Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:6]=[CH:7]C=1.[CH:17]1([C:20]2[CH:25]=[CH:24][N+:23]([O-:26])=[CH:22][C:21]=2I)[CH2:19][CH2:18]1.C[NH:29][C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:17]1([C:20]2[CH:25]=[CH:24][N+:23]([O-:26])=[CH:22][C:21]=2[N:11]2[CH2:12][CH2:13][N:9]([C:5]3[CH:6]=[CH:7][N:29]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[C:10]2=[O:14])[CH2:19][CH2:18]1
Reactant: O=C1NCCN1c1cccc(C(F)(F)F)c1
Reactant: [O-][n+]1ccc(C2CC2)c(I)c1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1N(c2ccnc(C(F)(F)F)c2)CCN1c1c[n+]([O-])ccc1C1CC1
Yield: 713.7 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(3-trifluoromethyl-phenyl)-imidazolidin-2-one (I-36b: 60 mg, 0.259 mmol) was reacted with 4-cyclopropyl-3-iodopyridine 1-oxide (I-50a: 81 mg, 0.31 mmol), copper iodide (5 mg, 0.025 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (4 mg, 0.025 mmol), potassium phosphate (165 mg, 0.77 mmol) and 1,4-dioxane (5 mL) to afford crude product. Purification by column chromatography on silica gel (1.5% methanol in chloroform) afforded 65 mg of pure product (71.4% yield).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[O-2:4].[Mn+2:5]>O>[C:1]([O-:4])(=[O:3])[CH3:2].[Mn+2:5].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: [O-2]
Agent: [Mn+2]
Solvent: O
Product: CC(=O)[O-]
Reaction time: 0.08 h

Procedure:
A mixed solution of 1 mole of manganese acetate, ethanol, and water was prepared. This mixed solution and Ketjen Black (KB) were introduced into a rotary reactor, the inner tube was rotated at a centrifugal force of 66,000 N (kgms−2) for 5 minutes to form a thin film of the reactant on the inner wall of the outer tube, and sheer stress and centrifugal force were applied to the reactant to allow promotion of chemical reaction, yielding KB supporting highly dispersed manganese oxide precursor.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[C:26]1([C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:32]([NH:34][C:35]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[S:36])(=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 89%).
Reaction SMILES: C(OC(C)(C)C)(=[O:4])NN.[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](Cl)=[O:23])=[CH:19][CH:20]=2)[C:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:14]1)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:4])=[O:23])=[CH:19][CH:20]=2)[C:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: c1ccncc1
Product: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution containing tert-butyl carbazate (0.79 g, 0.006 mol) in pyridine (30 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (1.7 g, 0.005 mol). The reaction mixture was allowed to stir at ambient temperature for 18 hours. Solvent was removed and water was added to the mixture. The reaction was extracted with ethyl acetate. Some 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid was isolated. The reaction mixture was treated with an equivalent of tert-butyl carbazate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in dichloromethane and allowed to stir overnight. The reaction was extracted with ethyl acetate. The product was taken up in a solution of 0.3% ammonia in methanol (˜50 mL) and allowed to stir overnight. The reaction mixture was extracted with dichloromethane, dried with magnesium sulfate, and concentrated. The material was purified by silica gel chromatography using 2% methanol in dichloromethane. The product was taken up in ethanol and gaseous hydrochloric acid was bubbled into solution. A solid precipitated out and was collected by filtration. This material was dried to provide the title compound (0.91 g, 56% yield). ES-MS (m/z) 271 [M+1]+.
