Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[CH3:10][C:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(C)[C:12]#N>C1COCC1>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)([CH3:12])[CH3:10])=[CH:4][CH:5]=1
Reactant: CC(C)(C#N)N1CCOCC1
Reactant: Brc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
Magnesium turnings (190 mg, 7.4 mmol) was added to dry THF (15 mL) under argon. 1,4-dibromobenzene (2.43 g, 10.3 mmol) was added and the solution was heated to reflux for 30 min. 2-Methyl-2-morpholinopropanenitrile (1 g, 6.6 mmol) was dissolved into THF (30 mL) and added dropwise to the solution at reflux. The mixture was stirred for 2 h and cooled to rt. The reaction was quenched with sat. K2CO3 solution and extracted with CH2Cl2 (200 mL), dried over MgSO4 and concentrated to an orange oil. The crude mixture was purified on a Biotage silica column (2-15% MeOH in CH2Cl2) to give the title compound as a yellow oil (204 mg, 10%). MS ESI 284.0, 286.0 [M+H]+, calcd for [C13H18BrNO+H]+ 284.1, 286.1.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]3[CH2:17][C@H:16]([S:18][C:19]4[C@H:20]([CH3:43])[C@@H:21]5[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:22]5[C:23]=4[C:24]([O:26]CC4C=CC([N+]([O-])=O)=CC=4)=[O:25])[CH2:15][N:14]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:12])[CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.[ClH:57]>O1CCCC1.O>[ClH:57].[N:1]1([C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]3[CH2:17][C@H:16]([S:18][C:19]4[C@H:20]([CH3:43])[C@@H:21]5[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:22]5[C:23]=4[C:24]([OH:26])=[O:25])[CH2:15][NH:14]3)=[O:12])[CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](n5cncn5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC[C@H](n5cncn5)C4)C3)[C@H](C)[C@H]12

Procedure:
528 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-3-(1,2,4-triazol-1-yl)pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 10 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.63 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 85 m of the title compound, as a powder.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH2:8][CH2:7][NH:6][C:5]1=[O:21].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.ClCCCN1CCCCC1>CC(N(C)C)=O.C1(C)C=CC=CC=1>[CH3:3][CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH2:8][CH2:7][N:6]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:5]1=[O:21]
Reactant: ClCCCN1CCCCC1
Reactant: CC1C(=O)NCCN1c1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC1C(=O)N(CCCN2CCCCC2)CCN1c1cccc(OC(F)(F)F)c1
Temperature: 75 °C
Yield: 84 %

Procedure:
NaH (55% dispersion in mineral oil, 36 mg, 0.82 mmol) was added portionwise at RT to a solution of 3-methyl-4-(3-trifluoromethoxy-phenyl)-piperazin-2-one (150 mg, 0.55 mmol) in DMA (3 mL), then after 1 h a solution of 1-(3-chloropropyl)-piperidine in toluene [prepared from commercially available 1-(3-chloropropyl)-piperidine hydrochloride (542 mg, 2.74 mmol) by partitioning between toluene (4 ml) and 1 M aq. sodium hydroxide solution (4 ml) and drying of the organic layer with MgSO4] was added. The reaction mixture was heated at 75° C. for 1 h, then partitioned between sat. aq. NaHCO3 solution and CH2Cl2. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc) afforded the title compound (184 mg, 84%). Light yellow oil, MS: 400.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 78.2 %

