Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C@@H:12]([OH:27])[CH2:11][CH2:10]1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1.[Cl-].[Na+].[CH3:41]N1CCCC1=O>>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:28][N:29]([CH3:41])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: CNCCc1ccc(C)cc1
Reactant: CN1CCCC1=O
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(CCN(C)CCCCC[C@@H]2Cc3cc(O)ccc3[C@@H]3[C@@H]2[C@@H]2CC[C@H](O)[C@@]2(C)C[C@@H]3F)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
660 mg of 7α-(5-bromopentyl)-11β-fluorooestra-1,3,5(10)-triene-3,17β-diol are dissolved in 10 ml of N-methylpyrrolidone, treated with 1.2 g of methyl-(2-p-tolylethyl)amine and stirred at a bath temperature of 80° C. for 3 hours. For work-up, the mixture is added to saturated sodium chloride solution, extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness in vacuo. Column-chromatographic purification on silica gel using an ethyl acetate-methanol-ammonia gradient and subsequent crystallization from ethyl acetate/methylene chloride/hexane yields 277 mg of 11β-fluoro-7α-{5-[methyl-(2-p-tolylethyl)amino]pentyl}oestra-1,3,5(10)-triene-3,17β-diol of melting point 142-143° C.
Reaction SMILES: FC1C=C(C2C3COCCC=3N([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([NH:20][CH3:21])=[O:19])=[O:15])N=2)C=CC=1F.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([F:46])=[C:35]([C:37]2[C:38]3[CH2:45][CH2:44][O:43][CH2:42][C:39]=3[NH:40][N:41]=2)[CH:36]=1.N[C@@H](C(C)(C)C)[C:49](NCCO)=[O:50]>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([F:46])=[C:35]([C:37]2[C:38]3[CH2:45][CH2:44][O:43][CH2:42][C:39]=3[N:40]([C:14]([NH:16][C@@H:17]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:18]([NH:20][CH2:21][CH2:49][OH:50])=[O:19])=[O:15])[N:41]=2)[CH:36]=1
Reactant: CC(C)(C)[C@H](N)C(=O)NCCO
Reactant: Fc1ccc(Cl)cc1-c1n[nH]c2c1CCOC2
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2cc(Cl)ccc2F)c2c1COCC2)C(=O)NCCO

Procedure:
Compound 96 was prepared according to the procedure for the synthesis of compound 28 by replacing intermediate 16 with intermediate 16C, and replacing tert-leucine methylamide with intermediate 23. LCMS (+ESI) m/z=453.3 [M+H]+. 1H NMR (CDCl3) δ 7.82 (d, J=9.3 Hz, 1H), 7.61-7.63 (m, 1H), 7.32-7.36 (m, 1H) 7.09 (t, J=9.2 Hz, 1H), 4.99 (d, J=8.0 Hz, 2H), 4.19 (d, J=9.3 Hz, 1H), 3.78-3.88 (m, 2H), 3.69 (s, 2H), 3.43 (m, 2H), 2.63 (br, 2H), 1.06 (s, 9H). Purity: 91%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10](O)=[O:11])[S:9][C:5]=2[CH:4]=1.CN([C:20]([O:24][N:25]1N=NC2C=CC=N[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][O:24][N:25]([CH3:26])[C:10]([C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:14]=[CH:13][C:6]=2[CH:7]=1)=[O:11]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2ccc(C(F)(F)F)cc2s1
Reaction time: 0.03 h

Procedure:
To 6-(Trifluoromethyl)-1-benzothiophene-2-carboxylic acid dissolved in DMF (0.5 M) was added HATU (1.2 equiv) at 0° C. and the reaction was stirred for 2 min followed by addition of N,O-dimethylhydroxylamine hydrochloride (1.5 equiv). The reaction was stirred for 2 min prior to the addition of iPr2NEt (5 equiv). The reaction was stirred for an additional 20 min at 0° C. The reaction was quenched with equivalent amounts of half-saturated aqueous NaHCO3 and H2O. The title compound was obtained as a solid and filtered on a Büchner funnel before being and air-dried.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C[S-].[Na+]>CN(C=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncccc2NS(=O)(=O)c2ccc(OC)cc2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cccnc1Nc1ccc(O)cc1)c1ccc(O)cc1
Temperature: 100 °C

Procedure:
The compound produced in Example 4 was dissolved in DMF and five equivalents of sodium methanethiolate was added to the solution. The resulting solution was heated at 100° C. and treated to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:36])[N:4]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[N:27]=3)[CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8]CC1C=CC(OC)=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3](=[O:36])[N:4]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:35])([CH3:33])[CH3:34])[N:27]=3)[CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(COc2cc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ncc3C)c(=O)c2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)cc(O)c(Cl)c1=O
Temperature: 25 °C
Yield: 87.9 %

