Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Cc1cc(N)cc(F)c1
Agent: Br
Product: Cc1cc(F)cc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 58.4 %

Procedure:
3-fluoro-5-methylaniline (0.091 mL, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.1 g, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-fluoro-5-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.053 g, 57%) as a white solid. Mass Spectrum: M+H+ 454. NMR Spectrum (CDCl3): 1.60 (d, 3H), 2.20 (s, 3H), 2.87 (bs, 3H), 3.07 (bs, 3H), 3.45-3.54 (m, 4H), 3.79-3.85 (m, 4H), 4.11 (d, 1H), 4.90-4.97 (m, 1H), 5.55 (s, 1H), 5.92 (ddd, 1H), 6.12 (s, 1H), 6.20 (d, 1H), 7.73 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Br:14]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[Br:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[CH:1]1[CH2:2][CH2:3]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C2CC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2CC2)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a mixture of methyl 4-cyclopropylbenzoate (compound 10.1, 500 mg, 2.84 mmol), N-bromosuccinimide (500 mg, 2.81 mmol) and trifluoroacetic acid (20 mL). The mixture was stirred overnight at 50° C., then cooled and carefully quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers were washed with brine (3×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as the eluent to yield 0.5 g (69%) of the title compound as a yellow oil.
Reaction SMILES: FC1C=C(C(C)(C)CC(O)(C(F)(F)F)C=O)C2OCCC=2C=1.NC1C(C)=CC=C2C=1C=CC(C)=N2.[F:36][C:37]1[CH:38]=[C:39]([C:46]([CH3:69])([CH3:68])[CH2:47][C:48]([OH:67])([C:63]([F:66])([F:65])[F:64])[CH:49]=[N:50][C:51]2[C:60]([CH3:61])=[CH:59][CH:58]=[C:57]3[C:52]=2[CH:53]=[CH:54][C:55]([CH3:62])=[N:56]3)[C:40]2[O:44][CH2:43][CH2:42][C:41]=2[CH:45]=1.C([BH3-])#N.[Na+]>>[F:36][C:37]1[CH:38]=[C:39]([C:46]([CH3:69])([CH3:68])[CH2:47][C:48]([OH:67])([C:63]([F:64])([F:66])[F:65])[CH2:49][NH:50][C:51]2[C:60]([CH3:61])=[CH:59][CH:58]=[C:57]3[C:52]=2[CH:53]=[CH:54][C:55]([CH3:62])=[N:56]3)[C:40]2[O:44][CH2:43][CH2:42][C:41]=2[CH:45]=1
Reactant: Cc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)c(C)ccc2n1
Agent: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: Cc1ccc2c(N)c(C)ccc2n1
Agent: [BH3-]C#N
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)c(C)ccc2n1

