Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1C=C(C(O)=O)C=[CH:4][N:3]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].BrC1C=C(C=CC=1)O[C@H](C1[CH:44]=[CH:43][C:29]([C:30]([NH:32][CH2:33][C:34]2[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=2[CH3:40])=[O:31])=[CH:28][CH:27]=1)C>>[CH3:40][C:39]1[CH:38]=[C:37]([CH3:41])[NH:36][C:35](=[O:42])[C:34]=1[CH2:33][NH:32][C:30]([C:29]1[C:43]([CH3:44])=[CH:4][N:3]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:2](=[O:1])[C:28]=1[CH3:27])=[O:31]
Reactant: C[C@H](c1ccccc1)n1ccc(C(=O)O)cc1=O
Reactant: Cc1cc(C)c(CNC(=O)c2ccc([C@H](C)Oc3cccc(Br)c3)cc2)c(O)n1
Product: Cc1cc(C)c(CNC(=O)c2c(C)cn(C(C)c3ccccc3)c(=O)c2C)c(=O)[nH]1

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,5-dimethyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxamide (70 mg) were separated by SFC (Condition: Column: AS (250*30 mm, 5 um), eluent: CO2:EtOH:NH3.H2O=78:22:0.1, flow rate: 50 ml/min, column temperature: 38° C., wavelength: 220 nm) to give 15.6 mg and 14.8 mg of two enantiomers. The LCMS and HNMR of two enantiomers were the same as the racemic compound. Although the separated enantiomers were not optically characterized, for convenience sake the (R) enantiomer was designated Compound I-201 and the (S) enantiomer was designated Compound I-202.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c([N+](=O)[O-])c1
Yield: 46.9 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 510 mg of 4-fluoro-3-nitroaniline in place of the 2,4-difluoroaniline. 339 mg of N-(4-fluoro-3-nitrophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12]Br>>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:11]1)(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCBr
Product: CCOC(=O)C1(C(C)=O)CC1

Procedure:
Ethyl acetoacetate is allowed to react with 1,2-dibromoethane to obtain ethyl 1-acetylcyclopropanecarboxylate. Next, ethyl 1-acetylcyclopropanecarboxylate is allowed to react with zinc powder and ethylbromoacetate to give ethyl 1-ethoxycarbonyl-β-hydroxy-β-methyl-cyclopropanoate.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH:20]=[O:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.C[Si]([C:35]([F:38])([F:37])[F:36])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH:20]([OH:21])[C:35]([F:38])([F:37])[F:36])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCCC[C@H](C=O)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC[C@@H](NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
430 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methyl-N-[(2R)-1-oxohexan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide (1.05 mmol) were initially charged in 30 ml of dry THF, and 194 μl of trimethylsilyl trifluoromethane (1.24 mmol) and 621 μl of tetrabutylammonium fluoride solution (1.0 M in THF; 0.62 mmol) were successively added dropwise at 0° C. The reaction mixture was slowly warmed to RT, and stirring was continued overnight. The mixture was then concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried, filtered and concentrated. Preparative HPLC separation (Method 9) afforded 41 mg of the target compound, which was once more purified by HPLC (Method 10). This gave 28.4 mg of the target compound. The diastereomer ratio was about 3:1 (1H NMR integration).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[N:14]([CH3:24])[C:13]2=[O:25])[CH2:8][CH2:7]1)=O)C.[BrH:26]>>[BrH:26].[CH3:24][N:14]1[C:15]2[C:20](=[CH:19][C:18]([CH3:23])=[CH:17][CH:16]=2)[C:21](=[O:22])[N:12]([CH:9]2[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]2)[C:13]1=[O:25]
Reactant: CCOC(=O)N1CCC(n2c(=O)c3cc(C)ccc3n(C)c2=O)CC1
Agent: Br
Product: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Yield: 99 %

