Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1([C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:11])[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1
Reactant: BrCc1ccccc1
Reactant: COC1(C(=O)O)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(C(=O)OCc2ccccc2)CCC(=O)CC1
Temperature: 60 °C
Yield: 76.2 %

Procedure:
To a flask containing 1-methoxy-4-oxocyclohexanecarboxylic acid (0.253 g, 1.469 mmol) was added potassium carbonate (0.406 g, 2.94 mmol). The mixture was diluted with DMF (5 mL) and benzyl bromide (0.192 mL, 1.616 mmol) was added. The mixture was heated to 60° C. for 15.5 h, then cooled to rt, diluted with water (20 mL), and extracted with ethyl acetate (20 mL). The organic layer was washed with water three times, then with sat. aq. NaCl, and was finally dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-50% EtOAc in hexanes gradient and a 12 g silica gel column to give the title product (0.294 g, 1.12 mmol, 76% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ=7.41-7.31 (m, 5H), 5.23 (s, 2H), 3.35 (s, 3H), 2.62-2.53 (m, 2H), 2.37-2.28 (m, 4H), 2.19-2.10 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Br:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C1COCC1>[Br:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH:27][C:12](=[O:14])[C@H:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=2[CH3:18])[C@@H:15]([OH:17])[CH3:16])=[O:25])=[CH:22][CH:21]=1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Br)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (5.0 g, 18.6 mmol), 4-bromobenzhydrazide (CAS 5933-32-4, 4.0 g, 18.6 mmol) and 1-Hydroxybenzotriazole hydrate (2.52 g, 18.6 mmol) were placed in a 250 mL round bottomed flask. Anhydrous THF (120 mL) was added and the mixture was cooled to −20° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (5.35 g, 27.9 mmol) was added, followed by Et3N (3.9 mL, 28.0 mmol). The reaction mixture was stirred at −20° C. for 1 h and room temperature for overnight. The reaction was quenched by adding water and extracted with EtOAc, which was washed with 5% aqueous NaOH, water, brine and dried over Na2SO4. The extracts were filtered and the filtrate was concentrated to provide a brown solid, which was purified by flash chromatography washed with 80% EtOAc in hexanes to afford the title compound (6.6 g, 76%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.87 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 5.55 (d, J=7.4 Hz, 1H), 4.39 (m, 1H), 4.10 (dd, J=3.3, 7.4 Hz, 1H), 2.36 (s, 3H), 1.35 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([Cl:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([Cl:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(Cl)c2)c2cc(Cl)ccc2CC1C
Agent: [Ni]
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(=O)N1N=C(c2ccc(N)c(Cl)c2)c2cc(Cl)ccc2CC1C
Reaction time: 0.75 h
Yield: 28.4 %

Procedure:
3.93 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-8-chloro-1-(3-chloro-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepine are dissolved in a mixture of 30 cm3 of methanol and 30 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from a mixture of ethyl acetate and hexane. Thus, 1.03 g (30%) of the title compound are obtained in the form of yellow solids melting at 143–144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[CH3:18].Cl[C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]2[CH:23]=[C:24]([CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[N:25]=[N:26][CH:27]=2)=[CH:4][C:3]=1[C:17]([F:19])([F:20])[CH3:18]
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC(F)(F)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Product: Cc1nccn1Cc1cc(-c2ccc(Cl)c(C(C)(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=349.4 (M+H+), was prepared from 2-[4-chloro-3-(1,1-difluoro-ethyl)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.CC[O:12][CH2:13][CH3:14]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([C:14]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOCC
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution of nitrile 1 (900 mg, 5.02 mmol) in ether (45 mL) at 0° C. was added via syringe ρ-fluorophenylmagnesium bromide (5.0 mL, 2.0 M solution in ether 10 mmol). The resulting turbid mixture was stirred at 0° C. for 5 min then warmed to r.t. and stirred for 6 h. At that time, the reaction was quenched with H2O (3 mL) and then diluted with ether (25 mL) and H2O (25 mL). The organic phase was separated, and the aqueous phase was extracted with ether (80 mL×2). The organic portions were combined, washed with saturated aqueous NaCl, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (30 g short path, 1%→10% EtOAc/hexane) to give the desired product (700 mg, 2.53 mmol, 50%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.97 (m, 2 H), 7.11 (m, 2 H), 5.79 (d, J=2.0 Hz, 1 H), 3.41 (s, 3 H), 2.97-2.81 (m, 3 H), 2.00 (m, 2 H), 1.82 (m, 1 H), 1.74 (m, 2 H), 1.65 (m, 1 H), 1.53 (m, 3 H), 1.21 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 199.0, 165.3 (d, J=253 Hz), 140.4, 133.7 (d, J=3.0 Hz), 130.4 (d, J=9.1 Hz), 118.8, 115.3 (d, J=22.0 Hz), 59.0, 36.6, 32.5, 31.6, 28.2, 26.4, 25.7, 21.6.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][N:21]=1>CS(C)=O>[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([O:18][C:20]4[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][N:21]=4)[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.331 g, 8.28 mmol, 60% disp. in mineral oil) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.5 g, 6.9 mmol) in dimethyl sulfoxide (15 ml). After 0.5 hours, 6-chloro-N-methyl-nicotinamide (D10) (2.34 g, 13.8 mmol) was added and the reaction mixture was heated to 100° C. for 18 hours. The reaction was allowed to cool to room temperature and then partitioned between ethyl acetate and water. The ethyl acetate layer was separated and the water layer washed with further volumes of ethyl acetate. The combined organic layers were then washed with water, brine, dried (Na2SO4) and then filtered. The mixture was concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.5:4.5:95 then 1:9:90) to afford the title compound (E121) which then was recrystallised from toluene. 1H NMR (DMSO-d6) δ 8.56 (1H, dd, J=2.4, 0.4 Hz), 8.48 (1H, br m), 8.20 (1H, dd, J=8.4, 2.4 Hz), 7.16 (1H, d, J=8.0 Hz), 7.03 (1H, dd, J=8.4, 0.4 Hz), 6.91 (1H, d, J=2.4 Hz), 6.86 (1H, dd, J=8.0, 2.4 Hz), 2.87-2.77 (8H, m), 2.36 (4H, m), 2.00 (2H, m), 1.78 (2H, m), 1.58 (2H, m); MS (ES+) m/e 352 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:28]O.[CH2:30]([OH:32])C>>[O:32]1[CH:30]=[N:28][C:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][N:11]([C@@H:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH2:17][OH:18])[S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[CH:25][CH:24]=2)=[N:27]1
Reactant: N#Cc1ccc(CN([C@@H]2CCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CCO
Reactant: NO
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution of 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (211 mg, 0.521 mmol) and 50% aqueous hydroxylamine (250 uL) was refluxed in ethanol (7 mL) overnight. The reaction was concentrated to dryness by rotary evaporation and co-evaporation with benzene. The dry amideoxime intermediate was then refluxed in triethylorthoformate (8 mL) under nitrogen for 5 h. After cooling to room temperature, boron trifluoride etherate (approximately 250 uL) was added and the reaction stirred overnight. The reaction was partitioned between ethyl acetate (25 mL) and brine (25 mL). The organic layer was concentrated and purified by flash chromatography on a 40 g silica gel column using a gradient of 10 to 60% ethyl acetate in hexane over 50 min to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (118 mg, 51%). 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (1H, s), 8.03 (2H, d), 7.70 (2H, d, J=8.56 Hz), 7.48 (2H, d, J=8.31 Hz), 7.43 (2H, d, J=8.56 Hz), 4.67 (1H, d, J=16.37 Hz), 4.106 (1H, d, J=16.37 Hz), 3.93-4.06 (1H, m), 3.33-3.61 (2H, m), 1.28-1.75 (8H, m). LC/MS R.T.=2.90 min; [M+H]+=448.16. HRMS [M+H]+ calc'd 448.1098, found 448.1087.