Procedure:
Analogously to Example 1, 4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-amino-2,6-dimethylquinoline into 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-2,6-dimethylquinoline, which is reduced with sodium cyanoborohydride to the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([O:21][NH:22][CH3:23])[CH:18]([CH3:20])[CH3:19]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:22]([CH3:23])[O:21][CH2:17][CH:18]([CH3:20])[CH3:19])[N:3]=1)[CH2:14][CH3:15]
Reactant: CNOCC(C)C
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(C)OCC(C)C)n1
Yield: 82 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with O-isobutyl-N-methyl-hydroxylamine hydrochloride as described in Example 13, affording LXXXII in 82% yield. ESI-MS (m/z) 297 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][C@H:18]([CH3:26])[C@:19]([CH3:25])([OH:24])[C:20]([F:23])([F:22])[F:21].CCN(C(C)C)C(C)C.NC1C=CC=CC=1>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[CH:11][N:17]2[C@@H:18]([C@@:19]([OH:24])([CH3:25])[C:20]([F:23])([F:22])[F:21])[CH3:26]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@H](N)[C@](C)(O)C(F)(F)F
Solvent: O
Solvent: Nc1ccccc1
Solvent: CS(C)=O
Product: C[C@@H](n1ccc2c(Cl)c(C#N)ccc21)[C@](C)(O)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
2-Chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.08 g, 0.318 mmol), (2S,3R)-3-amino-1,1,1-trifluoro-2-methylbutan-2-ol (Example 52C) (0.079 mg, 0.503 mmol), and Hunig's base (0.094 mL, 0.540 mmol) were combined in DMSO (1.0 mL) in a sealed tube and then heated to 100° C. Formation of the aniline intermediate was monitored by LCMS. Excellent conversion to this intermediate was realized after ca. 3 h of heating. The mixture was diluted with water and extracted with EtOAc. The combined organic portions were dried over Na2SO4 and concentrated to a brown oil. Further traces of DMSO were removed by high vac. The brown residue was diluted with NMP (ca. 1.0 mL) and then treated with KOtBu (0.095 mL, 1.0 M in THF). The resulting solution was then heated to 60° C. for 45 min at which time LCMS indicated formation of a very slightly less polar product. The UV trace of this product was far different from that of the aniline intermediate. The crude mixture was diluted with water and extracted with EtOAc. The combined organic portions were washed with water and brine and then dried over Na2SO4. Concentration afforded a thick brown oil that was purified by ISCO (24 g silica, hex/EtOAc up to 70%, detection at 254 and 230 nm) to afford the desired product as a pale yellow solid (0.078 g, 78%) in excellent purity: 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=3.5 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 6.68 (d, J=3.3 Hz, 1H), 6.50 (s, 1H), 5.03 (q, J=7.0 Hz, 1H), 1.51 (d, J=6.9 Hz, 3H), 1.37 (s, 3H); MS (ESI): m/z 317 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[CH3:18][N:2]([CH3:1])[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(C=CCN(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CC=Cc1ccc(/C=C/C(=O)O)cc1
Yield: 85 %

Procedure:
This product was prepared by refluxing for four hours, (E)-3-[4-(3-dimethylaminopropenyl)phenyl]acrylic acid, methyl ester with NaOH (0.16 g, 2 equiv.) in 10 mL of MeOH. After evaporation of the solvent in vacuo, treatment with 5 mL of HCl (1N) gave the title compound (0.4 g, 85%) as a gummy orange solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH3:14])(O)[CH2:5][CH2:6][O:7]2.FC(F)(F)C(O)=O.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2>ClCCl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:30]1[C:29]3[C:33](=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=[CH:27][CH:28]=3)[NH:32][CH:31]=1)([CH3:14])[CH2:5][CH2:6][O:7]2
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC1(O)CCOc2cc(F)cc(F)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C3(C)CCOc4cc(F)cc(F)c43)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
565 mg (2.82 mmol) of the compound from Example 171A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient) and subsequent flash chromatography on silica gel (mobile phase: dichloromethane). 632 mg (62% of theory) of the title compound were obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH:7]=[CH:6]3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
5-Formylindole (500 mg, 3.44 mmol) was dissolved in acetonitrile (10 mL), and the solution was added with 1-(tert-butoxycarbonyl)piperazine (961 mg, 5.16 mmol), acetic acid (3.90 mL, 68.1 mmol) and sodium triacetoxyborohydride (3.65 g, 17.2 mmol) little by little, followed by stirring at room temperature for 2 hours. The reaction mixture was added with water and sodium carbonate to adjust the pH to 9, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=19/1, 7/3, 1/1) to obtain 5-[4-(tert-butoxycarbonyl)piperazin-1-ylmethyl]indole (505 mg, yield 47%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[Cl-].[NH4+]>CO.[Fe]>[C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC1(c2ccc([N+](=O)[O-])cc2)CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CC1(c2ccc(N)cc2)CCCC1
Yield: 69.9 %