Procedure:
To a round bottom flask was added azepan-4-ol (300 mg, 2.60 mmol), 1-fluoro-4-nitrobenzene (368 mg, 2.60 mmol), Cs2CO3 (1018 mg, 3.13 mmol) and DMF (5 mL). The reaction was stirred at 100° C. for 10 hrs. The reaction was diluted with EtOAc (50 ml), washed with water (4×20 ml) and saturated aqueous NaCl (25 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/He) to give the product, 1-(4-nitrophenyl)azepan-4-ol (480 mg, 2.032 mmol, 78% yield) as a light yellow solid. Anal. Calcd. for C12H16N2O3 m/z 236.2, found: 237.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.18-8.03 (m, 2H), 6.71-6.57 (m, 2H), 4.00 (br. s., 1H), 3.74-3.60 (m, 1H), 3.60-3.41 (m, 3H), 2.22-2.01 (m, 2H), 1.95-1.72 (m, 4H); 13C NMR (101 MHz, CDCl3) δ ppm 153.41, 136.89, 126.38, 110.02, 69.88, 49.24, 44.00, 35.87, 34.96, 21.59.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:29])=[C:7]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)=[O:4].[CH:30](=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]([CH2:30][CH3:31])[C:7]2[CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH3:29])[CH2:21][CH2:20]1)=[O:23])([CH3:26])([CH3:28])[CH3:27]
Reactant: CC=O
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 23 °C
Reaction time: 24 h
Yield: 39.9 %

Procedure:
To a stirred solution of tert-butyl 4-{[3-(methoxycarbonyl)-2-methyl-5-(trifluoromethyl)phenyl]amino}piperidine-1-carboxylate (10.6 g, 25.4 mmol) in CH2Cl2 (200 mL) and AcOH (10 mL) was added acetaldehyde (2.80 g, 63.5 mmol) and sodium triacetoxyborohydride (13.4 g, 63.5 mmol). The reaction mixture was stirred at 23° C. for 24 hours. Then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 Heptane/EtOAc=5/1) to give the titled compound as oil (4.50 g, 40% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.82 (br. s., 1H), 7.45 (d, J=1.6 Hz, 1H), 3.96-4.18 (m, 2H), 3.92 (s, 3H), 3.08 (q, J=7.0 Hz, 2H), 2.89 (tt, J=11.0, 3.7 Hz, 1H), 2.69 (m, 2H), 2.55 (s, 3H), 1.73 (m, 2H), 1.49-1.56 (m, 2H), 1.45 (s, 9H), 0.86 (t, J=7.0 Hz, 3H); MS (ES) [M+Na] 467.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12](=[O:14])[CH3:13])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)cc(OC)c1OCCN1CCOCC1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
In a vial, 500 mg (2.5 mmol) of 3′,5′-dimethoxy-4′-hydroxyacetophenone was combined with 4-(2-chloroethyl)morpholine hydrochloride (600 mg, 3.2 mmol), and powdered potassium carbonate (1.5 g, excess). Dimethylformamide (2 mL) was added, the vial was sealed, and the rxn was heated to 80° C. overnight. The reaction was diluted with water and extracted with diethyl ether. The organic extract was washed with brine, dried (Na2SO4), and evaporated in vacuo to afford 540 mg (67%) of 14 as a white solid.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][CH:9]1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1.C(O)(=O)C.[H][H]>[Pd].O1CCCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][NH:8]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCC1CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCN1
Yield: 92.4 %

Procedure:
A suspension of 18.8 g (68.0 mmol) of 1-benzyl-2-[(t-butoxycarbonylamino)methyl]azetidine, 8.2 g (137 mmol) of acetic acid, 1.0 g of 20% palladium on carbon and 200 ml of tetrahydrofuran was shaken in a hydrogen atmosphere at pressures of 48.3-51.7 psi and temperatures of 21.5°-27° for 16 hours. The catalyst was removed by filtration and the solvent was removed. in vacuo to give 11.7 g (92%) of the title compound as a colorless viscous oil which was used without further purification.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([N:27]([CH3:39])[C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)[CH3:18])=[O:15])[CH3:2].I([O-])(=O)(=O)=[O:41].[Na+].I([O-])(=O)(=O)=O>CC(C)=O.O>[CH2:1]([S:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([N:27]([CH3:39])[C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)[CH3:18])=[O:15])=[O:41])[CH3:2]
Reactant: CCSCCCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)CCCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a stirred solution of 20-(11-(ethylthio)-undecanoyloxy)-4-methyl-5α-4-azapregnan-3-one (0.056 g, 0.1 mM) in acetone (5 mL) at room temperature was added a solution of sodium periodate (0.033 mg, 0.154 mM) in water (3 drops). After prolonged stirring with additional portions of the periodate added (0.046 g total) over 3 days, the solvents were removed in vacuo, and the residue extracted with methylene chloride. The methylene chloride was removed in vacuo, and the resulting residue was flash chromatographed on silica gel (30% acetone/methylene chloride eluant) to give the title compound as a glaze. MS M+ calculated for C34H59NO4 S, mw=577.90; observed m/e 577.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[N:16]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CC#N>[Si:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:21][CH2:20]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCCCCCN1CCN(C(=O)OCc2ccccc2)CC1
Yield: 69.8 %