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](O)=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1>C1C=CC=CC=1>[Cl:8][C:14]1[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]([F:10])=[CH:12][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DMF (10 ml) and thionyl chloride (14 ml) are added successively to 4-fluoro-2,6-dinitrophenol (26.00 g) in benzene (50 ml). The resulting solution is stirred at room temperature for 5 min (an intermediate precipitates) and then heated under reflux for 1.5 h (or until the starting material has reacted completely). The reaction mixture is cooled to room temperature, concentrated and the residue is poured onto ice/water. The precipitate is collected by filtration, washed three times with water and dried. After recrystallization from ethanol 23.50 g (83% of theory) of product are obtained in crystalline form.
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]2[O:20][CH2:21][C:22](=O)[C:15]=12>>[CH3:1][O:2][N:3]=[C:22]1[C:15]2[C:16](=[CH:17][N:18]=[CH:19][C:14]=2[Cl:13])[O:20][CH2:21]1
Reactant: O=C1COc2cncc(Cl)c21
Reactant: CON=C1COc2nnccc21
Product: CON=C1COc2cncc(Cl)c21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 4-chlorofuro[2,3-c]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[N:17]=[C:16]4[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:15]4=[C:14](Cl)[C:13]=3[CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].[C:28]1([NH:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CO.CCOCC.C(O)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:20][CH2:19][C:18]2[C:13]3=[CH:12][N:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:35]=[C:14]3[C:15]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:16]=3[N:17]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1ccc(N2CCc3nc4cc(Cl)ccc4c(Cl)c3C2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1ccc(NCCc2nc3cc(Cl)ccc3c3nn(-c4ccccc4)cc23)cc1
Yield: 25.7 %

Procedure:
A mixture of 1 g (2.5 mmol) of the compound of step C. above, 0.539 ml (5.48 mmol) of phenylhydrazine, 0.75 ml of conc. hydrochloric acid, and 30 ml of absolute ethanol is stirred under reflux for 6 hrs. The cooled precipitate is dissolved in methanol and treated with a Na2CO3 solution. The precipitate is collected and washed with water to yield 0.388 of a brown solid. Trituration with ether affords 0.303 g (26%) of the title compound as a light brown solid: m.p. 170°-172° C.; IR (KBr) 3320, 1687, and 1604 cm-1 ; NMR (DMSO-d6) δ 9.56 (s, 1H), 8.27 (d, 1H), 8.17 (d, 2H), 8.07 (s, 1H), 7.70 (m, 5H), 7.54 (t, 1H), 6.70 (d, 2H), 4.23 (q, 2H), 3.78 (m, 2H), 3.46 (t, 2H), 1.26 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH3:18]O>>[CH3:18][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:8][CH:9]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)c1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: Cl
Product: COC(=O)c1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
A mixture of 5-(4-carboxyphenyl)pyrazin-2(1H)-one (1.2 g) and anhydrous methanol was stirred with heating under reflux while a gentle steam of dry hydrogen chloride gas was passed through the solution. After two hours the solvent was evaporated under reduced pressure and the residue was purified by elution from a silica gel column with chloroform/methanol mixtures followed by crystallisation from methanol. This afforded the title compound as a crystalline solid (0.8 g); m.p. 240°-242° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][CH:3]=1.[C:15](#[N:19])[CH:16]([CH3:18])[CH3:17].[Sn](Cl)(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:19][C:15]([CH:16]([CH3:18])[CH3:17])=[C:8]([C:6]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)=[O:7])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(C)C#N
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C(=O)c1ccc(F)cc1)=C(N)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
5.00 g of methyl 4-fluorobenzoylacetate (24.2 mmol, concentration 95%) and 1.69 g of isobutyronitrile (24.2 mmol, concentration 98%) were dissolved in 25 ml of toluene and treated with 7.01 g of tin tetrachloride (26.6 mmol, concentration >99%) at room temperature after the course of 10 minutes. After 3 h at room temperature, the mixture was heated to 80° C. After 11.5 h, the suspension was again cooled to room temperature and treated with 25 ml of water. The mixture was diluted with 10 ml of ethyl acetate and the phases were separated. The organic phase was washed twice with 10 ml of 1N sodium hydroxide solution and concentrated in vacuo (40° C./25 mbar) after drying over magnesium sulphate. 6.18 g of crude product were obtained in the form of a yellow oil. After chromatography on silica gel (eluent: hexane/ethyl acetate 1.5:1), 3.84 g of methyl 3-amino-2-[1-(4-fluorophenyl)methanoyl]-4-methylpent-2-enoate were obtained in the form of an oil.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.[C:13](OCC)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)(=O)C>[O:20]=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCCCC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCC(=O)CP(=O)(OC)OC