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][C:11](=O)[C:10]2[C:15]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)[O:17][C:9]1=2)C1C=CC=CC=1.P(Cl)(Cl)([Cl:41])=O>>[Cl:41][C:11]1[CH:12]=[CH:13][N:8]=[C:9]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[C:15]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:10]=12
Reactant: O=c1ccn(Cc2ccccc2)c2oc(-c3ccc(OCCN4CCOCC4)cc3)c(-c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2oc(-c3ccc(OCCN4CCOCC4)cc3)c(-c3ccccc3)c12
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A resealable tube was charged with 7-benzyl-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-phenyl-7H-furo[2,3-b]pyridin-4-one (4c) (0.100 g, 0.197 mmol) and phosphorous oxychloride (2.0 mL). The system was flushed with argon and the tube was sealed. The mixture stirred at 110° C. for 1.5 h. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane and ice water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange brown oil. This oil was purified via preparative thin layer chromatography (eluting with 90:10:1, dichloromethane/methanol/ammonium hydroxide) to afford 4-chloro-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridine 6c as an off white solid. MS (MH+) 435.0; Calculated 434 for C25H23ClN2O3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]#[CH:36].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:35]#[C:36][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Reactant: C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1ccc(C(F)(F)F)cc1Cl
Yield: 20.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.044 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.012 g of desired product. 1H NMR (300 MHz, DMSO do): δ 3.89 (s, 3H), 7.52 (t, J=9.0 Hz, 1H), 7.56-7.75 (m, 6H), 7.83 (d, J=8.1 Hz, 1H), 8.02 (s, 1H), 12.78 (s, 1H); MS (m/z): 522.00 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.C(OO)(=O)C.[CH:17](=[O:21])[CH2:18][CH2:19]C.OO>C1(C)C=CC=CC=1.C(O)(=O)C.Cl[Cu]>[CH2:17]([O:21][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:18][CH3:19]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCC=O
Agent: Cl[Cu]
Agent: CC(=O)OO
Agent: OO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 g 2,2,6,6-tetramethyl-piperidin-4-ol (intermediate product of Ciba Specialty Chemicals Inc.) are suspended in 7 ml of toluene. 2.3 g of a 40% solution of peracetic acid in acetic acid are added at 0° C. and the reaction mixture is stirred at room temperature for 3 h. 4.2 ml butanal and 2.4 ml of a 30% aqueous hydrogen peroxide solution are added, followed by 50 mg CuCl after 15 min. The reaction mixture is stirred for 1.5 h at room temperature to give a greenish emulsion. The two phases are separated and the organic one is washed with 10% ascorbic acid solution, water, diluted sodium carbonate sol., diluted sodium chloride sol., and saturated sodium chloride sol. The organic phase is dried over sodium sulfate and finally evaporated to complete dryness under vacuum to afford 1.3 g product.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[CH:7]3[CH2:14][CH2:15][CH2:16][C:5]=1[C:6]=23)(=[O:3])[CH3:2].[H-].[Na+].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C>[C:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3([CH2:23][CH2:22][CH2:21][CH2:20][Br:19])[CH2:14][CH2:15][CH2:16][C:5]=1[C:6]=23)(=[O:3])[CH3:2]
Reactant: BrCCCCBr
Reactant: CC(=O)c1ccc2c3c1CCCC3C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c3c1CCCC3(CCCCBr)C(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A 170 ml portion of DMF solution of 6-acetyl-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (3.2 g, 14.9 mmol) was cooled to −5° C. Thereto was added 0.7 g of sodium hydride (16.4 mmol), and the resulting solution was stirred at 0° C. for 30 minutes and then cooled to −40° C. Thereto was added 8.9 ml of 1,4-dibromobutane (74.5 mmol), and the mixture was stirred overnight while gradually increasing the temperature in an atmosphere of argon. The reaction solution was extracted with ethyl acetate and washed with water. After drying (Na2SO4), the oily substance obtained by the evaporation of the solvent under a reduced pressure was purified by a silica gel column chromatography (700 cc; elution with ethyl acetate-hexane=2:3) and then recrystallized from ethyl acetate-hexane to obtain 2.26 g of the title compound (43% in yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:15]=3)[C:10]([S:22]([CH3:24])=[O:23])=[CH:9]2)=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1B(O)O>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:15]=3)[C:10]([S:22]([CH3:24])=[O:23])=[CH:9]2)=[N:6][CH:7]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(Br)cn3)c2c1
