Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.C[C:7]([O:9][CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[Bi](Cl)(Cl)Cl>CO>[NH2:18][CH:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][O:9][CH3:7])[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Bi](Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 20 ml of carbon tetrachloride were added 2.72 g of 7-ACA, 2.6 g of methanol, 2.7 g of stannic chloride and 15 g of bismuth trichloride. The mixture was heated at 50° C. for 40 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. The resulting precipitate was filtered off. To the filtrate was added 50 ml of water and, then, 0.3 g of activated carbon, and then the mixture was stirred, followed by filtration. The filtrate was adjusted to pH 3.5 with sodium bicarbonate, and concentrated by evaporation under reduced pressure, thereby to form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.29 g. The yield of the desired product was 53 %.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=CC(S(O[C@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(O[C@@H]2CCOC2)cc1
Temperature: 85 °C
Yield: 35.8 %

Procedure:
A mixture of 4-bromophenol (2.1 g, 12.4 mmole), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (2.5 g, 10.3 mmole) and K2CO3 (4.3 g, 30.9 mmole) in DMF (15 mL) was heated at 85° C. for 15 h. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by ISCO (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (896 mg). MS (ESI) m/z: Found: 244.3 (M++1). Calc. 243.1 (M+).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[CH3:40][N:41]([CH3:82])[C:42](=[O:81])[C@@H:43]([NH:52][C:53](=[O:80])[C@H:54]([N:62]([CH3:79])[C:63](=[O:78])[CH:64]([NH:76][CH3:77])[CH2:65][C:66]1[CH:75]=[CH:74][C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:67]=1)[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25](=[O:27])[N:76]([C@@H:64]([C:63](=[O:78])[N:62]([C@@H:54]([C:53](=[O:80])[NH:52][C@H:43]([C:42](=[O:81])[N:41]([CH3:82])[CH3:40])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[CH3:79])[CH2:65][C:66]1[CH:75]=[CH:74][C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:67]=1)[CH3:77])([CH3:14])([CH3:15])[CH3:16]
Reactant: CNC(Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(C)=O)C(=O)N(C)C
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (279 mg, 1.46 mmol) was added at 0° C. to a solution of (2E)-5-(tert-butyoxycarbonylamino)-5-methylhex-2-enoic acid (355 mg, 1.46 mmol) and 1-hydroxy-7-azabenzotriazole (199 mg, 1.46 mmol). The reaction mixture was stirred for 20 min at 0° C. A solution of the crude hydrochloride salt of (2S)-6-acetylamino-2-{(2R)-2-[N-methyl-N-(2-(methylamino)-3-(2-naphthyl)propionyl)amino]-3-phenylpropionylamino}hexanoic acid N,N-dimethylamide (857 mg, 1.46 mmol) in N,N-dimethylformamide (10 ml) and dichloromethane (20 ml) and ethyidiisopropylamine (0.75 ml, 4.38 mmol) were added subsequently. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed wtih a 10% aqueous solution of sodium hydrogen sulfate (200 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were wshed with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (120 g), using dichloromethane/methanol (10:1) as eluent, to give 719 mg of {(3E)4-[N-((1R)-1-{N-[(1R)-1-((1S)-5-acetylamino-1-(dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethyl]-N-methylcarbamoyl}2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[O:8][C@H:7]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O.[NH2:23][CH2:24][CH2:25][CH2:26][NH2:27]>>[NH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:7]1[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:8]1
Reactant: CCCCC[C@H]1O[C@H]1C/C=C\CCCCCCCC(=O)OC
Reactant: NCCCN
Product: CCCCCC1OC1CC=CCCCCCCCC(=O)NCCCN

Procedure:
Derivative 17 was prepared from methyl vernolate and 1,3-diaminopropane according to the procedure described in Example 1(f) and shown in Scheme 14.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[Cl:18][C:19]1[C:24]([Cl:25])=[C:23]([Cl:26])[CH:22]=[CH:21][C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[C:24]([Cl:25])=[C:23]([Cl:26])[CH:22]=[CH:21][C:20]=1[S:27]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][C:6]3[C:15](=[CH:16][CH:17]=[C:4]([O:3][CH3:2])[CH:5]=3)[C:10]=2[N:11]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3Cl)nc1-2