Procedure:
Intermediate 19 (2.6 g, 8.8 mmol) was added to a stirring solution of benzyl piperazine-1-carboxylate (1.1 mL, 5.87 mmol) in CH3CN (80 mL). The reaction mixture was refluxed over night, cooled, and quenched with satd. NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated to give the crude (3.8 g) as opaque oil. The chromatography (1:3, hexanes/EtOAc) afforded the title compound (1.78 g, 70%) as clear oil. ES/MS calcd. for C24H43N2O3Si+ 435.3. Found m/z=435.2 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[CH2:4][CH2:3]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]1([CH2:43][NH:44][CH2:45][CH2:46][CH2:47][N:48]1[CH2:49][CH2:50][O:51][CH2:52][CH2:53]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((3-morpholinopropylamino)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (69 mg, 0.095 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 3 h then was concentrated under reduced pressure. The residue was purified by prep. HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to afford the title compound (36 mg, 0.054 mmol, 56.5% yield) as a white foam. LCMS: m/e 671.5 (M+H)+, 2.17 min (method 6). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=8.03 Hz, 2H),7.15 (d, J=8.03 Hz, 2H), 5.29 (d, J=4.52 Hz, 1H), 4.71 (br. s., 1H), 4.62 (br. s., 1H), 3.73 (br. s., 4H), 3.09-3.26 (m, 3H), 2.65 (d, J=12.30 Hz, 1H), 2.56 (br. s., 6H), 2.42 (br. s., 1H), 1.69 (s, 3H), 1.07 (s, 3H), 1.05-2.14 (m, 24H), 1.00 (s, 3H), 0.97 (s, 3H), 0.93 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NCC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:26]#[C:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CN1Cc2c(C#Cc3ccccc3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 20 hours with 1.12 g (11 mmol) of phenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 20 ml of diethylamine. The reaction mixture was diluted with methylene chloride and washed twice with water. The organic phase was dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 7-chloro-4,5-dihydro-5-methyl-3-(phenylethynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 205°-206°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH2:11][C:12]1[CH:13]=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Reactant: Oc1ccc(Cl)c(Cl)c1
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(COc2ccc(Cl)c(Cl)c2)cc([N+](=O)[O-])c1

Procedure:
0.5 mmole 3,4-Dichloro-phenol and 1 mmole KI were added to a solution of 0.5 mmole 1-Chloromethyl-3,5-dinitrobenzene in 2.5 ml 1-Butanol. The mixture was stirred under reflux overnight. After evaporation the 1-Butanol, the residue was washed with 2×10 ml 1 N HCl and 2×10 ml EtOAc, and dried. 1H NMR (DMSO-d6, 400 MHz) 5.44 (s, 2H); 7.14 (d, 1H); 7.43 (s, 1H); 7.58 (d, 1H); 8.73 (s, 2H); 8.81 (s, 1H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:20][C:19]([CH3:21])=[C:18]3[C:14]=2[CH2:15][C@H:16]2[C:22]([CH3:24])([CH3:23])[C@H:17]23)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:20][C:19]([CH3:21])=[C:18]3[C:14]=2[CH2:15][C@H:16]2[C:22]([CH3:24])([CH3:23])[C@H:17]23)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: ClCC1CO1
Reactant: Cc1sc(C(=O)CCc2ccc(O)c(Cl)c2)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1sc(C(=O)CCc2ccc(OCC3CO3)c(Cl)c2)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.3 %

