Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH:7]=[O:8].[C-:17]#[N:18].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:7]([OH:8])[C:17]#[N:18])[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14]
Reactant: [C-]#N
Reactant: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(O)c1ccc(OC(F)F)c(OC(F)F)c1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To 132A (470 mg, 2.0 mmol) in ethyl acetate (5 mL) was added a solution of KCN (676 mg) and NaHSO3 (1.08 g) dissolved in H2O (5 mL). It was left stirring overnight before it was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 132B (383 mg, 72% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.56 (d, J=5.27 Hz, 1H) 6.32-6.77 (m, 2H) 7.32-7.36 (m, 1H) 7.40-7.44 (m, 1H) 7.45 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]3)[CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C@@H:29]([N:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[C@@H:33]([CH3:38])[CH2:32]2)[CH3:30])[CH2:24][CH2:23]1>>[OH:37][C@H:34]1[CH2:35][CH2:36][N:31]([C@@H:29]([CH3:30])[CH2:28][N:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:27][CH2:26]2)[CH2:32][C@@H:33]1[CH3:38]
Reactant: O=C(O)c1cc2c(OCC3CC3)cccc2[nH]1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCC5CC5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid, 77 (see example 4) and amine 56.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([CH:7]([CH:14]=[CH2:15])[CH2:8][C:9]([O:11]CC)=O)#[N:6].O>C(OCC)C>[CH:14]([CH:7]1[C:5]2([CH2:2][CH2:1]2)[NH:6][C:9](=[O:11])[CH2:8]1)=[CH2:15]
Reactant: C=CC(C#N)CC(=O)OCC
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Product: C=CC1CC(=O)NC12CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl magnesium bromide (3.0 M in ether, 2.2 mL, 6.6 mmol) was added dropwise over a period of 1 hour to a solution of ethyl 3-cyanopent-4-enoate (500 mg, 3.27 mmol) and Ti(Oi-Pr)4 (1.1 mL, 3.6 mmol) in diethylether (16.4 mL) at room temperature. The reaction mixture was diluted by the dropwise addition of water (3.27 mL) and stirred at room temperature for an additional 30 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether, Rf=0.3) to afford 7-ethenyl-4-azaspiro[2.4]heptan-5-one as a white solid. MS ESI calc'd. for C8H12NO [M+H]+ 138. found 138. 1H NMR (400 MHz, CDCl3) δ 6.09 (br s, 1H), 5.68-5.60 (m, 1H), 5.08-5.00 (m, 2H), 3.01-2.96 (m, 1H), 2.70-2.64 (m, 1H), 2.40-2.36 (m, 1H), 0.83-0.75 (m, 2H), 0.65-0.58 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([N:12]([CH2:14][C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:13])[CH:5]=[CH:4][N:3]=1.O.[NH2:26][NH2:27]>O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]2[CH2:17][C@H:15]2[CH2:14][N:12]([CH3:13])[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:26][NH2:27])[C:7]=2[C:8]([F:11])([F:10])[F:9])=[CH:19][CH:20]=1
Reactant: CN(C[C@@H]1C[C@H]1c1ccc(F)cc1)c1ccnc(Cl)c1C(F)(F)F
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CN(C[C@@H]1C[C@H]1c1ccc(F)cc1)c1ccnc(NN)c1C(F)(F)F
Yield: 92.9 %

Procedure:
A mixture of trans 2-chloro-N-((2-(4-fluorophenyl)cyclopropyl)methyl)-N-methyl-3-(trifluoromethyl)pyridin-4-amine (1.2 g, 3.34 mmol) and hydrazine hydrate (3.32 mL, 66.9 mmol) in dioxane (20 mL) was heated to reflux under nitrogen for 6 h. The reaction mixture was concentrated. The reaction mixture was diluted with EtOAc and washed with aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 mL) and brine (20 mL), dried over magnesium sulfate, and concentrated to give trans-N-((2-(4-fluorophenyl)cyclopropyl)methyl)-2-hydrazinyl-N-methyl-3-(trifluoromethyl)pyridin-4-amine (1.1 g, 80% yield), which was used for the next reaction without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[C:10]=1Cl)=[O:5])C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl>CCOC(C)=O>[F:24][C:23]([F:25])([F:26])[C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=1)[CH2:12][N:9]1[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:6]([C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:5])[N:7]=[N:8]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)N1CCOCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Dissolve 1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester in morpholine (20 eq). Stir at 70° C. overnight then increase temp to 80° C. and continue stirring for another 60 hours. Cool to RT, pour into separatory funnel with EtOAc and 1N HCl. Separate layers and wash organic layer with 1N HCl and then with brine. Dry over MgSO4, filter, and concentrate. Purify via silica gel chromatography using a gradient of 1:1 to 1:5 hexanes:EtOAc to give the desired product. MS (IS) 494.2 (M+1). Rf=0.16 (1:1 Hexanes:EtOAc)
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH3:38][O:37][C:31]1[CH:30]=[C:29]([C:25]2[O:26][C:27]([CH3:28])=[C:23]([CH2:22][N:12]3[C:13]4[C:9](=[C:8]([CH3:16])[C:7]([CH2:6][CH:5]([O:17][CH2:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)[N:24]=2)[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1C)OCC
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(OC)cc(OC)c3)oc2C)c1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(4-methyl-1H-indol-5-yl)-propionic acid ethyl ester [preparation 10h)] was reacted with 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxy-propionic acid as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[CH3:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([O:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH3:18])[N:3]=1
Reactant: CC(O)c1ccccn1
Reactant: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(OC(C)c3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile, (RS)-alpha-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 344 (M+Na+, 20), 322 (M+H+, 100).
Reaction SMILES: C([O:14][C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[N:31][CH:30]=1)[CH:24]([S:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=1)[C:23]2=[O:49])=[O:19])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)=O>[C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[N:31][CH:30]=1)[CH:24]([S:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=1)[C:23]2=[O:49])=[O:19])([OH:16])=[O:14]
Reactant: CN(C)CCNc1ncc(C2=C(NC(=O)CC(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(Sc4ccc(Cl)c(Cl)c4)C3SC2)s1
Solvent: O=CO
Solvent: COc1ccccc1
Product: CN(C)CCNc1ncc(C2=C(NC(=O)CC(=O)O)N3C(=O)C(Sc4ccc(Cl)c(Cl)c4)C3SC2)s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
A mixture of 2-benzhydryloxycarbonyl-7-(3,4-dichlorophenylthio)-acetamido-3-[2-(2-dimethylamino-ethylamino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene (1.5 g), anisole (5 cc) and formic acid (25 cc) is stirred for 30 minutes at 50° C. The mixture is concentrated to dryness under reduced pressure (0.1 mm Hg; 0.013 kPa) and the residue is then taken up in ethanol (3×50 cc) and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The solid obtained is washed with acetone (50 cc) and then with ethyl ether (50 cc). It is dried under reduced pressure (0.1 mm Hg; 0.013 kPa), giving 2-carboxy-7-(3,4-dichloro-phenylthio)-acetamido-3-[2-(2-dimethylamino-ethylamino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1 g) in the form of a yellow powder.
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].[C:5]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[N:13]([CH3:24])[C:14](=[O:23])[C:15]([OH:22])=[C:16]([C:18](OC)=[O:19])[N:17]=1>C1COCC1>[CH:2]([NH:4][C:18]([C:16]1[N:17]=[C:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:13]([CH3:24])[C:14](=[O:23])[C:15]=1[OH:22])=[O:19])([CH3:3])[CH3:1]
Reactant: CC(C)N
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Temperature: 110 °C
Yield: 13.9 %

Procedure:
A sealed tube containing propan-2-amine (202 mg, 292 μl, 3.42 mmol), methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.1 g, 285 μmol) and THF (1.7 ml) was heated at 110° C. in a microwave oven for 20 minutes. The crude reaction mixture was cooled and evaporated to dryness. Purification by preparative HPLC provided the desired product as a light pink solid (0.015 g; 14%). LCMS: m/z=379 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:12][CH:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][NH2:15])[CH2:8][CH2:9][CH2:10][CH3:11]>>[CH2:17]([O:16][CH:13]([O:12][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][NH:15][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCOC(CN)OCCCCC
Product: C=C(C)C(=O)NCC(OCCCCC)OCCCCC