Procedure:
In 50 ml of 48% hydrobromic acid was dissolved 5.0 g (14.5 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline (Compound g) obtained in Reference Example 7, and the solution was heated under reflux for 1.5 hours. After evaporation of the solvent, ethanol was added to the residue. The precipitated crystals were collected by filtration to give 5.04 g (yield: 99%) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[NH:25][CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[N:25]([S:37]([CH3:36])(=[O:39])=[O:38])[CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ncc[nH]1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)n1ccnc1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-3-{[1-(methylsulfonyl)-1H-imidazol-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1H-imidazol-2-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 403) and methanesulfonyl chloride following General Procedure U.
Reaction SMILES: Cl.[Br:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=O.[BH4-].[Na+]>CO.C(OCC)(=O)C>[Br:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH2:25][C:24]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:23]=3[Cl:22])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N[C@H]1CCN(c2cccc(Br)n2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: Clc1ccc(CN[C@H]2CCN(c3cccc(Br)n3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve (3S)-1-(6-bromopyridin-2-yl)-pyrrolidin-3-ylamine hydrochloride (131 mg, 0.47 mmol) in methanol. Add triethylamine (200 μL, 1.44 mmol) and 2,4-dichlorobenzaldehyde (116 mg, 0.66 mmol). Stir at room temperature overnight. Add sodium borohydride (100 mg, 2.63 mmol) and stir 2 hours. Pour onto a column of Dowex® 50wx4-200 and wash with methanol. Elute with 10:90 triethylamine:methanol, concentrate to give a residue. Chromatograph the residue on silica gel eluting with 100:0 to 40:60 ethyl acetate:hexanes to give the title compound. Combine the title compound and ethyl acetate and add 1 N hydrochloric acid in methanol (1.5 mL). Concentrate to dryness to give the hydrochloride salt of the title compound (174 mg, 85%). 1H NMR (400 MHz, MeOH-d4) δ 7.67 (d, 1H, J=2.0 Hz), 7.64 (d, 1H, J=8.0 Hz), 7.49 (dd, 1H, J=8.0, 2.0 Hz), 7.40 (t, H, J=8.0 Hz), 6.79 (d, 1H, J=8.0 Hz), 6.49 (d, 1H, J=8.0 Hz), 4.46 (s, 2H), 4.17-4.11 (m, 1H), 3.95-3.91 (m, 1H), 3.79-3.75 (m, 1H), 3.73-3.66 (m, 1H), 3.54-3.48 (m, 1H), 2.65-2.56 (m, 1H), 2.38-2.29 (m, 1H); MS (ES): m/z=400 [M+H].
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:15]1([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(N2CCNCC2)cc1
Yield: 77 %

Procedure:
A mixture of tert-butyl 4-bromobenzoate (4.8 g, 18.8 mmol), piperazine (9.7 g, 0.11 mol), palladium acetate (85 mg, 0.38 mmol), (S)-(−)-BINAP (352 mg, 0.57 mmol), and sodium tert-butoxide (2.7 g, 28.2 mmol) in toluene (50 ml) was refluxed under a nitrogen atmosphere for 2 hours. Ethyl acetate and water were added to the reaction mixture and the insoluble substances were removed by filtration though Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=5/1) to afford tert-butyl 4-(piperazin-1-yl)benzoate (3.8 g, yield 77%) as a gray powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([C:32]([O:34][CH3:35])=[O:33])[C:15]2[NH:16][C:17]3[CH:18]=[C:19]([CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:20]=[CH:21][C:22]=3[C:23]=2[N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:32]([O:34][CH3:35])=[O:33])[C:15]3[NH:16][C:17]4[CH:18]=[C:19]([CH2:25][N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:20]=[CH:21][C:22]=4[C:23]=3[N:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(CN3CCOCC3)ccc12
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1cc(CN3CCOCC3)ccc12
Temperature: 70 °C
Yield: 73.7 %