Procedure:
A stirred solution of [1-(4-nitro-phenyl)-cyclopentyl]-acetic acid tert-butyl ester [1.0 g, Reference Example 6(a)] in methanol (40 mL) was treated with water (40 mL), ammonium chloride (0.87 g) and iron powder (325 mesh, 0.55 g). The mixture was stirred at gentle reflux for 2.5 hours and then the hot mixture was filtered through hyflo. The filter pad was washed well with methanol. The combined filtrate and washings was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and then evaporated to give the title compound (0.63 g) as a golden oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[O:20][N:19]=1)[CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:10])=[O:9].C([Li])CCC.C[O:31][B:32](OC)[O:33]C>C1COCC1>[B:32]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[O:20][N:19]=1)[CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:10])=[O:9])([OH:33])[OH:31]
Reactant: COB(OC)OC
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Temperature: -95 °C
Reaction time: 0.17 h

Procedure:
To a solution of the title compound of step C (22.16 g, 52.85 mmol) in 264 ml THF at -95° C., n-butyl lithium (2M solution in pentane, 29.07 ml, 58.14 mmol) was added. The mixture was stirred at -95° C. for 10 minutes and trimethylborate (6.59 g, 63.42 mmol) was added and stirred at -78° C. for 15 minutes. The cold bath was removed and the mixture was warmed to room temperature slowly and stirred at room temperature for 0.5 hr. The mixture was then cooled to 0° C. and 100 ml 3N HCl was added dropwise. After stirring for 30 minutes, the mixture was extracted with CH2Cl2 (300 ml, 100 ml). The combined organic extracts were washed with 30 ml brine, dried and concentrated to give 2-borono-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide as a gum.
Reaction SMILES: [NH2:1][N:2]([CH2:16][CH2:17][OH:18])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([Cl:14])=[CH:8][C:7]=1[Cl:15])=[O:4].[CH2:19]=O>C(Cl)Cl>[Cl:15][C:7]1[CH:8]=[C:9]([Cl:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=1[NH:5][C:3]([N:2]1[CH2:16][CH2:17][O:18][CH2:19][NH:1]1)=[O:4]
Reactant: C=O
Reactant: COc1cc(NC(=O)N(N)CCO)c(Cl)cc1Cl
Solvent: ClCCl
Product: COc1cc(NC(=O)N2CCOCN2)c(Cl)cc1Cl
Temperature: 42 °C
Reaction time: 2 h

Procedure:
A mixture of 29.4 g (0.1 mol) of N-amino-N-2-hydroxyethyl-N′-(2,4-dichloro-5-methoxyphenyl)urea and 9 g (0.11 mol) of a 37% strength formaldehyde solution in 500 ml of methylene chloride was stirred at 42° C. for 2 h. After cooling, the reaction mixture was filtered with suction with about 300 ml of silica gel and washed with methylene chloride. Analysis by thin-layer chromatography gave a higher Rf value than that of the reaction mixture which had not been treated with silica gel and remained on the methyleneimino stage. Concentration under reduced pressure gave 27.8 g (81.8% of theory) of the title compound of m.p. 128-130° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:19])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([CH3:9])[CH3:8])C.Cl.O>CO>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:19])=[O:5]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(Oc1ccc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.4 %

Procedure:
A 5 N aqueous NaOH solution (0.83 ml) was added to a solution of 2-(2,4-dichloro-phenoxy)-2-methyl-propionic acid ethyl ester (383 mg, 1.38 mmol) in MeOH (6 ml) at room temperature. The mixture was stirred at room temperature for four hours, and 1 N HCl (4.5 ml) and H2O were then added, followed by extraction with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure to give 2-(2,4-dichloro-phenoxy)-2-methyl-propionic acid (359 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Br:31])[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:33]([O:37][C:38](N1CCCC1C1NC(C2C=CC3C(=CC=C(Br)C=3)C=2)=CN=1)=O)(C)(C)C.COC(NC(C1CCOCC1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([CH:6]1[CH2:8][CH2:38][O:37][CH2:33][CH2:7]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Br:31])[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Agent: COC(=O)NC(C(=O)O)C1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C1CCOCC1
Yield: 43 %

Procedure:
This compound was synthesized using the same procedure used to synthesize (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester from 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.469 g, 1.13 mmol) using Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.295 g, 1.356 mmol). [2-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester (0.264 g, 43% yield). LCMS-ESI+: calc'd for C26H29BrN4O4: 540.14 (M+); Found: 542.08 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)C=O)[CH3:2].C([C:14](=[O:18])[C:15]([O-:17])=[O:16])C.[OH-].[Na+]>C(O)C>[O:18]=[C:14](/[CH:2]=[CH:1]/[C:3]1[CH:10]=[CH:9][CH:8]=[CH:5][C:4]=1[F:11])[C:15]([OH:17])=[O:16]
Reactant: CCc1cccc(C=O)c1F
Reactant: CCC(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)/C=C/c1ccccc1F
Reaction time: 0.75 h
Yield: 57.2 %

Procedure:
To a magnetically stirred solution of ethyl 2-fluorobenzaldehyde (11.7 ml, 110 mmol) and ethylglyoxalate (11.1 ml, 100 mmol) in ethanol (50 ml) was slowly added a solution of sodium hydroxide (4.4 g (110 mmol) in 50 ml water) in a nitrogen atmosphere while the temperature was kept between 0° C. and 10° C. After stirring for another 45 minutes the reaction mixture was allowed to attain room temperature and stirred for 2 hours. The formed precipitate was collected by filtration and successively washed with ethanol and a 1N HCl solution (200 ml) and subsequently dried to give E-2-oxo-4-(2-fluorophenyl)-but-3-enoic acid (11.1 gram, 57% yield) Melting point: 100-102.5° C. 1H-NMR (400 MHz, CDCl3) δ 7.13-7.27 (m, 2H), 7.45-7.53 (m, 1H) 7.66-7.74 (m, 2H), 8.26 (d, J=16, 1H), invisible —OH proton.
Reaction SMILES: [OH-].[K+].[I-].[K+].[OH:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][C:7]=1[CH3:18].[CH2:19](Br)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.CO>[CH2:19]([O:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][C:7]=1[CH3:18])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(=O)n2ccc(C)c(O)c2n1
Reactant: BrCC=Cc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(=O)n2ccc(C)c(OCC=Cc3ccccc3)c2n1
Reaction time: 1 h

Procedure:
To a solution of 6.6 g of potassium hydroxide (85%) and 0.2 g of potassium iodide in 100 ml of water is added 150 ml of methanol and 19.0 g of 9-hydroxy-2,8-dimethyl-4H-pyrido[ 1,2-a]-pyrimidin-4-one and the whole stirred for about 1 hour. To this is added 20.1 g of cinnamyl bromide dissolved in 20 ml of methanol. The mixture is stirred at room temperature for about 18 hours and then worked up to give 9-[ (cinnamyl)oxy] -2,8-dimethyl-4H-pyrido[ 1,2-a] pyrimidin-4-one.
Reaction SMILES: C(O[C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C@@H:23]([O:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:37])[C@@H:18]4[CH2:36][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=O)C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:28]([O:27][C@H:23]1[CH2:24][C@@:25]2([CH3:26])[C@@H:11]([CH2:10][CH:9]=[C:5]2[C:6](=[O:8])[CH3:7])[C@H:12]2[C@H:22]1[C@:20]1([CH3:21])[C:15]([CH:14]=[CH:13]2)=[CH:16][C:17](=[O:37])[C@@H:18]2[CH2:36][C@H:19]12)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@@H](OC(=O)c3ccccc3)C[C@@]21C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@@H](OC(=O)c3ccccc3)C[C@]12C
Yield: 79.5 %