Procedure:
The title compound was prepared from 7-methoxy-4,5-dihydronaphtho(1,2-D)(1,3)thiazol-2-amine hydrobromide (85 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 ng) as described in the synthetic METHOD B to give a white solid (13.1 mg) with purity >90%: MS (pos) m/z 475.3, 477.3
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][CH2:5]Cl.[CH:7]([N+:14]([O-:16])=[O:15])([N+:11]([O-:13])=[O:12])[N+:8]([O-:10])=[O:9].[K]>>[Br:1][CH2:2][CH2:3][O:4][CH2:5][C:7]([N+:14]([O-:16])=[O:15])([N+:11]([O-:13])=[O:12])[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Reactant: ClCOCCBr
Agent: [K]
Product: O=[N+]([O-])C(COCCBr)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
2,2,2-trinitroethyl 2-nitroxyethyl ether (TNEN) is prepared by the reaction of potassium nitroform with chloromethyl 2 2-bromoethyl ether to form 2,2,2-trinitroethyl 2-bromoethyl ether which is then reacted with silver nitrate to form the desired product TNEN as shown in the following reaction scheme: ##STR1## Example 1 shows a method of preparing the starting material chloromethyl 2-bromoethyl ether. Example 2 illustrates suitable conditions for reacting potassium nitroform with chloromethyl 2-bromoethyl ether to produce the intermediate product 2,2,2-trinitroethyl 2-bromoethyl ether. Finally, example 3 illustrates suitable conditions for reacting the 2,2,2-trinitroethyl 2-bromoethyl ether with silver nitrate to produce the final product 2,2,2-trinitroethyl 2-nitroxyethyl ether.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:10]([CH3:16])[C:11]=2[N+:13]([O-])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:10]([CH3:16])[C:11]=2[NH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)c2c(c([N+](=O)[O-])c1C)N(C(C)=O)CC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)c(N)c2c(c1C)CCN2C(C)=O
Temperature: 55 °C
Reaction time: 2 h

Procedure:
In a 100-ml autoclave, 1-acetyl-7-nitro-5-ethoxycarbonylmethyl-4,6-dimethylindoline (5.0 g) obtained in Example 5 and 7.5% palladium on charcoal (wet, 3.76 g) were suspended in ethanol (50 ml). After degassing with nitrogen for 3 times (5 kg/cm2 for each) and replacing nitrogen with hydrogen for 3 times (5 kg/cm2 for each) successively, the resulting mixture was stirred for 2 hours at 55° C. under a pressurized hydrogen atmosphere (5 kg/cm2). The reaction mixture was filtered to remove palladium on charcoal, which was washed with ethanol (50 ml). The filtrate and washing were combined and concentrated under reduced pressure to give a fraction of the title compound. Furthermore, palladium on charcoal separated above was suspended in dichloromethane (50 ml), and after stirring at room temperature, the catalyst was removed by filtration and washed with dichloromethane (25 ml). The filtrate and washing were combined and concentrated under reduced pressure to give another fraction of the title compound. The title compound (4.1 g, yield: 90%) was obtained by combining two fractions of the title compound obtained above.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[C:17]([CH3:19])=[CH:18][C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:3][C:4]=2[O:20][CH3:21])=[CH:11][CH:12]=1
Reactant: COc1cc(Br)cc(C)c1C(=O)NCc1ccc(F)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of 4-bromo-N-[(4-fluorophenyl)-methyl]-2-methoxy-6-methyl-benzamide (2.7 g, 7.67 mmol) in N-methyl-2-pyrrolidone (10 ml) is added morpholine (0.93 g, 10.7 mmol) at RT. The reaction mixture is degassed and flushed with argon for 30 min followed by addition of sodium tert-butoxide (0.95 g, 9.9 mmol). The reaction mixture is heated to 40° C. At this temperature are added tris(dibenzylideneacetone)dipalladium(0) (0.31 g, 0.34 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.47 g, 0.76 mmol) and stirred at 100° C. for 12 h. After completion of the reaction (monitored by TLC), the mixture is diluted with water (50 ml) and extracted with ethyl acetate (3×75 ml). The organic layer is washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 40% acetone/hexane) to yield N-[(4-fluorophenyl)-methyl]-2-methoxy-6-methyl-4-morpholin-4-yl-benzamide (2.50 g, 6.90 mmol, 91%).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:5]1=2)(=[O:3])[CH3:2].[ClH:45]>O1CCOCC1.CCOCC>[ClH:45].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 88 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (56.3 mg, 94.2 μmol) in 4 M HCl in dioxane (471 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (44.4 mg, 88%) as a white solid. MS m/z 498 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][NH:23][CH2:24][CH2:25][OH:26].C1N=CN([C:38](N2C=NC=C2)=[O:39])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C@H:7]([CH2:22][N:23]2[CH2:24][CH2:25][O:26][C:38]2=[O:39])[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]1=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CNCCO)c(OC)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2CCOC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a solution of benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-(((2-hydroxyethyl)amino)methyl)-4-oxoazetidin-3-yl)carbamate (4.47 g, 10.08 mmol) in chloroform (50 ml) was added CDI (4.90 g, 30.2 mmol). After stirring at rt for 30 min it was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-5%), affording the title compound (3.84 g, 81%) as a white foam. LCMS: Rt=0.76 min, m/z=470.1 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:27]([O-:41])([O:29][CH2:30][C@H:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35]O)=[O:28].CCN=C=NCCCN(C)C.C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:30][O:29][N+:27]([O-:41])=[O:28])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC/C(=C(\C(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Yield: 63.6 %