Procedure:
To a solution of 3-chloro-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-4-((4-methoxybenzyl)oxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (2.53 g, 5.00 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (1.0 mL). The solution was stirred for several hours at room temperature. The solution was concentrated, diluted with water and extracted several times with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated to provide 1.7 g of the title compound: MS (M+H) 388.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.CC([O-])(C)C.[Na+].[Br:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.C(Cl)(Cl)Cl>O1CCCC1>[Br:26][C:27]1[CH:28]=[N:29][C:30]([O:1][CH2:2][C:3]2[N:4]=[C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)=[N:31][CH:32]=1
Reactant: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Reactant: Clc1ncc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3ncc(Br)cn3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
4-Hydroxymethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole (0.538 g, 2.0 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (10 ml) followed by the addition of NaOtBu (0.231 g, 2.4 mmol). After stirring for 15 min at r.t., 5-bromo-2-chloro-pyrimidine (0.426 g, 2.2 mmol) in THF (5 ml) is added slowly over a period of 10 min and stirred for further 30 min at r.t. Chloroform (25 ml) is added; the mixture is washed with 0.5N hydrochloric acid (HCl) and water, dried over MgSO4 and concentrated in vacuo. After flash column chromatography (100% chloroform) 5-bromo-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl-methoxy}-pyrimidine can be isolated as an off-white solid. Yield 0.60 g (71%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4]C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.C[O-].[Na+].Cl>CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:2](=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl oxalate (18.80 g, 0.159 mol) and 4′-fluoroacetophenone (20.0 g, 0.145 mol) were charged to a 1000 mL round-bottom flask and diluted with methanol (400 mL). The reaction flask was placed in a sonication bath (Bransonic 1200), and sodium methoxide (25% in methanol, 70 mL) was added over 25 minutes. The reaction was sonicated at 45° C. for 16 hours. The reaction became an insoluble mass during this time. The solid was mechanically broken up, then poured into a hydrochloric acid solution (1N, 500 mL). A magnetic stirrer was added, and the white suspension was stirred vigorously at room temperature for 60 minutes. The suspension was cooled to 0° C. and held for 30 minutes. The solid was filtered, and the filter cake was then washed with cold water (100 mL). Upon drying, methyl 4-[4-fluorophenyl]-2,4-diketobutanoate was obtained (22.91 g, 70.6%) as the enol: 1H NMR (CDCl3/300 MHz) 8.03 (ddd, J=8.86 Hz, J=8.66 Hz, J=5.03 Hz, 2H), 7.19 (dd, J=8.86 Hz, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H). 19F NMR (CDCl3/282.2 MHz) −103.9 (m).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11].[N+:18]([CH:21]([N+:23]([O-:25])=[O:24])[CH3:22])([O-:20])=[O:19]>CCOCC>[N+:18]([C:21]([N+:23]([O-:25])=[O:24])([CH3:22])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])([O-:20])=[O:19]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=C(C(=O)OC)C(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C(CC(C)([N+](=O)[O-])[N+](=O)[O-])C(=O)OC
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Triethylamine was added dropwise to a solution of 1.4 g (0.010 mol) of dimethyl methylenemalonate and 1.6 g (0.0133 mol) of 1,1-dinitroethane in 15 ml of ether at 0°, until yellow coloration persisted in the solution. The solution was allowed to stand 1 hr at ambient temperature and was then washed with 10% sodium bicarbonate, 1 N hydrochloric acid and water. The solution was dried over sodium sulfate, and the solvent was removed under vacuum. Column chromatography on a 100 g column of silica gel (CCl4 --CH2Cl2) and recrystallization of the product (methylene chloride-hexane, -78°) gave 1.9 g (72%) of dimethyl 2,2-dinitropropylmalonate, a white crystalline solid, mp 44°: NMR (CDCl3) 3.75 (s, 6 H, CH3), 3.1-3.5 (m, 3 H, CHCH2) and 2.13 (s, 3 H, C--CH3); IR (neat) 1730 (C=O) and 1570 cm-1 (NO2).
Reaction SMILES: [Na].[CH:2]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][C:4](=[N:11]O)[CH2:3]2>C1(C)C=CC=CC=1.CC(O)C>[CH:2]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH:4]([NH2:11])[CH2:3]2
Reactant: ON=C1CC2CCCC(C1)C2
Agent: [Na]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: NC1CC2CCCC(C1)C2
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, to a refluxing suspension of sodium (2.401 g, 104 mmol) in toluene (20 mL) at a temperature of about 115° C. was added dropwise over 30 min bicyclo[3.3.1]nonan-3-one oxime (QS, 1.60 g, 10 44 mmol) in 2-propanol (8 mL). The mixture was stirred at reflux for 2 hr. After addition of the oxime solution is completed, 2-propanol (3 mL) was added dropwise. The reaction mixture was heated to reflux until all of the Na was consumed followed by cooling to a temperature of about 25° C. The reaction mixture was then quenched by the addition of H2O (20 mL). The organic layer was separated, and washed twice with 1N HCl (30 mL each). The acidic solution was made alkaline by the addition of 2N NaOH (50 mL), and extracted thrice with Et2O (50 mL each). The organic layers were combined and washed with saturated NaCl (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give of bicyclo[3.3.1]non-3-ylamine QA. This compound was used in the next step without purification in 2-propanol solution.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:14])=O>ClC(Cl)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1ccc(F)cc1
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a solution of 4-fluorobenzoic acid (5.0 g. 35.7 mmol) in dichloroethane (50 mL) was added oxalyl chloride (5.6 g, 44.6 mmol) drop wise. The reaction was stirred for 16 h. The excess oxalyl chloride and solvent were removed under reduced pressure. The residue was chased with benzene to give the desired product (5.4 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:30][C@H:31]1[C@@H:34]([CH2:35][N:36]2[C:40]([CH3:41])=[N:39][CH:38]=[N:37]2)[NH:33][C:32]1=[O:42].CCN=C=NCCCN(C)C.N1C=CC=CC=1>CN(C=O)C>[C:25]([O:24][C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16](/[C:12](=[N:11]/[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:29])/[C:13]([NH:30][C@@H:31]2[C:32](=[O:42])[NH:33][C@@H:34]2[CH2:35][N:36]2[C:40]([CH3:41])=[N:39][CH:38]=[N:37]2)=[O:15])[N:17]=1)=[O:23])([CH3:26])([CH3:28])[CH3:27]
Reactant: Cc1ncnn1C[C@H]1NC(=O)[C@H]1N
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ncnn1C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (310 mg, 0.72 mmol), (3S,4R)-3-amino-4-((5-methyl-1H-1,2,4-triazol-1-yl)methyl)azetidin-2-one (130 mg, 0.72 mmol) and EDCI (150 mg, 0.79 mmol) in DMF (5 mL) at 0° C. was added pyridine (64 μL, 0.79 mmol). After stirring at rt for 24 h it was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 10%), affording the title compound (190 mg, 45%) as a white solid. LCMS: m/z=593.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:13]2[C@H:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][O:15][C:14]2=[O:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.CO[CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([C:11](=[O:12])[N:13]2[C@H:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:16][O:15][C:14]2=[O:25])[CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCNC(=O)OCc1ccccc1
Reactant: O=C(CCc1ccc(F)c(F)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a solution of (4R)-3-[3-(3,4-difluorophenyl)propanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (1 g, 2.90 mmol) in dichloromethane (29.0 ml) at −60° C. was added TiCl4 (0.335 ml, 3.04 mmol) dropwise. After 30 min, DIPEA (0.556 ml, 3.19 mmol) was added and the solution stirred at 1 h at 0° C. phenylmethyl [(methyloxy)methyl]carbamate (1.131 g, 5.79 mmol)[prepared according to Barnett, C. J. et al, Tetrahedron Lett. 1997, 38, 5, 735.] was added and the reaction mixture stirred at 0° C. for 4 h. The solution was quenched with aqueous saturated ammonium chloride solution and extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (0-50% EtOAc in hexanes) affording phenylmethyl {(2S)-2-[(3,4-difluorophenyl)methyl]-3-oxo-3-[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]propyl}carbamate (548 mg, 0.506 mmol, 17.49% yield) as a clear oil:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[OH:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[C:4]=1[C:23](=[O:24])[CH:22]=[CH:21][C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: O=C(Cl)C=Cc1ccc([N+](=O)[O-])cc1
Product: COc1cc(O)c(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)c(OC)c1OC
Temperature: 80 °C
Yield: 22 %