Procedure:
n-Butyllithiium (130 ml. of 1.6 M. solution) is slowly added to a solution of dimethyl methylphosphonate (25.6 g.) in 475 ml. of tetrahydrofuran (THF) at about -65° C. To the mixture is added a solution of ethyl heptanoate (18.4 g.) in 50 ml. of THF, annd the resulting mixture is stirred at about -70° C. for 2 hrs. Then, 16 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with dichloromethane (about 400 ml.) and water (about 50 ml.) shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:18](=[O:21])(O)[O-:19].[Na+].C1COCC1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C(OCC)C.O>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH:8][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3].[C:18](=[O:21])([O-:19])[NH2:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Product: NC(=O)[O-]
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a 0° C. suspension of L-tyrosine tert-butyl ester (Bachem, 1.0 eq) and sodium bicarbonate (2.0 eq) in a 1:1 mixture of THF and water was added slowly with stirring benzyl chloroformate (1.1 eq). After the addition, the mixture was stirred at 0° C. for 3 h and at room temperature for 24 h. The mixture was diluted with diethyl ether, and the aqueous layer was separated. The organic extracts were washed with saturated sodium chloride, treated with anhydrous magnesium sulfate, filtered, and evaporated to afford N-benzyloxycarbonyl-L-tyrosine tert-butyl ester of sufficient purity for immediate conversion of the tyrosine hydroxyl into a carbamate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]([CH3:24])([CH3:23])[C:12]([N:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N:25]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([N:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:12](=[O:13])[C:11]([CH3:24])([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:3]=1)[CH3:23])[CH:16]([CH3:18])[CH3:17]
Reactant: NCCCN1CCCCC1
Reactant: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Temperature: 100 °C

Procedure:
A mixture of 2-(3-chloro-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide (2.39 g), 3-piperidino-propylamine (1.9 g, 2 eq) and potassium carbonate (1.8 g, 2 eq) in DMF (40 ml) is heated at 100° C. for 24 hours then cooled down to ambient temperature. Water and ethyl acetate are added to the medium. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue obtained by flash chromatography on silica gel (eluent: dichloromethane 100% to dichloromethane/methanol 6:4) produces the expected compound in the form of a yellow oil (1.6 g, 51% yield).
Reaction SMILES: [CH2:1]([O:15][C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:35](I)[CH3:36]>O>[CH2:35]([O:22][C:21]([C:19]1[S:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23])[CH3:36]
Reactant: CCI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 10.6 g (0.031 mole) of 5-tetradecyloxy-2-thiophene carboxylic acid, 4.3 g (0.034 mole) of potassium carbonate, and dimethylformamide is stirred at room temperature after which 15.6 g (0.10 mole) of ethyl iodide is added. The mixture is heated at 50° C with stirring overnight and poured into water and extracted with the ether. The ether layer is washed with water and salt water and then dried over sodium sulfate, filtered, and the ether is distilled off to give 5-tetradecyloxy-2-thiophenecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:8][CH2:7][C:6]=2[C:5]([NH2:23])=[C:4]([N+:24]([O-])=O)[CH:3]=1>CO.[Pd]>[BrH:1].[F:21][C:19]([F:20])([F:22])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:2][CH:3]=[C:4]([NH2:24])[C:5]=3[NH2:23])[CH2:10]2)=[CH:18][CH:17]=1
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CCN(Cc1ccc(C(F)(F)F)cc1)C2
Agent: [Pd]
Solvent: CO
Product: Br
Product: Nc1ccc2c(c1N)CCN(Cc1ccc(C(F)(F)F)cc1)C2
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
A solution of product from Example 24 (0.91 g, 2.1 mmol) in methanol (100 mL was shaken over 20% Pd/C under hydrogen and pressure for 15 minutes. The catalyst was filtered off and concentrated under vacuum to give the title compound (0.75 g, 88 % yield) as a red-brown solid, mp=131-136° C.