether, poured into saturated sodium bicarbonate, and extracted three times with diethyl ether. The organic layers were combined, washed with saturated sodium chloride, dried over sodium sulfate, and filtered. The volatiles were removed in vacuo and the residue was purified by FC (40% ethyl acetate in hexanes) to afford 4.31 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:20]=1[C:21]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])=[O:22]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 72 h
Yield: 86.2 %

Procedure:
5-Chloro-2-nitroaniline (1 g; 5.8 mmol) and pyridine (0.64 ml; 8.1 mmol) were dissolved in dichloromethane (10 ml) and cooled to 0° C. This was added dropwise over 5 minutes to a solution of 2-chloro-5-nitrobenzoyl chloride (1.34 g; 6.1 mmol) in dichloromethane (5 ml). The reaction was stirred at room temperature for 72 hours before adding further acid chloride (1.34 g) and pyridine (0.64 ml). After 30 minutes, the solvent was evaporated and the bisacylated residue treated with 1:1 concentrated ammonia/acetonitrile (10 ml). All the solvent was removed after 5 minutes and the residue crystallised from 1:1 chloroform/heptane (30 ml) to give 2-chloro-N-(5-chloro-2-nitro-phenyl)-5-nitro-benzamide (1.78 g, 86%)
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[N-:12]=[N+:13]=[N-:14].[Na+]>CS(C)=O.O>[N:12]([CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5])=[N+:13]=[N-:14]
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCC[C@@H](O)c1ccccc1
Temperature: 40 °C
Yield: 78.7 %

Procedure:
(R)-α-(2-Chloroethyl)benzenemethanol (0.73 g, 4.3 mmol) and sodium azide (417 mg, 1.5 eq.) in DMSO (3 ml) was stirred and heated at 40° C. for 1.5 h. The reaction mixture was diluted with water (50 ml) and the products extracted into ethyl acetate(2×75 ml). The combined extracts were dried (magnesium sulphate) and concentrated to an oil. Purification was achieved on silica gel eluting with 50% diethyl ether/isohexane to afford the azide as a colourless oil (0.6 g, 79%).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)([CH3:17])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1.O[Li].O.Cl>O.C1COCC1>[Cl:25][C:20]1[CH:19]=[C:18]([C:4]([CH3:17])([CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:11][CH2:12]2)[C:3]([OH:26])=[O:2])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: COC(=O)C(C)(CCN1CCN(S(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(CCN1CCN(S(C)(=O)=O)CC1)(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.15 g (2.7 mmol) 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester and 0.171 g (4.08 mmol) LiOH.H2O in 25 mL water and 25 mL THF was stirred at room temperature for 16 h. The mixture was treated with 4N HCl aq. and evaporated to dryness. The residue was used without further purification in the subsequent step. MS(m/e): 409.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:34](Br)[C:35]#[CH:36].O>CN(C=O)C>[CH2:36]([CH:14]([C:12](/[CH:11]=[CH:10]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=1)=[O:13])[C:15](=[O:16])/[CH:17]=[CH:18]/[C:19]1[CH:27]=[C:24]([C:22]([OH:23])=[CH:21][CH:20]=1)[O:25][CH3:26])[C:35]#[CH:34]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC(C(=O)/C=C/c1ccc(O)c(OC)c1)C(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 49 h
Yield: 47 %

Procedure:
Curcumin (5 g, 13.57 mmol) and K2CO3 (1.88 g, 13.62 mmol) were dissolved in 60 mL DMF, and 1.62 g (13.61 mmol) of propargyl bromide was added. The mixture was stirred at room temperature under Ar for 49 h. H2O was added to the mixture and solvent was removed under vacuum. The product was purified on column chromatography, eluting with CH2Cl2: hexane 50:50- CH2Cl2. Yield 47%. NMR NMR 1H (CDCl3), δ (ppm): 2.54 (s, 1H); 3.94 (d, 6H); 4.81 (d, 2H); 5.82 (s, 1H); 5.93 (s, 1H); 6.47-6.52 (t, 2H); 6.93-7.15 (m, 6H); 7.59-7.61 (dd, 2H). MS (ESI) calcd. for C24H22O6: 406.43. Found: 407.2 [M+H]+, 445.2 [M++K].