Product: COc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N(C)C)cc43)nc2)c1

Procedure:
Suzuki reaction of 1-(5-bromopyrimidin-2-yl)-N,N-dimethyl-3-(methylsulfinyl)-1H-indole-6-carboxamide (0.15 g, 0.37 mmol; intermediate in the preparation of synthesis example 267) with 2-fluoro-5-methoxyphenylboronic acid (0.13 g, 0.74 mmol) in analogy to the procedure detailed for example 261). White solid. Yield: 0.06 g (36% of theory)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH2:7][C:8]([OH:15])([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11].N1([CH:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:25][C:26](=[O:28])[O-:27])C=CC=N1>CC#N>[C:32]([O:31][C:30](=[O:36])[N:29]=[C:24]([NH:25][C:26]([O:27][C:3]([CH3:4])([CH3:18])[CH3:2])=[O:28])[NH:1][CH2:2][C:3]1[CH:18]=[CH:17][CH:16]=[C:5]([CH2:6][CH2:7][C:8]([OH:15])([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])[CH:4]=1)([CH3:33])([CH3:34])[CH3:35]
Reactant: CCCC(O)(CCC)CCc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)NC(NC(=O)[O-])n1cccn1
Solvent: CC#N
Product: CCCC(O)(CCC)CCc1cccc(CNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1

Procedure:
Reaction of 4-(3-(aminomethyl)phenethyl)heptan-4-ol with tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate in CH3CN gives tert-butyl(tert-butoxycarbonylamino)(3-(3-hydroxy-3-propylhexyl)benzylamino)methylenecarbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[O:18][CH3:17])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:16]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: COc1ccccc1C(=O)Cl
Product: CCn1c2ccccc2c2cc(NC(=O)c3ccccc3OC)ccc21

Procedure:
3-Amino-9-ethylcarbazole (5.6 g; 0.027 mol) was reacted with 2-methoxybenzoyl chloride (4.35 ml; 0.029 mol) by working in a manner similar to that described in Example 4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
To a chilled (ice-bath) solution of 4-fluorophenylamine (2.9 mL, 30 mmol) and anhydrous pyridine (3.7 mL, 45 mmol) in methylene chloride (50 mL) was slowly added a solution of acetyl chloride (2.4 mL, 33 mmol) in methylene chloride (10 mL). After 15 minutes, the mixture was concentrated in vacuo and the residue was diluted with cold water. The resulting precipitate was filtered, washed with water and dried to afford 4.2 g of N-(4-fluorophenyl)acetamide as an off white solid. MS m/z 154 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][N:22]1[C:26]([NH:27][C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31]3)=[CH:25][CH:24]=[N:23]1.Cl.CCN=C=NCCCN(C)C.Cl.C1C=CC2N([OH:65])N=NC=2C=1>O.CN(C=O)C.C(N(CC)CC)C>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:9]=[C:10]([C:13]([N:36]4[CH2:35][CH2:34][C:33]5([CH2:32][C:31](=[O:65])[C:30]6[C:40](=[CH:41][CH:42]=[C:28]([NH:27][C:26]7[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=7)[CH:29]=6)[O:39]5)[CH2:38][CH2:37]4)=[O:15])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: Cn1nccc1Nc1ccc2c(c1)CCC1(CCNCC1)O2
Reactant: O=C(O)c1cc(-c2nnn[nH]2)c2ccn(C3CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(-c4nnn[nH]4)c4ccn(C5CC5)c4c3)CC1)O2
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Triethylamine and water (1.5 mL) were added to a DMF (6 mL) solution of 1-cyclopropyl-4-(tetrazol-5-yl)-1H-indole-6-carboxylic acid (348 mg), 6-[(1-methyl-1H-pyrazol-5-yl)amino]spiro[chroman-2,4′-piperidin)]one hydrochloride, WSC hydrochloride and HOBT, and stirred at 90° C. for 30 minutes. Water was added to it at room temperature to obtain a white precipitate. This was dried under reduced pressure, washed with a mixed solvent of methanol and diethyl ether, and again dried under reduced pressure to obtain the title compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 7.92 (1H, s), 7.83 (2H, d, J=3.2 Hz), 7.64 (1H, d, J=3.2 Hz), 7.32 (1H, d, J=1.7 Hz), 7.17-7.12 (3H, m), 7.00 (1H, d, J=9.0 Hz), 5.90 (1H, d, J=1.7 Hz), 4.45-4.05 (1H, br m), 3.60 (3H, s), 3.60-3.53 (1H, m), 3.47-3.21 (3H, br m), 2.83 (2H, s), 2.14-1.70 (4H, br m), 1.14-0.98 (4H, m). MS [M+H]+=564.