Procedure:
A solution of 3-(3-chloro-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (139 mg, 0.385 mmol, Intermediate 6) in isopropanol (4 mL) and 3 N aq. NaOH (1.7 mL) is treated with epichlorohydrine (110 mg, 1.16 mmol). The reaction mixture is stirred at rt for 18 h. The mixture is diluted with acetic acid (0.3 mL) and the solvent is removed under reduced pressure. The residue is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm ID, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 3-(3-chloro-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (39 mg) as a pale yellow oil; LC-MS: tR=1.15 min, [M+1]+=417.21.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[Se:10][C:9]=1[C:17]([O:19]CC)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[Se:10][C:9]=1[C:17]([NH2:2])=[O:19])[CH3:5]
Reactant: [NH4+]
Reactant: CCOC(=O)c1[se]c2ncccc2c1N=NN(C)C
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1c(C(N)=O)[se]c2ncccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (15 mL) was added a solution of ethyl 3-[(dimethylamino)diazenyl]selenopheno[2,3-b]pyridine-2-carboxylate (150 mg) in THF (5 mL) for 5 min and stirred at rt for 16 h. The solution was poured into ice cooled water and extracted with ethyl acetate (3×100 mL). The combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a light green color solid, which was recrystallized from chloroform-methanol-hexane (25 mg, 20%), mp 230-232° C. IR (Neat) νmax 3327, 3152, 2913, 1701, 1634, 1360, 1330, 1104, 1058, 1016, 878, 802 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 8.80 (1H, d, J=8.4 Hz, H-4), 8.59 (1H, d, J=3.2 Hz, H-6), 8.18 (1H, s, —CONH2), 7.99 (1H, s, —CONH2), 7.46 (1H, dd, J=8.2, 4.6 Hz, H-5), 3.66 (3H, s, —NCH3), 3.26 (3H, s, —NCH3); 13C NMR (100 MHz, DMSO-d6): δ 164.4, 161.1, 148.3, 142.5, 136.2, 131.5, 130.4, 120.6, 43.6, 36.5; LC-MS (positive ion mode): m/z 318, 320 (M+Na)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([NH:13][CH:14]([CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C@@H:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1)[OH:16])=[O:12].[C:33]([OH:42])(=[O:41])[CH:34]([CH:36]([C:38]([OH:40])=[O:39])[OH:37])[OH:35]>C(O)(C)C.CO>[C:38]([CH:36]([CH:34]([C:33]([OH:42])=[O:41])[OH:35])[OH:37])([OH:40])=[O:39].[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([NH:13][C@H:14]([CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C@@H:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1)[OH:16])=[O:12]
Reactant: O=C(CC1Cc2ccccc2C1)NC(CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CO
Solvent: CC(C)O
Product: O=C(CC1Cc2ccccc2C1)N[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide (compound 3h) (0.15 g, 0.34 mmol) in isopropanol (10 ml) was added a solution of (+)-tartaric acid (0.05 g, 0.34 mmol) in MeOH (5 mL). The resulting mixture was stirred 30 minutes, then concentrated in vacuo. EtOAc was added followed by diethyl ether (excess). The resulting solid was stirred 30 minutes, then allowed to set overnight. The solid was filtered, washed with diethyl ether, and dried overnight under high vacuum to yield 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide tartrate, 0.16 g, 79% desired white solid. ESI-MS m/z 437.2 (M+H+). mp=174-175° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]1)=[O:20])=[N:5]2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 67 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 67%). 1H NMR (300 MHz, CDCl3) δ 3.30 (m, 4H), 3.76 (m, 4H), 4.15 (s, 3H), 6.80-6.82 (m, 1H), 6.87-6.91 (m, 2H), 7.19-7.22 (m, 1H), 7.29 (br s, 1H), 7.49-7.51 (m, 1H), 7.60 (br s, 1H).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([NH2:29])[CH3:28]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:24][N:29]=[C:27]([CH3:28])[N:26]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: CC(N)=NO
Product: CCc1ccc(C2CC(c3nc(C)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 24 mg (0.22 mmol, 1.1 eq.) of N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 58 mg (79% of theory)