Procedure:
A mixture of 3-chlorophenylboronic acid (34 mg, 0.22 mmol), methyl 2-bromo-7-(morpholinomethyl)-5H-pyrido[3,2-b]indole-4-carboxylate (75 mg, 0.19 mmol), powdered potassium phosphate tribasic (95 mg, 0.45 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (15 mg, 0.037 mmol), and Pd(OAc)2 (4.2 mg, 0.019 mmol) in a microwave vial was flushed with nitrogen. THF (928 μL) was added, the vial was capped, and the reaction was heated in a 70° C. oil bath for 24 hr. The reaction was partitioned between EtOAc and water. The organic phase was extracted with brine and dried with sodium sulfate. The solvents were removed and radial chromatography (step gradient elution with DCM containing 0 to 2% MeOH) afforded methyl 2-(3-chlorophenyl)-7-(morpholinomethyl)-5H-pyrido[3,2-b]indole-4-carboxylate (59 mg, 0.14 mmol, 73% yield) as a yellow oil. MS (ESI) m/z 435.9 (M+H). 1H NMR (400 MHz, chloroform-d) δ ppm 9.54 (1H, s), 8.40 (1H, d, J=8.06 Hz), 8.26 (1H, s), 8.23 (1H, t, J=1.76 Hz), 8.06 (1H, dt, J=7.74, 1.42 Hz), 7.56 (1H, s), 7.46 (1H, t, J=7.68 Hz), 7.33-7.43 (2H, m), 4.13 (3H, s), 3.75-3.80 (4H, m), 3.73 (2H, s), 2.51-2.58 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:4](=[O:22])[C:3]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=1)[CH2:63][NH2:64]>C(Cl)Cl.O.CC(C)=O.CCCCCC>[F:59][C:60]1[CH:61]=[C:62]([CH2:63][NH:64][C:23]([C:3]2[C:4](=[O:22])[N:5]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:6]3[C:11]([C:2]=2[CH3:1])=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=3)=[O:24])[CH:65]=[CH:66][CH:67]=1
Reactant: Cc1c(C(=O)O)c(=O)n(C2CCOCC2)c2cc(C(F)(F)F)ccc12
Reactant: NCc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(=O)n(C2CCOCC2)c2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
To a stirred solution of 280 mg (0.79 mmol) 4-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid in DCM (5 ml) were added 360 mg (0.95 mmol) HATU and 54 μl (3.15 mmol) DIPEA at 0° C. The reaction mixture was stirred for 5 min at 0° C. followed by the addition of 90 μl (0.79 mmol) 3-fluoro-benzylamine. The reaction mixture was stirred at RT for 4 h. Then the mixture was diluted with water (5 ml) and extracted with DCM (3×10 ml). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over anhydrous Na2SO4 and concentrated in vacuum. After CC (acetone/hexane 1:3) of the residue, 210 mg (0.45 mmol, 57%) N-[(3-fluorophenyl)-methyl]-4-methyl-2-oxo-1-tetrahydro-pyran-4-yl-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide (example 44) were obtained. MS: m/z 463.2 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+:2]=[N-:3].[O:28]1[CH:32]=[CH:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:7]2[C:8]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[O:10])=[C:4]([N:1]3[CH:32]=[C:31]([CH2:30][CH2:29][OH:28])[N:3]=[N:2]3)[CH2:5][C@H:6]12)[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N=[N+]=[N-])C[C@H]12
Reactant: C1=COCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(n3cc(CCO)nn3)C[C@H]12

