Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[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].[CH3:18][S:19]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:20])=[O:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)c1ccc(C(=O)NN)cc1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoic acid (3.33 g, 13.07 mmol), 4-(methylsulfonyl)benzohydrazide (3.08 g, 14.38 mmol) and anhydrous THF (200 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (1.77 g, 13.07 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (3.76 g, 19.61 mmol) at −15° C. followed by triethylamine (2.73 mL, 19.61 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. After 17 h, the mixture was filtered under vacuum and the residue washed with THF (50 mL). The THF solution was concentrated to ca. 20 mL, whereupon EtOAc (100 mL) was added followed by water (50 mL). The phases were partitioned and the organic phase washed with water (30 mL), brine (30 mL) dried (Na2SO4) and concentrated to furnish a light brown solid (5.82 g). This crude product was chromatographed [100% EtOAc as eluent] to afford a pale yellow solid (5 g). The crude product was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[NH2:8][C:9]1[CH:10]=[CH:11][C:15]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:17][CH:16]=3)[CH:12]=[N:13]2)=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(F)cc4)ccc32)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 135.1 %

Procedure:
4-Fluoro-N-(1H-indazol-5-yl)benzamide (10.3 g, 40 mmol), 4-fluoronitrobenze (4.3 mL, 40 mmol) and cesium carbonate (13 g, 40 mmol) were taken up in DMSO (400 mL). The solution was heated to 100° C. and stirred for 24 h. After the solution was cooled it was diluted with water until a precipitate formed and stirred well for 5 min. Filtration gave a yellow solid, which was then washed well with water, followed by hexanes. After the solid was dried under vacuum it was taken up in ethanol and stirred at RT under nitrogen. The solution was treated with Pd(OH)2 (100 mg) and placed under a balloon of H2 gas. After stirring at RT for 24 h, the catalyst was removed via filtration through celite. The filtrate was concentrated under reduced pressure to give 9.36 g (67%) of a crude product as a yellow solid
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]([NH2:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][C:17]1[CH:16]=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[C:13]([NH:11][CH:9]([C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH3:10])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cc1cc(C)cc(C(C)N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(C(C)Nc2cc(F)ccc2[N+](=O)[O-])c1
Yield: 67.7 %

Procedure:
1-(3,5-Dimethylphenyl)ethanamine (670 mg, 4.2 mmol), 2,4-difluoronitrobenzene (764 mg, 4.2 mmol) and N,N-diisopropylethylamine (1.08 mg, 8.4 mmol) were stirred at room temperature in dry acetonitrile (50 mL) for 6 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated to collect the title compound (820 mg, 61% yield). 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 8.19 (m, 1H), 6.45 (s, 2H), 6.30 (m, 3H), 4.48 (m, 1H), 3.76 (s, 6H), 1.62 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[C:31]([CH2:32]Cl)=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:32][C:31]2[C:23]([Cl:22])=[CH:24][C:25]3[O:29][CH2:28][O:27][C:26]=3[CH:30]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cc2c(cc1Cl)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2cc3c(cc2Cl)OCO3)cc1
Yield: 34.6 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 5-chloro-6-chloromethyl-benzo[1,3]dioxole (125 mg, 0.6 mmol) to afford the title product (80 mg, 40% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:23][CH:21]([O:20][C:18](=[O:19])[O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:22]
Reactant: OCc1ccc(OCc2ccccc2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.07 g (5.0 mmol) 4-benzyloxybenzyl alcohol and 0.786 g (5.5 mmol) 1-chloroethyl chloroformate in 25 ml CH2Cl2 is cooled to 0° C. and 0.435 g (5.5 mmol) pyridine added. After stirring at rt for 2 h the reaction mixture is quenched with 1N HCl, the organic phase separated and washed with sat. NaHCO3 solution and brine, dried over Na2SO4 and evaporated: 1.58 g (98%) (RS)-carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethyl ester as light yellow oil. 1H-NMR (CDCl3): 1.81 d, J=6 Hz, 3H; 5.07 s, 2H; 5.14 and 5.17, AB-system J=15 Hz, 2H; 6.43 q, J=6 Hz, 1H; 6.97 d, J=8.5 Hz, 2H and 7.30–7.45 m, 7H.
Reaction SMILES: NC1C=CC(C)=CC=1[C:4](O)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:4]([NH:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1)=[O:5])=[O:21]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: Nc1nccs1
Agent: COc1ccccc1C(=O)c1cc(C)ccc1N
Product: COc1ccccc1C(=O)c1cc(C)ccc1NC(=O)Nc1nccs1
Yield: 72 %

