Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc([N+](=O)[O-])cc1
Yield: 91.5 %

Procedure:
A mixture of 1-ethyl-4-nitro-benzene (3.4 mL, 25 mmol), N-bromosuccinimide (4.38 g, 24.6 mmol) and benzoylperoxide (0.04 g, 0.18 mmol) in carbon tetrachloride (30 mL) was refluxed 1 h, cooled and filtered, washing with 1:1 ethyl acetate:hexanes. The filtrate was evaporated and purified by flash chromatography (SiO2) eluted with 2:98 ethyl acetate:hexanes to provide 1-(1-bromo-ethyl)-4-nitro-benzene (5.18 g, 90% yield) as a yellow oil. 1H-NMR (CDCl3, 500 MHz) 8.22 (d, 2H), 7.62 (d, 2H), 5.22 (q, 1H), 2.08 (d, 3H) ppm; HPLC (Method A) 3.837 min.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([CH2:23][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Fc1cccc(CCl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CCCC1=O
Reaction time: 0.08 h
Yield: 37.4 %

Procedure:
40% Methanolic Triton B (2.06 mL, 4.53 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (930.0 mg, 3.82 mM) in 5 mL of DMF at 0° C. After 5 minutes, 3-fluorobenzyl chloride (664.0 mg, 4.59 mM) was added and the resultant mixture stirred at 0° C. for 3 h, then at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed three times with 1 N HCl, three times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 502.3 mg (37%) of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow foam. 1H NMR (CDCl3) δ7.4-7.2 (m, 4H), 6.9 (m, 1H), 6.7 (m, 2H), 5.35 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.65 (t, 2H, J=6 Hz), and 2.3 (m, 2H). IR (CDCl3, cm−1) 3050, 2950, 1725, 1654, 1464, 1451, 1440, 1288 and 1119. MS (ES) m/e 350, 352.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.Cl.[NH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46][CH2:45]1>C(#N)C.C(O)C.C(N(CC)CC)C>[C:50]1([N:47]2[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][CH2:41][CH2:40][NH:39][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])[CH2:49][CH2:48]2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCCCCN1CCN(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1CCN(c2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.90 g (7.82 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.51 g (7.88 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a solution of 2.02 g (5.89 mM) of 1-(4-aminobutan-1-yl)-4-phenylpiperazine trihydrochloride and 4.1 ml (29.4 mM) of triethylamine in ethanol (10 ml) and the mixture was further stirred for one hour. The solvent was distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 50% methanol-chloroform=1:10). After concentration, ethanol was added to the residue and the resulting crystal crop was harvested by filtration to provide the title compound as rouge-colored crystals.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN1CCOCC1>CN1CCCC1=O>[N:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCN(c2ccncc2)CC1

Procedure:
Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 mL) and the resulting solution heated at 100° for 48 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL), washed with water and brine (2×100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (5%MeOH/CH2Cl2) to afford 21-1 as a crystalline solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.Cl[Ni]Cl>[CH2:21]([C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2ccccc2n1
Agent: Cl[Ni]Cl
Solvent: C1CCOC1
Product: c1ccc(Cc2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)cc1
Temperature: 50 °C