Procedure:
The monomer (1) was prepared by reaction of methacryloyl chloride and aminoacetaldehyde di-n-pentyl acetal in anhydrous solution.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].[OH-].[Na+].S([O-])([O-])=[O:17].[Na+].[Na+]>O1CCCC1.[C].[Pd]>[CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([OH:17])=[O:13]
Reactant: Cc1c(C=O)ccc2c1OCCO2
Reactant: O=S([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 0.8 g of 5-methyl-1,4-benzodioxan-6-carbaldehyde, then 27 ml of a 1% sodium hydroxide aqueous solution was added dropwise to the solution and further 0.5 g of a 10% palladium-carbon was added thereto, and the mixture was refluxed under heating for 1.5 days. The mixture was cooled to room temperature, 10 ml of a 10% sodium sulfite aqueous solution was added thereto and after stirring for 30 minutes, the mixture was filtered and the tetrahyctrofuran was removed under reduced pressure. The residue was adjusted to pH 3 with a 5% hydrochloric acid and extracted with diethyl ether. The diethyl ether layer was washed successively with water and saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 0.53 g of the titled 5-methyl-1,4-benzodioxan-6-carboxylic acid (yield: 61%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:15][C:12]1[CH:11]=[CH:10][C:9]([N:8]=[N:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(N=Nc2ccccc2)cc1

Procedure:
A mixture of 4-phenylazophenol (9.9 g; 50 mmol), iodomethane (7.1 g; 50 mmol), potassium carbonate (6.9 g; 50 mmol), and acetone (100 ml) was refluxed 48 h. After evaporating off the solvent, the residue was dissolved in water (25 ml), diethyl ether (50 ml) and THF (30 ml). The aqueous layer was extracted with ether (3×20 ml) and the combined organic solutions were washed with saturated NaCl solution (1×20 ml) and dried (MgSO4). After filtration and evaporation, the residue was recrystallized from 96% ethanol to give 8.7 g (82%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Br
Reactant: N#Cc1ccccc1-c1ccc(F)c(N)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1-c1ccc(F)c(Br)c1
Temperature: 3 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A warm solution of 3′-amino-4′-fluorobiphenyl-2-carbonitrile (4.24 g, 20 mmol) in 1,4-dioxane (30 ml) was treated with 48% hydrobromic acid (100 ml) and the resulting suspension stirred and cooled to 3° C. (internal temp). A solution of sodium nitrite (1.59 g, 23 mmol) in water (4 ml) was then added dropwise over 20 min keeping the internal temperature <5° C. Stirring at <5° C. was continued for 2 h before adding a cooled (5° C.) solution of copper(I) bromide in 48% hydrobromic acid (30 ml). The resulting purple reaction mixture was stirred at 5° C. for 10 min then warmed to 50° C. for 20 min. The reaction was diluted with ice-cold water (500 ml) and extracted with ethyl acetate (2×200 ml). The organics were combined, washed with 5% aqueous sodium sulfite and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification on silica, eluting with isohexane on a gradient of ethyl acetate (2-12%) afforded 3′-bromo-4′-fluorobiphenyl-2-carbonitrile as a white solid (2.5 g, 45%): δH (400 MHz, CDCl3) 7.22-7.27 (1H, m), 7.45-7.53 (4H, m), 7.66 (1H, td, J 8 and 2), 7.73 (1H, dd, J 8 and 2), 7.77 (1H, dd, J 8 and 2).
Reaction SMILES: [NH2:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:3]=1[C:4](N(OC)C)=[O:5].[CH2:16](OCC)C.Cl>C1COCC1.O>[NH2:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:3]=1[C:4](=[O:5])[CH3:16]
Reactant: CON(C)C(=O)c1c(Cl)ccc(Cl)c1N
Reactant: CCOCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(Cl)ccc(Cl)c1N
Yield: 27.7 %

Procedure:
2-Amino-3,6-dichloro-N-methoxy-N-methyl-benzamide (2491 mg, 10 mmol) were dissolved in THF (100 ml). At −78° C. under nitrogen 1.6 M methyllithium solution in diethylether (25.0 ml, 40 mmol) were added dropwise and the reaction was allowed to reach room temperature and was stirred over night. The reaction was cooled in an icebath and 2N aqueous hydrogen chloride solution (30 ml) were added and the reaction was stirred for 30 min (r.t.). The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (CH2Cl2) to yield the product as an orange oil (565 mg, 28%).
Reaction SMILES: [C:1]([CH:3]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])#[CH:2].[CH2:19]([SnH:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])/[CH:2]=[CH:1]/[CH:3]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(CCCCCCCC)OC1CCCCO1
Product: CCCCCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)OC1CCCCO1
Temperature: 110 °C

Procedure:
To 0.05 g (0.19 mmol) of the titled product of Example 8 is added 0.6 ml (0.22 mmol) of tri-n-butyltin hydride, and 20 mg of azoisobutyronitrile (AIBN). The reaction mixture was heated at 110° C. for 3 hours, whereupon thin layer chromatography indicated that the reaction was complete, producing the titled product. The product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([CH3:18])[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.CCN(CC)CC>CN(C=O)C>[N+:8]([C:7]1[C:2]([NH:17][C:13]2[CH:12]=[C:11]([CH3:18])[CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (2.28 g, 14.4 mmol), m-tolylamine (2.78 g, 25.9 mmol) and Et3N (3.6 mL, 25.9 mmol) in DMF (10 mL) was stirred at 90° C. for 16 h under a nitrogen atmosphere. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in cyclohexane) to afford the title compound as an orange solid (2.31 g, 70%). LCMS (Method C): RT 3.81 min [M+H]+ 230.1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>CO>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(-n2nc(C)cc2C)ccc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1cc(-n2nc(C)cc2C)ccc1N

Procedure:
Prepared by catalytic reduction (palladium, 10% on charcoal) of methyl 2-nitro-5-(3,5-dimethyl-pyrazol-1-yl)-benzoate in methanol.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:6][P:7]([N:12]1[CH:18]2[CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:17]2)([O:9][CH2:10][CH3:11])=[O:8])[CH3:5]>C1COCC1.[Cu]I>[CH2:4]([O:6][P:7]([NH:12][CH:18]1[CH:13]([CH3:1])[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:17]1)([O:9][CH2:10][CH3:11])=[O:8])[CH3:5]
Reactant: C[Mg]Br
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOP(=O)(NC1CN(C(=O)OCc2ccccc2)CCC1C)OCC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a suspension of CuI (0.3 equiv.) in anhydrous THF (0.1M) was added methyl magnesium bromide (3M solution in Et2O, 10 equiv.) at −40° C. The reaction was stirred for 30 min, followed by addition of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in THF (0.1M) at −40° C. Allowed the reaction to warm to 10° C. over 5 h, then quenched with water and extracted with ethyl acetate. The organic phase was concentrated under vacuo and purified via silica gel column chromatography eluting with ethyl acetate and hexanes (50% to 100% ethyl acetate) to yield benzyl 3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate in 35% yield. LCMS (m/z): 385.0 (MH+), Rt=3.38 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:30]=1.C(N(CC)CC)C>ClCCl>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([NH:28][C:6](=[O:7])[C:5]2[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH2:1][CH3:2])=[CH:30][C:31]=1[C:37]([F:38])([F:39])[F:40])#[N:34]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-ethoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[C:28]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:23]4=[N:22][C:21]=3[C:35]([O:37]CC)=[O:36])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[C:28]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:23]4=[N:22][C:21]=3[C:35]([OH:37])=[O:36])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C(=O)O)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 20b (2.07 g, 3.85 mmol) was placed in a 100 mL round bottom flask equipped with a stir bar and then THF (35 mL) was added. 1M NaOH (7.7 mL) was added and the reaction was stirred at rt for 3 d. Additional 1 M NaOH (8 mL) was added followed by addition of MeOH until the reaction went homogeneous. The reaction was stirred for 4 h and then the solvent was removed under reduced pressure. The residue was dissolved in water (100 mL) and extracted with Et2O (2×20 mL). The aqueous phase was acidified with 10% citric acid resulting in a precipitate. The mixture was diluted with DCM (100 mL) and the organic phase was separated. The aqueous layer was extracted with DCM (3×50 mL) and then the combined organic extracts were washed with water (30 mL) and dried over MgSO4. The solution was filtered and the solvent was removed under reduced pressure to afford compound 20c. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.58 (d, J=2.0 Hz, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.91 (dd, J=8.9, 2.3 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.14 (d, J=5.9 Hz, 1H), 3.97-4.06 (m, 4H), 3.90-3.97 (m, 4H), 3.61-3.70 (m, 4H), 3.52-3.60 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=O)=[N:6][CH:7]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][N:19]2[CH2:24][CH2:23][CH:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCN1CCC(N2CCCC2)CC1

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-(4-oxopiperidin-1-ylcarbonyl)aminobenzamide (100 mg, 0.268 mmol) and pyrolidine (0.045 mL, 0.54 mmol) yielded the title compound.