Procedure:
(2-Amino-5-methyl-phenyl)-(2-methoxy-phenyl)-methanone (843 g, 35%) was prepared from 2-amino-5-methyl-benzoic acid (1.51 g, 0.1 mol) following the general procedure S. 1-[2-(2-methoxy-benzoyl)-4-methyl-phenyl]-3-thiazol-2-yl-urea (132 mg, 72%) was prepared from (2-amino-5-methyl-phenyl)-(2-methoxy-phenyl)-methanone (121 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[OH-].[Na+].[CH2:17]1[O:19][CH2:18]1.Cl>C(O)C>[ClH:1].[OH:19][CH2:18][CH2:17][CH:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:14]=2)[CH2:9][CH2:10][NH:11]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: C1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)C(CCO)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.01 g, 23.3 mmol) in ethanol (200 ml) at 0° C. in a pressure bottle was added 2.5 M sodium hydroxide solution (10 ml). This solution was stirred for 0.2 h before ethylene oxide (4.2 ml) was added and the bottle was capped and the solution was stirred overnight while slowly allowing it to warm to ambient temperature. The solvent was concentrated and the aqueous solution was extracted twice with dichloromethane. The combined and dried (magnesium sulfate) extracts were concentrated to give an oil. This oil was immediately dissolved in ethanol (125 ml) and hydrochloric acid in ethanol was added until a distinctly acidic solution was obtained. After cooling, the title compound was collected and isolated as an off-white solid (3.76 g, 62%), m.p. 213° C. (dec.).
Reaction SMILES: [CH:1]([Si:4]([O:11][C:12](=[O:43])[N:13]([C@H:31]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]1)[CH2:14][CH2:15][C:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=2)[CH:19]=[N:18][CH:17]=1)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(N(CC)CC)C>C(Cl)Cl.O>[CH:1]([Si:4]([O:11][C:12](=[O:43])[N:13]([CH2:14][CH2:15][C:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=2)[CH:19]=[N:18][CH:17]=1)[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)([CH:5]([CH3:6])[CH3:7])[CH:8]([CH3:9])[CH3:10])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(C(=O)OC(C)(C)C)C1)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCNC1)(C(C)C)C(C)C
Reaction time: 2 h

Procedure:
(S)-N-[1-(tert-Butoxycarbonyl)pyrrolidin-3-yl]-N-{2-[1-(4-cyano-3-fluorobenzyl)-1H-imidazol-5-yl]ethyl}carbamic acid triisopropylsilyl ester, as described above in Step G, (395 mg, 0.643 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (2 mL, 2.56 mmol) was added. After 2 hours, the reaction was neutralized with triethylamine, diluted with water and extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3]([NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2)=[O:4].[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C)C=O>[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23][N:8]1[C:7]2[C:11](=[N:12][CH:13]=[N:14][C:6]=2[NH:5][C:3](=[O:4])[CH:2]([CH3:15])[CH3:1])[N:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)C(=O)Nc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ncnc2ncn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-methyl-N-(7H-purin-6-yl)propanamide (1.5 g, 24.36 mmol) in dimethylformamide (20 mL), sodium hydride (0.88 g, 36.55 mmol) was added portion wise in 10 minutes at 0° C. The above suspension was stirred for 10 minutes at 0° C. followed by addition of 2-(trimethylsilyl)ethoxymethyl chloride (4.87 g, 29.24 mmol) slowly at 0° C. under nitrogen atmosphere. The reaction was stirred at room temperature for 16 h. After completion of the reaction, the mixture was quenched with saturated aqueous solution of ammonium chloride and product was extracted with dichloromethane (2×50 mL). The organics were then separated, dried (magnesium sulfate) and concentrated to dryness under vacuum and the crude was purified by flash chromatography eluting with 2% methanol in dichloromethane. Concentration of the desired fractions afford 2-methyl-N-[7-(2-trimethylsilylethoxymethyl)purin-6-yl]propanamide (2) as white solid. Yield: 2 g, 24%.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([OH:21])=O)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:27][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: NN1CCCC1
Product: O=C(NN1CCCC1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and 1-pyrrolidinamine (CAN 16596-41-1) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 372.1899 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[OH:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:35](=[O:36])[C:34]([OH:33])([CH3:39])[CH3:38])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.5 %

Procedure:
To a mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (60 mg, 0.14 mmol), 2-hydroxyisobutyric acid (17 mg, 0.17 mmol) and DIPEA (29 μL, 0.17 mmol) in DCM (1 mL) was added HATU (63 mg, 0.17 mmol). The resulting yellow mixture was stirred for 1.5 h at r.t. then the reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-6%) affording 721 as a foam (41 mg, 56%). LCMS (method I): RT 3.00 min, [M+H]+ 519.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-7.97 (1 H, m), 7.75-7.74 (1 H, m), 7.27-7.25 (2 H, m), 4.62 (1 H, s), 4.33 (5 H, s), 4.20 (1 H, s), 3.93 (1 H, s), 3.86 (4 H, t, J=4.72 Hz), 3.76 (3 H, s), 3.64 (1 H, s), 3.34 (3 H, q, J=7.44 Hz), 3.15-3.14 (2 H, m), 1.43-1.42 (9 H, m)
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH2:9]([N:11]([CH2:12][CH3:13])[C:1](=[O:8])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])[CH3:10]
Reactant: C/C=C/C=C/C(=O)O
Reactant: CCNCC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C/C=C/C(=O)N(CC)CC
Yield: 99 %

Procedure:
Sorbic acid (5.01 g, 44.7 mmol) and diethylamine (3.59 g, 49 mmol) were dissolved in dimethylformamide (100 ml) and the solution was stirred under ice-cooling. To the solution was added diphenylphosphoryl azide (15.0 g, 54.5 mmol) and the mixture was stirred for 20 hours while allowing to rise the temperature to room temperature. The reaction mixture was diluted with ethyl acetate and washed with an aqueous saturated sodium chloride solution. The ethyl acetate layer was washed with an aqueous saturated sodium carbonate and aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=200:1-50:1) to obtain sorbic acid N,N-diethylamide (7.40 g, 99.9%) as pale yellow solid. This compound has the following NMR spectrum.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[C:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)#[N:18].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.O>[C:2]([C:3](=[CH:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([C:17]#[N:18])[CH:20]=1)[C:4]([NH:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])(=[O:1])[CH3:16]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(=O)CC(=O)NCC=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CC(=O)C(=Cc1cccc(C#N)c1)C(=O)NCC=Cc1ccccc1

Procedure:
541 mg (2.49 mmol) of 3-oxo-N-(3-phenyl-2-propene-1-yl)butyramide, 328 mg (2.50 mmol) of 3-cyanobenzaldehyde and 0.2 ml (2.02 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluene Sulfonic acid in 30 ml of benzene overnight while water was removed. Ethyl acetate was added to the reaction mixture, which was washed with 2 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2-acetyl-3-(3-cyanophenyl)-N-(3-phenyl-2-propene-1-yl) acrylamide. This product was heated together with 387 mg (2.5 1 mmol) of 2-cyanoethyl 3-aminocrotonate at 80° C. under stirring in 20 ml of 2-propanol for four days. 2-Propanol was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform/methanol=100/1) to obtain the title compound.
Reaction SMILES: [Br:1]Br.[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18]([O:25]C(=O)C)=[CH:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:29][CH3:30])[CH:8]=1)(=[O:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].OS([O-])=O.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@H:17]([Br:1])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:29][CH3:30])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(OC(C)=O)=CC[C@H]3[C@@H]1CC2
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@H](Br)C[C@H]3[C@@H]1CC2