Procedure:
To a solution of the above-prepared (2-chloroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (123 mg, 0.43 mmol) in THF (5 mL) is added NiCl2 (dppp) (12 mg, 2.1.10−5 mol), followed by 1M benzylmagnesium chloride in THF (2.15 mL, 2.15 mmol). The solution is heated at 50° C. for 20 hours and the reaction mixture is then quenched with aqueous NH4Cl and the product extracted in ethyl acetate. The solvent is evaporated and the residue purified by flash chromatography to yield the desired (2-benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[O:16][CH:15]([CH2:18]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][C:13]=3[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:32][NH2:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=3[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2c(c(-c3ccc(F)c(Cl)c3)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3ccc(F)c(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.052 g, 46%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.14 g, 0.31 mmol) and methylamine (0.097 g, 3.1 mmol). mp 197-199° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17](Br)[CH:16](Br)[C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]1=2)=[O:12])=[O:4].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]#[C:16][C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]1=2)=[O:12])=[O:4]
Reactant: O=C(CCCCCNC(=O)C(F)(F)F)N1Cc2ccccc2C(Br)C(Br)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CCCCCNC(=O)C(F)(F)F)N1Cc2ccccc2C#Cc2ccccc21
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Pyridine hydrobromide perbromide (0.948 g, 2.97 mmol) was added to a solution of 3 (1.05 g, 2.70 mmol) in CH2Cl2 (4 ml) at room temperature, and the reaction mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with 5% aqueous hydrochloric acid (20 mL), dried over MgSO4, and solvent removed under vacuum. The residue was passed through a short pad of silica gel (CH2Cl2) to give 1.2 g of crude N-(trifluoroacetamidohexanoyl)-5,6,11,12-tetrahydro-11,12-dibromodibenzo[b,f]azocine (4) as an oil. Solution of crude 4 (1.2 g, 2.082 mmol) in THF (5 mL) was added to a solution of potassium t-butoxide (0.584 g, 5.21 mmol) in THF (10 ml) at room temperature, the reaction mixture was stirred for 1 hour, diluted with ethyl acetate (20 mL), washed with 5% aqueous hydrochloric acid, brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by chromatography (hexanes:ethyl acetate, 2:1 to 1:1) to afford 0.76 g (1.834 mmol, 88%) of 5 as brown oil. 1H NMR: δ 7.68 (d, J=7.6 Hz, 1H), 7.45-7.21 (m, 7H), 6.79 (br s, 1H), 5.16 (d, J=14.4 Hz, 1H), 3.67 (d, J=13.6 Hz, 1H), 3.22-3.14 (m, 1H), 3.11-3.02 (m, 1H), 2.24-2.16 (m, 1H), 1.41-1.22 (m, 4H), 1.11-0.9 (m, 2H); MS: m/z 414 [M+]. Calcd for C23H21F3N2O2 414.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:31])[CH2:29][Cl:30])[C:18]2=[O:32])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:33][NH:34][CH3:35].O1CCCC1.Cl>C(#N)C.C(O)C.C(OCC)(=O)C.CCOCC>[ClH:30].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:31])[CH2:29][N:34]([CH3:35])[CH3:33])[C:18]2=[O:32])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)cc1OC
Reactant: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CN(C)C)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of N-{2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}-2-chloroacetamide (1.3 g, 2.7 mmol), and dimethylamine in tetrahydrofuran (4.5 mL, 2N, 9.0 mmol) in acetonitrile (20 mL) was stirred at room temperature overnight. The solvent was removed in vacuo to give an oil. The oil was stirred in ethanol (5 mL). The resulting suspension was filtered and the solid washed with ethanol to give a yellow solid. To a stirred solution of the solid in ethyl acetate (10 mL) was added hydrogen chloride in ether (3.0 mL, 1N). After 5 min, ether (10 mL) was added. The resulting suspension was filtered and washed with ether to yield N-{2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}-2-(dimethylamino)acetamide hydrogen chloride as a yellow solid (1.07 g, 74% yield); mp, 178-180° C.; 1H NMR (DMSO-d6) δ 2.69 (brs, 6H, 2CH3), 3.02 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.88 (brs, 2H, CH2), 4.16 (dd, J=4.2, 14.3 Hz, 1H, CHH), 4.34 (dd, J=10.8, 14.4 Hz, 1H, CHH), 5.79 (dd, J=4.2, 10.4 Hz, 1H, NCH), 6.92-6.97 (m, 2H, Ar), 7.10 (d, J=1.4 Hz, 1H, Ar), 7.65 (d, J=7.2 Hz, 1H, Ar), 7.85 (t, J=7.7 Hz, 1H, Ar), 8.37-8.40 (m, 1H, Ar), 10.15 (s, 1H, HCl), 10.68 (s, 1H, NH); 13C NMR (DMSO-d6) δ 41.06, 44.18, 47.31, 52.95, 55.55, 55.59, 59.85, 111.26, 111.65, 119.16, 119.69, 127.00, 129.49, 121.64, 134.99, 136.09, 148.71, 148.76, 166.92, 167.34; Anal Calcd for C23H27N3O7S+1.25 HCl+0.4H2O: C, 50.94; H, 5.40; N, 7.75; Cl, 8.17; H2O, 1.33. Found: C, 51.30; H, 5.50; N, 7.37; Cl, 8.28; H2O, 1.68.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](=[O:34])[CH2:22][C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.C(OC(NC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=CC=2)=CC=1)=O)(C)(C)C>C(Cl)(Cl)Cl.CO>[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21](=[O:34])[CH2:22][C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:17][CH:18]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Agent: CC(C)(C)OC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NCC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1