Procedure:
A solution of 3 g of (2Z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid, 1.7 g of (2R)-6-hydroxyhexane-1,2-diyl dinitrate, 10 mmol of DMAP and 10 mmol of EDCI was stirred in 40 mL of dichloromethane at rt for 2 h. Then, acetic anhydride (0.5 mL) was added and the mixture was filtered through a pad of silica gel and washed with EtOAc, evaporated, purified by flash chromatography (15-50% EtOAc/hexane) to afford 2.8 g of the desired compound as a white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.79 (d, 2H), 7.45 (d, 2H), 7.21-7.16 (m, 1H), 7.13-7.08 (m, 2H), 5.52-5.44 (m, 1H), 5.21 (s, 1H), 4.98 (dd, 1H), 4.72 (dd, 1H), 4.29 (t, 2H), 3.09 (s, 3H), 1.92 (s, 3H), 1.89-1.74 (m, 4H), 1.60-1.48 (m 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl.Cl[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: ClCc1cscn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2cscn2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 77 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (3.62 g) is alkylated using 4-chloromethyl-thiazole hydrochloride (2.62 g; 15.4 mmol) and K2CO3 (4.41 g; 31.2 mmol) at 50° C. for 3 days. After aqueous work-up and purification by chromatography (SiO2; cyclohexan/EtOAc gradient) the pure material (3.80 g) is de-acetylated in MeOH (100 ml) using DBU (1.6 ml) at 70° C. in 1.5 h. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-thiazol-4-ylmethyl-1,3-dihydro-indol-2-one (3,37 g) is obtained and used without further purification.
Reaction SMILES: [CH3:1][C:2]([NH:14]C(=O)C)([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].Cl.[OH-].[Na+]>O>[CH3:3][C:2]([NH2:14])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[N:5]=1)[CH3:1]
Reactant: CC(=O)NC(C)(C)c1cccc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)c1cccc(C(F)(F)F)n1
Temperature: 90 °C
Yield: 85.6 %

Procedure:
Add N-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethyl]-acetamide (20 g; 81.2 mmol) to a mixture of water (30 mL) and concentrated hydrochloric acid (30 mL; 365 mmol). Heat the mixture to 90° C. for 16 hours. Cool the mixture to 15° C. and add 100 mL 5 N sodium hydroxide to pH 13. Extract the mixture three times with t-butylmethyl ether (100 mL). Combine the t-butylmethyl ether layers and extract with 1 N HCl (100 mL), then twice with 0.5 N HCl (100 mL). Combine the acidic aqueous layers and stir with t-butylmethyl ether (50 mL). Clarify the mixture by filtration and separate the layers. Add brine (100 mL) and 5 N NaOH (70 mL) to pH 13. Extract the aqueous layer 3 times with t-butylmethyl ether (100 mL). Combine the t-butylmethyl ether layers and wash with a mixture of brine (95 mL) and 5 N NaOH (5 mL). Separate the layers and add sodium sulfate to the t-butylmethyl ether layer. Filter and concentrate the filtrate under reduced pressure to afford the title compound as a brown oil (14.2 g, 69.54 mmol; 86%) 1H NMR 500.174 MHz (CDCl3) δ 7.79 (t, J=7.96 Hz, 1H), 7.64 (d, J=7.69 Hz, 1H), 7.49 (d, J=7.69 Hz, 1H), 2.0 (s, 2H), 1.50 (s, 6H). HRMS (ESI) m/z (M+H)1 calcd for C9H12F3N2: 205.0947, found 205.0946.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[CH:27][C:21]=3[CH2:20][S:19](=[O:34])(=[O:33])[C:18]=2[CH:35]=1)=[O:13]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30][NH:1][CH2:2][CH2:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:33])(=[O:34])[C:18]=2[CH:35]=1)=[O:13]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: NCCc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCCc3ccccn3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 7 h