Procedure:
A solution of Br2 (0.4 g, 2.5 mM) in 10 ml of carbon tetrachloride is added over a period of 5 min to a suspension of 1,17-diacetoxy-3-methoxyestra-1,3,5(10),16-tetraene (0.95 g, 2.5 mM), potassium carbonate (0.53 g) and 40 ml of carbon tetrachloride at 0°. After an additional 5 min the colorless suspension is added to a solution of NaHSO3 (1 g) in 75 ml of H2O. The layers are separated and the aqueous layer is extracted with 3 × 25 ml of chloroform, the organic layers are combined and evaporated in vacuo after drying with MgSO4. Trituration of the residue with a small amount of methanol gives 1-acetoxy-16α-bromo-3-methoxyestra-1,3,5(10)-trien-17-one, yield 0.94 g (90%); m.p. 188°-190° (methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.COC(Cl)[Cl:13]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:13])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: COC(Cl)Cl
Product: O=C(Cl)c1cc(Br)cs1

Procedure:
A suspension of 4-bromothiophene-2-carboxylic acid (47.0 mmol crude, from previous step) in α,α-dichloromethyl methyl ether (13.0 mL, 150 mmol) was slowly heated to reflux. As the reaction mixture was heated a pale brown solution formed, and gas evolution was evident. After stirring at a gentle reflux for 5 hours, the reaction solution was allowed to cool and was then concentrated under reduced pressure to afford 4-bromothiophene-2-carbonyl chloride as a brown liquid. This liquid was dissolved in CH2Cl2 (150 mL) and the reaction flask was cooled in an ice bath. The cold reaction solution was treated with a small amount of 4-(N,N-dimethylamino)pyridine, N,O-dimethylhydroxylamine hydrochloride (5.5 g, 56 mmol), and finally N,N-diisopropylethylamine (14 mL, 80 mmol). After stirring for 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After stirring for 16 hours, the pale brown reaction solution was quenched by the addition of ice-cold H2O, and diluted with CH2Cl2 (500 mL). The layers were separated, and the organic layer was washed with 1 N HCl (100 mL), H2O (50 mL), and saturated aqueous NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford a brown liquid. The crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 30% ethyl acetate/hexane on silica. The product peak was collected to afford 4-bromothiophene-2-carboxylic acid methoxymethylamide as a yellow oil. (9.9 g, 83% yield over three steps). 1H-NMR (400 MHz, CDCl3): δ 7.83 (1H, d, J=1.5 Hz), 7.45 (1H, d, J=1.5 Hz), 3.78 (3H, s), 3.37 (3H, s).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)C1CC=CCC1>>[CH:1]1([O:7][N:8]2[C:9]([CH3:17])([CH3:18])[CH2:10][CH:11]([OH:16])[CH2:12][C:13]2([CH3:15])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CC=CCC1
Agent: O=CC1CC=CCC1
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1

Procedure:
In analogy, 1-Cyclohex-3-enyloxy-2,2,6,6-tetramethyl-piperidin-4-ol, compound H, can be prepared using 1,2,3,6-tetrahydrobenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[C:21]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=2)[C:26](=O)[CH2:25]1)(=[O:23])[CH3:22].[B][B][B][B][B][B][B][B][B][B]>>[C:21]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=2)[CH:26]([NH:19][C:17]2[CH:16]=[CH:15][C:14]([F:20])=[C:13]([C@@:4]3([CH3:12])[N:3]=[C:2]([NH2:1])[N:7]([CH3:8])[C:6](=[O:9])[C:5]3([CH3:10])[CH3:11])[CH:18]=2)[CH2:25]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CC(=O)c2ccc(F)cc21
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CC(=O)N1CC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)c2ccc(F)cc21

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 1-acetyl-6-fluoro-1,2-dihydro-indol-3-one using decaborane yielded a mixture of epimers of the title compound as a light red waxy solid. MS (ESI): m/z=456.4 [M+H]+.