Procedure:
The title compound was synthesized using the same procedure employed for Example 281, but with (1E,6E)-1-{4-[2-(tert-butoxycarbonylamino)acetylamino]phenyl}-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (18 mg, 39 μmol, synthesized in Example 268) as the starting material instead of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel chromatography (chloroform/methanol=95/5 to 80/20). The product was obtained as a solid (1.5 mg, 11%) having the following characteristic.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5](=[O:21])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:10][CH:9]=1)[CH3:3].[C-]#N.[Na+]>CN(C)P(N(C)C)(N(C)C)=O.[Cl-].[NH4+]>[CH3:22][C:2]([CH3:3])([O:4][C:5](=[O:21])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)[CH3:1]
Reactant: COC(=O)C(C)Cc1ccc(SCC(=O)OC(C)(C)C)cc1
Agent: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(Cc1ccc(SCC(=O)OC(C)(C)C)cc1)C(=O)O
Temperature: 70 °C

Procedure:
Dissolve 4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]thio]-alpha-methyl-benzenepropanoic acid, methyl ester (10.5 g, 32.4 mmol) in anhydrous hexamethylphos-phoramide (160 mL) and treat with sodium cyanide (1.59 g, 32.4 mmol). Heat at 70° C. for 48 hours, cool and dilute with saturated ammonium chloride (300 mL). Extract with ethyl ether (400 mL), wash with water (2×300 mL), then brine (300 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH2:11]=[C:12]1[N:13]=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:15][C:16](=[O:25])/[C:17]/1=[CH:18]/[C:19](=[CH:23]\[CH3:24])/[C:20](Cl)=[O:21]>C1COCC1.C(OCC)(=O)C>[CH2:11]=[C:12]1[N:13]=[C:14]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:15][C:16](=[O:25])/[C:17]/1=[CH:18]/[C:19](/[C:20]([C:10]1[N:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[CH:3][C:2]=1[CH3:1])=[O:21])=[CH:23]\[CH3:24]
Reactant: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)Cl
Reactant: Cc1cc2ccccn2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)cc2ccccn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
A solution of 2-methylindolizine (11.5 g; 87.7 mmol) in 35 mL of THF is added dropwise to a suspension of (2E)-2-[(E)-(4-methylidene-6-oxo-2-phenyl-4H-1,3-oxazin-5(6H)-ylidene)methyl]but-2-enoyl chloride (25 g; 87.7 mmol) in 140 mL of THF at 0° C. under nitrogen. After 18 h of stirring at ambient temperature, the reaction medium is diluted in ethyl acetate, and the solution is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM) to give 22.75 g (69%) of a yellow powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][C@:5]2([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]#[N:10].[BH4-].[Na+].[Na+].[Cl-].Cl>C(O)C>[OH:1][CH:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][C@:5]2([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]#[N:10]
Reactant: N#C[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Product: N#C[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
0.9 g (4.3 mmol) of (1S,2S,4S)-5-Oxo-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile (86) were dissolved using 20 mL of ethanol and 161 mg (4.3 mmol) of NaBH4 was added at −70° C. The mixture was stirred at ambient temperature for 1 h, 100 mL of a saturated aqueous NaCl-solution was added and the pH adjusted to 2-3 using aqueous HCl-solution. The mixture was extracted three times using 50 mL of ethyl acetate each. The organic layer was dried over MgSO4 and evaporated to yield 0.9 g of (87) as a single diastereomer as a colourless oil. Rt=0.76 min (Method 18). Detected mass: 214.1 (M+H+)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 39.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.055 g, 0.114 mmol) obtained in Example 125, step 2 and ethanesulfonamide (0.062 g, 0.569 mmol), the title compound (0.026 g, 47%) was obtained.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:30]([O:29][C:27]([N:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:14]1[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccccc3)C2)nc1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of ethyl (2E)-3-{6-[[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl) amino]-3-pyridyl}acrylate (5.45 g) in toluene (55 ml) was added 1-chloroethyl chloroformate (2.59 g) at room temperature and stirred at 20° C. for 1 hour. 1-Chloroethyl chloroformate (795 mg) and N,N-diisopropylethylamine (0.736 ml) was added to the mixture, and the solution was stirred at 20° C. for 15 minutes. After it was concentrated under reduced pressure, the resulting residue was dissolved in EtOH (70 ml). The mixture was stirred at 65° C. for 30 minutes, and concentrated under reduced pressure. The residue was poured into a mixture of aq NaHCO3 solution (80 ml) and dichloromethane (100 ml). The organic layer was separated and dried over sodium sulfate, and evaporated under reduced pressure to give crude oil. The oil was purified by column chromatography (silica gel 125 g, dichloromethane/MeOH (60/1 to 15/1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as oil (2.0 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(C(C)C)C(C)C)C.[F:33][CH2:34][C:35](OC)=[O:36]>CN(C)C=O>[F:33][CH2:34][C:35]([NH:2][C@H:3]1[CH2:4][C:5](=[O:23])[N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:7]1)=[O:36]
Reactant: COC(=O)CF
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CF)N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 50 °C
Yield: 27.8 %