Procedure:
One gram of 17α-acetoxy-11β-benzoyloxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione is dissolved in 10 ml of "Dowtherm" (filtered over A12O3). The solution is heated under a stream of nitrogen gas for 30 minutes to 285° C. After cooling, the mixture is diluted with hexane, introduced into a silica gel column, and the "Dowtherm" is eluted with hexane. The thus-prepared compound is now eluted with methylene chloride and a gradually increasing proportion of chloroform. The individual fractions are tested for content and purity by thin-layer chromatography. The fractions having the desired compound are combined, concentrated, and the residue is recrystallized from benzene, thus obtaining 700 mg of 11β-benzoyloxy-1α,2α-methylene-4,6,16-pregnatriene-3,20-dione (79% of theory), m.p. 227°-229° C.
Reaction SMILES: [C:1]([C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4]OC)#[N:2].[N:11]1([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCCC1>[C:1]([C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:2]
Reactant: COC=C(C#N)C(=O)OC
Reactant: CCCCC=CN1CCCC1
Solvent: C1CCOC1
Product: COC(=O)C(C#N)=CC1=C(N2CCCC2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
1-Cyano-2methoxy-1-methoxycarbonyl-ethene (8.5 g, 0.06 mol) in tetrahydrofuran (60 ml) was chilled to -25° C. At this temperature, a solution of 1-pyrrolidino-hexene (9.1 g, 0.06 mol) in tetrahydrofuran (30 ml) was added dropwise. Cooling was then stopped and the reaction mixture was allowed to warm up to room temperature. The solution was then stirred for 1 hour and then evaporated. The resulting gum was triturated with isopropanol and the resulting solid material collected by vacuum filtration. After drying, yellowish crystals of 1-cyano-1-methoxycarbonyl-2-(2-pyrrolidino-cyclohexenyl)-ethene (9.5 g, 60.9% of theoretical yield; m.pt. 133° C.-134° C.) Were obtained. The compound migrated in tlc uniformly and was used for the next step without further purification.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5])[CH3:3].[NH:22]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:23]([C:32]([OH:34])=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CO.C1COCC1.[Pd]>[NH:22]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:23]([C:32]([NH:1][C@@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5])[CH3:3])=[O:34])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94212.5 %

Procedure:
A suspension of Z-D-Ala-Gly-OMe (26) (5.88 g, 0.02 mmol) and 10% Pd-C (0.4 g) in methanol (300 ml) was stirred under a hydrogen atmosphere at room temperature for 1.5 hr. The catalyst was filtered and the filtrate was evaporated in vacuo. The residue and Z-Tyr (6.30 g, 0.02 mol) was dissolved in dry THF (300 ml), cooled to 0° C. and HOBt (2.70 g, 0.02 mol) and DCC (4.12 g. 0.02 mol) were added successively at 0° C. The solution was stirred for 3 hr at 0° C. and overnight at room temperature. The precipitated crystals were filtered. The filtrate was evaporated under reduced pressure, the residual crystals were dissolved in EtOAc and the solution was washed with 5% NaHCO3, 0.2 N Hcl and water, and dried over anhyd. Na2SO4. The solvent was removed in vacuo and the resulting solid was purified by silica gel column chromatography using CHCl3 --CH3OH (98:2) as eluant to give Z-Tyr-D-Ala-Gly-OMe (27) (8.62 g, 94.3%), mp 154°-155° C. (AcOEt-hexane); [α]D22 33.4° (C=1.0, MeOH); NMR (CDCl3 -DMSO-d6 (4:1) δ: 1.25 (3H, d, J=7 Hz, CH3), 2.82-3.03 (2H, m, CH2,), 3.70 (3H, s, CH3O), 3.80-3.95 (2H, m, CH2PhOH), 4.15-4.60 (2H, m, 2 CH), 5.05 (2H, s, CH2O), 6.70-7.25 (4H, m, ArH), 6.70-6.90 (1H, br, NH), 7.36 (5H, s, ArH), 7.70-8.10 (2H, br, NH). Rf (I)=0.48; Rf (VI)=0.08.