Procedure:
A mixture of p-nitrobenzyl (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]-carbapen-2-em-3-carboxylate (75 mg, 0.2 mmol) and 2,3-dihydrofuran (0.25 ml) in anhydrous tetrahydrofuran (5 ml) containing excess sodium bicarbonate is kept at 4° C. for 1 week. The mixture is filtered and the filtrate evaporated under vacuum. The residue is purified by preparative thin layer chromatography on silica gel to afford p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[4-(2-hydroxyethyl)-1,2,3-triazol-1-yl]carbapen-2-em-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH:8]1([Mg]Br)[CH2:10][CH2:9]1.O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCOCC.C1COCC1>[Br:1][C:2]1[C:3]([CH:8]2[CH2:10][CH2:9]2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Br[Mg]C1CC1
Reactant: Brc1cncnc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Brc1cncnc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of 5-bromopyrimidine (3 g, 18.87 mmol) in Et2O (120 mL) and THF (20 ml) was added cyclopropylmagnesium bromide (39.6 mL, 19.81 mmol) at 0° C. The resulting white suspension was stirred at room temperature for 1 h and quenched with water (0.340 mL, 18.87 mmol) followed by addition of DDQ (4.28 g, 18.87 mmol) in THF (10 ml). The resulting black mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with NaOH (1N) and brine. The crude product was purified by BIOTAGE® (0-15% EtOAc/hexanes, 1.2 L) to afford the title compound (700 mg, 20%) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.87 (1 hr, s), 8.66 (1 hr, s), 2.40-2.56 (1 hr, m), 1.13-1.32 (4 hr, m).
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[N:20]O)[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:6]=1>C(O)C.[Zn]>[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([NH2:20])[CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:6]=1
Reactant: ON=C(CCC1CCOCC1)c1cccnc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(CCC1CCOCC1)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
Acetic acid (16 mL) was added to a suspension of 1-(3-pyridyl)-3-(4-oxanyl)propan-1-one oxime (1.60 g, 6.83 mmol) in 95% ethanol (40 mL) over a period of 15 min. Zinc dust (12 g, 180 mmol) was added and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered through a Celite plug, which was then washed with ethanol (50 mL). The combined filtrates were concentrated by rotary evaporation. The solid residue was made basic by addition of 50% aqueous NaOH (with ice bath cooling), saturated with solid NaCl and extracted with chloroform (5×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give pure product as a colorless viscous liquid (1.40 g, 82% yield).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6](C(OCC)=O)[CH2:5][CH:4]1[NH:13][CH3:14]>O>[OH:1][CH2:2][CH:3]1[CH2:7][NH:6][CH2:5][CH:4]1[NH:13][CH3:14]
Reactant: CCOC(=O)N1CC(CO)C(NC)C1
Solvent: O
Product: CNC1CNCC1CO

Procedure:
34 g (0.168 mol) of ethyl 4-hydroxymethyl-3-methylaminopyrrolidine-1-carboxylate are heated under reflux with 100 g of Ba(OH)2.8H2O in 400 ml of water overnight. The BaCO3 is filtered off with suction, the filtrate is concentrated and the residue is boiled up ten times with 100 ml of dioxane each time. The dioxane solutions are filtered, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])=[CH:4][CH:3]=1.Br[CH2:14]Br.Cl>CCOCC.[Zn].[Cu]Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH2:9][CH:10]2[CH2:14][CH2:11]2)=[CH:6][CH:7]=1
Reactant: C=CCC(O)c1ccc(Cl)cc1
Reactant: BrCBr
Agent: Cl[Cu]
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Product: OC(CC1CC1)c1ccc(Cl)cc1
Yield: 44 %

Procedure:
Crude 4-(4-chlorophenyl)but-1-en-4-ol from the previous reaction (85.37 g, approximately 92% pure, approximately 430 mmol), zinc dust (121.5 g, 1.86 mol), copper(I) chloride (18.69 g, 187 mmol) and dibromomethane (163.6 g, 936 mmol) in dry ether (250 ml) were heated under reflux for 3 hours in a sonic bath and then poured into 2M hydrochloric acid. The mixture was extracted with ether and the extract washed with 2M hydrochloric acid and brine, dried and evaporated in vacuo. Chromatography [SiO2, hexane-ethyl acetate (90:10)] gave 1-(4-chlorophenyl)-2-cyclopropylethanol (37.24 g, 44% from 4-chlorobenzaldehyde).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]#[N:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:13]([NH:16][OH:17])=[NH:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: NO
Reactant: N#Cc1sc(N)nc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1sc(N)nc1-c1ccccc1

Procedure:
2-Amino-4-phenyl-thiazole-5-carbonitrile (0.13 g, 0.6 mmol) was suspended in 1:1 water/ethanol (v/v) (24 mL) and added hydroxylamine hydrochloride (1.47 g, 21 mmol) and potassium carbonate (1.86 g, 13 mmol). The reaction mixture was heated at reflux for 3 days, then the solvent was reduced and the aqueous phase was extracted with dichloromethane. The organic layer was washed with water and brine, and was dried over sodium sulfate. The solvent was evaporated to yield a yellow solid. Yield: 0.1 g, 66%.
Reaction SMILES: [N:1]1([C:7](=[O:33])[CH2:8][CH2:9][CH2:10][C@@H:11]2[C@H:16]3[C@H:17]4[C@H:26]([CH2:27][CH2:28][C@:14]3([CH3:15])[C:13](=[O:32])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([C:29]([OH:31])=O)=[CH:23][CH:24]=2)[CH2:19][CH2:18]4)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N.C[N:36]1CCOCC1.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[N:1]1([C:7](=[O:33])[CH2:8][CH2:9][CH2:10][C@@H:11]2[C@H:16]3[C@H:17]4[C@H:26]([CH2:27][CH2:28][C@:14]3([CH3:15])[C:13](=[O:32])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([C:29]([NH2:36])=[O:31])=[CH:23][CH:24]=2)[CH2:19][CH2:18]4)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CN1CCOCC1
Reactant: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1[C@@H](CCCC(=O)N1CCOCC1)CC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Product: C[C@]12CC[C@@H]3c4ccc(C(N)=O)cc4CC[C@H]3[C@@H]1[C@@H](CCCC(=O)N1CCOCC1)CC2=O
Temperature: 25 °C