Procedure:
A mixture of 3,4,5-trimethoxyphenol (1.85 g, 10 mmol) and 4-nitrocinnamoyl chloride (2.11 g, 10 mmol) was dissolved in BF3-Et2O complex (10 ml) and heated to 80° C. for 10 min, and then quenched with excess of water. The aqueous layer was extracted with dichloromethane. The combined organic layer was concentrated and the residue was purified by column chromatography on silica gel (CH2Cl2:EtOAc:Hexane=1:1:3) gave 7a (0.79 g, 22%) and 7b (1.54 g, 43%). 1H NMR (400 MHz, CDCl3) μ 3.81 (s, 3H), 3.90 (s, 3H), 3.91 (s, 3H), 6.29 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.76 (d, J=16.0 Hz, 1H), 8.01 (d, J=16.0 Hz, 1H), 8.26 (d, J=8.8 Hz, 2H), 13.44 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH3:30])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18]C(=O)CC3C=CC=CC=3)[C@H:5]2[S:4]1=[O:29].CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>C(Cl)Cl>[ClH:13].[Br:1][CH2:2][C:3]1([CH3:30])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH2:18])[C@H:5]2[S:4]1=[O:29]
Reactant: CC1(CBr)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC1(CBr)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1=O
Product: Cl
Temperature: -15 °C
Reaction time: 2 h
Yield: 146.3 %

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate- 1-oxide (1.12 g) was dissolved in dried methylene chloride (10 ml). To this solution were added dimethyl aniline (0.36 g) under cooling at -15° C. and then phosphorus pentachloride (0.6 g), and the mixture was stirred for 3 hours. To the solution was added anhydrous methanol (0.7 g) under cooling at -40° C. and the solution was stirred for 2 hours and further stirred for 1 hour at -15° C. After the reaction, precipitated crystals were collected by filtration, washed with a small amount of methylene chloride and then dried to give 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate-1-oxide hydrochloride (0.70 g), mp 147° to 154° C. (dec.).
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH2:17]([NH:19][C:20]([N:14]1[C:15](=[O:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:21])[CH3:18]
Reactant: CCN=C=O
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CCNC(=O)N1C(=O)C2(CCCCC2)NC12CCCCC2
Reaction time: 6 h

Procedure:
5.5 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 1.76 parts of ethyl isocyanate and a trace of 1,4-diaza bicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residue was stirred in 100 of water for 6 hours. 6.4 Parts of a solid were separated by filtration and crystallised twice from ethanol to yield 14-ethylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one as colourless crystals of melting point 185° to 188°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[CH2:14][Cl:15].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)=O>O>[CH2:16]([NH:23][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[CH2:14][Cl:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[CH2:14][NH:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: ClCCCN1c2ccccc2CC1CCl
Solvent: O
Solvent: CC(C)=O
Product: ClCC1Cc2ccccc2N1CCCNCc1ccccc1
Product: ClCCCN1c2ccccc2CC1CNCc1ccccc1
Reaction time: 10 h

Procedure:
A mixture of 2.44 g of 1-(3-chloropropyl)-2-chloromethyl-indoline, 3.2 g of benzylamine, 30 ml of acetone and 20 ml of water is boiled for 10 hours. 1-(3-Benzylaminopropyl)-2-chloromethyl-indoline and 1-(3-chloro-propyl)-2-benzylaminomethyl-indoline are formed intermediately and are not isolated. After the customary working up, 2-benzyl-2,3,4,5,11,11a-hexahydro-1H-1,4-diazepino-[1,2-a]indole is obtained.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH3:20][S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(C(=O)O)CC1
Yield: 73 %

Procedure:
1-Methanesulfonyl-piperidine-4-carboxylic acid benzyl ester (0.8 g, 26.7 mmol) from step 4, was dissolved in ethyl acetate (100 ml) and methanol (10 ml), Pd/C 10% (80 mg) was added and the resulting mixture was hydrogenated at 1 bar. The catalyst was filtered over celite, the solvent was removed under reduced pressure to give a white solid. Yield 73%, 0.4 g
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:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl>[C:21]1([CH2:20][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[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:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 97 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (2.0 g, 7.77 mM), benzyl bromide (0.94 ml, 7.93 mM), and potassium carbonate (2.15 g, 15.5 mM) in 39 mL DMF was stirred at room temperature for 22 hours. The mixture was diluted with ethyl acetate and 1N HCl. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined ethyl acetate layers were extracted with 1N HCl twice, once with water and once with brine. After drying (NaSO4), evaporation in vacuo afforded 2.61 g (97%) of 9-[(phenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ 7.6-7.4 (m, 6H), 7.0 (m, 2H), 5.4 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.65-2.45 (m, 3H), 2.3 (dd, J=15 and 9 Hz, 1H), 1.1 (d, J=7 Hz, 3H). MS (ES) m/e 316, 348.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][NH:22][C:8](=[O:9])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])[CH2:20][CH2:19]1
Reactant: NCC1CC1
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Product: CC(C(=O)NCC1CC1)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 380° C. and MS: m/e=279 (M+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and cyclopropylmethylamine.