Reaction SMILES: [CH2:1]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][C@H:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[N+:45]([O-])=O)[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][CH:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[N+:23]([O-])=O.O.O.Cl[Sn]Cl.C(Cl)(Cl)Cl.CO>CO>[CH2:3]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[NH2:23])[CH2:2][CH2:1][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][CH:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[NH2:45]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3[N+](=O)[O-])cc2OC)C1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=C1CC(CO)N(C(=O)c2cc(N)c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3N)cc2OC)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
A mixture of the diol 76 (0.98 g, 1.49 mmol) and SnCl2.2H2O (3.36 g, 14.9 mmol) in MeOH (35 mL) was heated at reflux and the progress of the reaction monitored by TLC (90% CHCl3/MeOH). After 45 minutes, the MeOH was evaporated in vacuo and the resulting residue was cooled (ice), and treated carefully with saturated NaHCO3 (120 mL). The mixture was diluted with EtOAc (120 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give a brown solid. Flash chromatography (95% CHCl3/MeOH) afforded the pure bis-amine 77 as an orange solid (0.54 g, 61%): [α]19D=−31.8° (c=0.30, CHCl3); 1H NMR (270 MHz, CDCl3) δ 6.74 (s, 2Harom), 6.32 (s, 2Harom), 5.00 (br s, 2H, NCH2C═CH2), 4.93 (br s, 2H, NCH2C═CH2), 4.54 (br s, 2H, NCHCH2OH), 4.24-4.14 (m, 4H, OCH3CHCH2O), 3.98-3.50 (m, 14H, NCHCH2OH, NCH2C═CH3 and OCH3), 2.76 (dd, 2H, J=8.61, 15.91 Hz, NCH2C═CH2CH2), 2.46-2.41 (m, 2H, NCH2C═CH2CH2), 2.33-2.28 (m, 2H, OCH2CH2CH2O); 13C NMR (67.8 MHz, CDCl3) δ 171.0 (NC═O), 151.0 (Cquat), 143.5 (Cquat), 141.3 (Cquat), 140.6 (Cquat), 112.4 (C—Harom), 111.9 (Cquat), 107.8 (NCH2C═CH2), 102.4 (C—Harom), 65.2 (OCH2CH2CH2O), 65.0 (NCHCH2OH), 59.8 (NCHCH2OH), 57.1 (OCH3), 53.3 (NCH2C═CH2), 34.4 (NCH2C═CH2CH2), 29.0 (OCH2CH2CH2O); MS (FAB) (Relative Intensity) 596 (M+., 13), 484 (M-NCH2CCH2CH2CHCH2OH, 14), 389 (10), 371 (29), 345 (5), 224 (8), 206 (44), 166 (100), 149 (24), 112 (39), 96 (34), 81 (28); IR (NUJOL®) 3600-3000 (br. OH), 3349 (NH2), 2922, 2852, 2363, 1615, 1591 (NH2), 1514, 1464, 1401, 1359, 1263, 1216, 1187, 1169, 1114, 1043, 891, 832, 761 cm−1.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[N+:8]([O-:11])(O)=[O:9].[CH:12]1[CH2:17]CC=[CH:14][CH:13]=1>>[N+:8]([CH:13]1[CH2:14][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:17]=[CH:12]1)([O-:11])=[O:9]
Reactant: C1=CCCC=C1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Product: CC(=O)OC1C=CC([N+](=O)[O-])CC1

Procedure:
To 166 ml. of acetic anhydride were dropped 27.7 g. 20% nitric acid at 25° C. under ice cooling over a 45 minute period. This was followed by the hour long addition of 19.5 g. of 1,3-cyclo hexadiene at 25° C. (ice cooling from time to time). After an additional hour stirring the reaction was poured onto ice and worked up as above. Purification over silicagel yielded acetic acid (4-nitro-cyclohex-2-en-1-yl)ester as a cis/trans mixture.