Procedure:
A solution of 100 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.3 ml of N,N-dimethylformamide is treated successively with 100 μl (0.6 mmol) of N-ethyl-diisopropylamine and 55 μl (0.6 mmol) of methyl fluoroacetate. The resulting beige suspension is heated to 50° C. for 18 hours. For the working-up, the reaction mixture is evaporated, thereafter, the residue is dissolved in dichloromethane and the solution washed with 1 ml of hydrochloric acid (1N). The organic layer is separated, dried over sodium sulfate, and evaporated. For purification, the crude product is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 30 mg (28% of theory) of (S)-2-fluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=378 (M+NH4)+.
Reaction SMILES: [N:1](OCCCC)=[O:2].[C:8]1([N:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18](C)[C:17]=2[CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(=O)C>[C:8]1([N:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15](=[O:28])[C:16]2[CH:17]([CH3:27])[C:18](=[N:1][OH:2])[C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCON=O
Reactant: Cc1c(C(=O)N(c2ccccc2)c2ccccc2)ccc(S(C)(=O)=O)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CC1C(C(=O)N(c2ccccc2)c2ccccc2)=CC=C(S(C)(=O)=O)C1=NO
Temperature: 0 °C

Procedure:
A solution of 0.7 g (6.9 mmol) of n-butyl nitrite (97%) and 2 g (5.3 mmol) of N,N-diphenyl-2,3-dimethyl-4-methylsulfonyl-benzamide in 30 ml of dimethylformamide is cooled to from −55 to −60° C., and a solution of 1.4 g (12 mmol) of potassium tert-butoxide in 10 ml of dimethylformamide is added dropwise at this temperature, over a period of 20 minutes. The reaction is monitored by HPLC. For work-up, initially 10 ml of water are added, and the mixture is then adjusted to pH 5-6 using glacial acetic acid. The mixture is then poured onto 100 ml of ice-water and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 3.0 g of a partially crystalline crude product, which is purified by silica gel chromatography using the mobile phase toluene/acetone.
Reaction SMILES: N[C@H](C(O)=O)CCSC.Cl.C[O:12][C:13](=[O:40])[C@H:14]([CH2:36][CH:37]([CH3:39])[CH3:38])[NH:15][C:16](=[O:35])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C@@H:25]([NH2:28])[CH2:26][SH:27])=[CH:19][C:18]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH-].[Li+]>>[NH2:28][C@@H:25]([CH2:26][SH:27])[CH2:24][NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C@H:14]([C:13]([OH:40])=[O:12])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[C:18]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(NC[C@@H](N)CS)cc1-c1ccccc1
Agent: CSCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Li+]
Product: CC(C)C[C@H](NC(=O)c1ccc(NC[C@@H](N)CS)cc1-c1ccccc1)C(=O)O

Procedure:
This compound was prepared with the same method as for the preparation of the methionine derivative (see Example 26, section D), using 4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl-(S)-leucine methyl ester hydrochloride and lithium hydroxide. 1H NMR (CD3OD) δ 7.42 (d, 8.5 Hz, 1H), 7.29-7.38 (m, 5H), 6.73 (d, 8.5 Hz, 1H), 6.66 (s, 1H), 4.32 (dd, 3.3 and 5.9 Hz, 1H), 3.41-3.57 (m, 3H), 2.94 (dd, 4.3 and 14.5 Hz, 1H), 2.78 (5.2 and 14.5 Hz, 1H), 1.45 (t, 6.7 Hz, 2H), 1.17-1.26 (m, 1H), 0.78-0.83 (t, 8.5 Hz, 6H).