Procedure:
430 mg 15α-(4-morpholin-4-yl-4-oxobutyl)-17-oxoestra-1(10),2,4-triene-3-carboxylic acid is dissolved in DCM. 3 eq NH3 solution (0.5 M in 1,4 dioxane), 3 eq 4-methyl morpholine, 1.75 eq hydroxybenztriazole and 2 eq EDCl are added slowly in an ice-bath. After stirring at RT for a couple of hours, the reaction mixture is left over night without stirring. The mixture is extracted twice with NaHCO3 (5% in H2O), twice with 1M KHSO4 and with brine. The combined organic layers are dried (Na2SO4) and the solvent removed. Purifying by column chromatography (EtOAc/EtOH, 25:1) gives 135 mg pure 15α-(4-morpholin-4-yl-4-oxobutyl)-17-oxoestra-1(10),2,4-triene-3-carboxamide (EXAMPLE 1)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:12])[CH:10]=[CH2:11])[CH:5]=[CH:4][C:3]=1[OH:13].I[CH2:15][C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:12])[CH:10]=[CH2:11])[CH:5]=[CH:4][C:3]=1[O:13][CH2:15][C:16]([OH:18])=[O:17]
Reactant: C=CC(=O)c1ccc(O)c(Cl)c1Cl
Reactant: O=C(O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Yield: 35.7 %

Procedure:
2,3-Dichloro-4-acryloylphenol (4.85 g, 0.0224 mole), iodoacetic acid (4.5 g, 0.24 mole), potassium carbonate (3.33 g, 0.024 mole) and acetone (200 ml) were united, stirred and refluxed for 20 hours. The reaction mixture was cooled and the solid removed by filtration, dissolved in water (100 ml) and acidified to a pH of 1 with concentrated hydrochloric acid. The material that separated was extracted with chloroform, the organic layer removed, washed with water, dried over MgSO4, filtered and the solvent removed by evaporation in vacuo. The residue was recrystallized from carbon tetrachloride to give 2.2 g of (2,3-dichloro-4-acryloylphenoxy)-acetic acid, m.p. 111°-113° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][C:11]3=[CH:10][CH:9]=[CH:8][CH:7]4[C:6]2=[O:24])[CH2:3][CH2:2]1.[H][H]>>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C:12]34[C:15]5[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:16]=5[O:17][CH:11]3[CH2:10][CH2:9][CH:8]=[C:7]4[C:6]2=[O:24])[CH2:2][CH2:3]1
Reactant: COc1cccc2c1OC1=CC=CC3C(=O)N(CC4CC4)CCC123
Reactant: [H][H]
Product: COc1cccc2c1OC1CCC=C3C(=O)N(CC4CC4)CCC321

Procedure:
Catalytic hydrogenation of 3-cyclopropylmethyl 9-methoxy-2,3-dihydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-4[4H]-one (Example 4c) is carried out as in Example 4d but the reaction is stopped after one mole equivalent of hydrogen has been taken up, giving 3-cyclopropylmethyl-9-methoxy-2,6,7,7a-tetrahydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-4[3H]-one. This, on treatment with m-chloroperbenzoic acid gives 3-cyclopropylmethyl-4a,5-epoxy-9-methoxy-2,4a,5,6,7,7a-hexahydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-4[3H]-one which is reduced with lithium aluminum hydride to 3-cyclopropylmethyl-9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinolin-4a-ol.