Reaction SMILES: I.N[C@@H:3]1C(=O)N2[C@@H]1SCC(/C=C/CN1CCC(O)CC1)=C2C(O)=O.[CH:25]1[C:34]2[C:29](=CC=C[CH:33]=2)[CH:28]=[CH:27][C:26]=1[S:35][CH2:36][C:37]([OH:39])=[O:38].S1C2C=CC=CC=2N=C1SCC(O)=O>>[CH3:3][C:28]1[CH:27]=[C:26]([S:35][CH2:36][C:37]([OH:39])=[O:38])[CH:25]=[C:34]([CH3:33])[CH:29]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C/CN3CCC(O)CC3)CS[C@H]12
Reactant: O=C(O)CSc1ccc2ccccc2c1
Agent: I
Agent: O=C(O)CSc1nc2ccccc2s1
Product: Cc1cc(C)cc(SCC(=O)O)c1

Procedure:
By operating in an analogous manner to the procedure described in Example 1, (E)-(6R,7R)-7-amino-3-[3-(4-hydroxy-piperidin-1-yl)-propenyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydroiodide was acylated with naphthalen-2-ylsulfanyl-acetic acid, with benzothiazol-2-ylsulfanyl-acetic acid, and with (3,5-dimethyl-phenylsulfanyl)-acetic acid, respectively, to give the following compounds as pale-yellow solids:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.C(N(CC)CC)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1CCN(c2ccc(Br)cc2)CC1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
A 500 mL round-bottomed flask was charged with 1-(4-bromophenyl)piperazine (10.00 g, 41.5 mmol, Combi-Blocks, San Diego, Calif.) and 100 mL of CH2Cl2. To this was slowly added triethylamine (6.94 mL, 49.8 mmol) and benzenesulfonyl chloride (6.15 mL, 47.7 mmol). After 15 min at room temperature, the mixture was diluted with water (100 mL) and layers were separated. The organics were dried (MgSO4) and concentrated. The resulting solid was slurried with diethyl ether (200 mL) to give 1-(4-bromophenyl)-4-(phenylsulfonyl)piperazine (15.00 g) as a white solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH:8]([OH:10])=O.[CH2:11]1[N:22]2[C:23]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH:18]([CH2:28][NH2:29])[NH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=32)[CH2:12]1.CO>C(Cl)(Cl)Cl>[CH:8]([N:19]1[CH:18]([CH2:28][NH:29][CH:5]=[O:7])[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:12][CH2:11][N:22]([C:23]=23)[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]1=2)=[O:10]
Reactant: NCC1Nc2ccccc2N2CCc3cccc1c32
Reactant: O=CO
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=CNCC1c2cccc3c2N(CC3)c2ccccc2N1C=O
Reaction time: 0.33 h

Procedure:
Acetic anhydride (8.0 ml) and formic acid (9.12 ml) were mixed together and stirred at -10° C. (methanol/ice) for 1 hour. This solution now containing formic-acetic acid mixed anhydride was added to a solution of 1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-methanamine (10.0 g) in chloroform (250 ml) at 0° C. in one portion. The mixture was handshaken for 20 minutes. The final solution was treated with excess methanol and concentrated to an oil. Purification was conducted by flash chromatography on silica gel (170 g, eluted with 2 liters of dichloromethane and 2 liters of 2% methanol/dichloromethane). Fractions containing the pure product were pooled and concentrated to a solid, (11.17 g). Recrystallization from hot ethanol (370 ml) gave 9.51 g of crystals, m.p. 201°-202° C.