Procedure:
2-(2-Aminoethyl)pyridine (8.13 mmol) and tetrabutylammonium iodide (0.010 g, 0.027 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.7 g, 1.62 mmol) in dry methanol (10 mL). The reaction mixture was stirred at 110° C. for 7 h in an atmosphere of nitrogen. It was concentrated and treated with a methanolic HCl solution (10 mL), refluxed overnight, concentrated, treated water and 10% aqueous sodium bicarbonate solution to pH 7. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.225 g, (26.81%). 1H NMR (DMSO-d6): δ 2.70 (s, 3H, CH3), 3.0-3.10 (m, 6H, 3CH2), 3.40-3.55 (m, 2H, CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.45 (t, 1H, NH), 6.80 (s, 1H, Ar), 6.83 (s, 1H, Ar), 7.30-7.50 (m, 3H, Ar), 7.80 (t, 1H, Ar), 8.20 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS (CI+): m/e 516 (M+1).
Reaction SMILES: F[B-](F)(F)F.[C:6]1(=[O:23])[N:10]([CH2:11][CH2:12][CH2:13][N+:14](C)([CH3:16])[CH3:15])[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:7]12.CN(C=CC)C.C(N(CC)CC)C.C1(=O)OC(=O)C2=CC=CC=C12>C1(C)C(C)=CC=CC=1>[CH3:15][N:14]([CH2:13][CH2:12][CH2:11][N:10]1[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:7]2[C:6]1=[O:23])[CH3:16]
Reactant: C[N+](C)(C)CCCN1C(=O)c2ccccc2C1=O
Agent: CC=CN(C)C
Agent: F[B-](F)(F)F
Agent: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CN(C)CCCN1C(=O)c2ccccc2C1=O

Procedure:
There was prepared (3-phthalimidopropyl)trimethylammonium tetrafluoroborate by dissolving 145 grams, 1.42 moles, of dimethylaminopropylene, and 3.92 grams, 0.039 moles of triethylamine in one liter of xylene, in a two litered three necked round bottom flask equipped with a stirrer, a thermometer, a heating mantle, a Dean-Stark trap, and a reflux condenser. Subsequently 191.3 grams, 1.29 moles of phthalic anhydride was added, and the mixture was refluxed at a temperature of 140 degrees centigrade. Subsequent to refluxing for 24 hours, 24 milliliters of water was collected in the Dean-Stark trap. The xylene and excess amines were then removed from the reaction mixture on a rotary evaporator yielding the crude product N-(dimethylaminopropyl)phthalimide, in a yield of 300 grams. The crude imide separated was a brown syrup which crystallized on standing. This imide product, subsequent to purification by vacuum distillation, was identified by elemental analysis and infrared spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.OC1C2N=NNC=2C=CC=1.CNC(N=C=NCC)CCNC.C(NC(C)C)(C)C>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NC(CCNC)NC
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.98 g of para-nitrobenzoic acid in 50 mL of dichloromethane are successively added under argon, at 0° C., 0.781 mL of pyrrolidine, 0.13 g of hydroxybenzotriazole, 2.3 g of 1,3-dimethylaminopropyl-3-ethyl carbodiimide and 3.43 mL of diisopropylamine. The reaction mixture is then stirred at room temperature for 15 hours and then washed with water. The organic phase is then washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 1.9 g of (4-nitrophenyl)pyrrolidin-1-yl-methanone, the characteristics of which are as follows: