Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:21])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Reaction time: 8 h

Procedure:
4-(2-Bromo-tetrafluoroethoxy)benzoic acid prepared as in Example 1 (26.6 g, 0.083 mol) is transferred to a 250 mL round-bottomed flask along with 150 mL of methylene chloride. Oxalyl chloride (11.64 g, 0.92 mol) is added and the mixture is stirred under nitrogen overnight to form a turbid solution which is concentrated by rotary evaporation and distilled at 80°-90° C./0.1 mmHg to yield 20.88 g of 4-(2-bromotetrafluoroethoxy)benzoyl chloride as a colorless liquid, leaving 6.16 g of unreacted acid (76.8% conversion, 96.5% yield). The benzoyl chloride is added slowly with stirring to 8 mL of cold ammonium hydroxide (0.12 mol). The product amide precipitates as fine white needles which are filtered and dried under vacuum to yield 14.74 g of 4-(2-bromotetrafluoroethoxy)benzamide (75% conversion, 99% yield, m.p. 150.5°-151.5° C.), along with 4.8 g of 4-(2-bromo-tetrafluoroethoxy)benzoic acid which is recovered from the mother liquor (24.3% recovery).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CN1CCN(C(=O)c2cccc(-c3cccc4cc(C(=O)N[C@H]5CN6CCC5CC6)oc34)c2)CC1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 23.5 mg (0.23 mmol) of N-methylpiperazine are reacted together by general method E. 29.6 mg (41.9% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)(=O)C1C=CC=CC=1>CC(C)=O>[CH2:1]([N:4]([CH:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[S:34]([C:31]1[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH:2]=[CH2:3]
Reactant: C=CCNC(C)c1ccccc1
Reactant: O=C(Oc1ccc(S(=O)(=O)Cl)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C(C)c1ccccc1)S(=O)(=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 1.61 g (0.01 mol) of N-allyl-N-α-methylbenzylamine and 1.38 g of potassium carbonate in 15 ml of acetone was dropped a solution of 2.62 g (0.084 mol) of 4-benzoyloxybenzenesulfonyl chloride in 5 ml of acetone under ice-cooling conditions. The mixture was subjected to the reaction at room temperature for 30 minutes and then at 50° C. for 1 hour. After completion of the reaction, the inorganic salt was removed by filtration and the acetone was distilled off, then, the contents were admixed with 150 ml of a 20% potassium hydroxide solution in ethanol, followed by refluxing for 30 minutes. After completion of the reaction, the reaction mixture was poured into ice-water to permit crystals to precipitate. The crystals were washed with a dilute acidic solution and a dilute alkaline solution, followed by sufficiently washing with water, drying in vacuum and recrystallizing from a mixed solvent of benzene and n-hexane to obtain 2.00 g of N-allyl-N-α-methylbenzyl-4-hydroxybenzenesulfonamide (melting point 128° to 129° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:19])=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:20](Br)[CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:19])=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:20]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCC(Br)c1nc2sc(Br)c(Br)c2c(=O)n1Cc1ccccc1
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2sc(Br)c(Br)c2c(=O)n1Cc1ccccc1

Procedure:
A solution of 3-benzyl-5,6-dibromo-2-(1-bromopropyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-5, 35 mg, 0.066 mmol, 1 equiv) and N,N-dimethylethylenediamine (17 mg, 0.198 mmol, 3 equiv) in ethanol (5 mL) was heated at reflux for 18 h. The reaction was concentrated, and the residue was partitioned between EtOAc and brine. The organic layer was dried (MgSO4) and concentrated to provide 3-benzyl-5,6-dibromo-2-{(1-([2-(dimethylamino)ethyl]amino}propyl)thieno-[2,3-d]pyrimidin-4(3H)-one (2-7) as a yellow gum. MS(M+1)=526.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=1.[CH2:28](Br)[CH:29]=[CH2:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]([CH2:30][CH:29]=[CH2:28])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=1
Reactant: C=CCBr
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A suspension of 3.69 g (8.1 mmol) 3-benzyloxycarbonylamino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester, 1.37 ml (16.2 mmol) allyl bromide, 2.24 g (16.2 mmol) potassium carbonate in 8 ml DMF is stirred at 50° C. for 4 h. The mixture is diluted with water and extracted with EtOAc. The organic phase is washed with water and dried over sodium sulfate. The product is purified by chromatography on silica gel (EtOAc/hexanes 1:4, 1:2, 1:1, 2:1). The title compound is isolated as a yellow resin.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[CH3:10].Cl.[O-:12][C:13]#[N:14].[K+]>O>[CH3:10][C:5]1[N:4]([CH2:3][CH2:2][NH:1][C:13]([NH2:14])=[O:12])[C:8]([CH3:9])=[CH:7][CH:6]=1
Reactant: N#C[O-]
Reactant: Cc1ccc(C)n1CCN
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc(C)n1CCNC(N)=O

Procedure:
6.9 g (0.05 mol) of 1-(2-aminoethyl)2,5-dimethylpyrrole are dissolved in 8 ml of water. While cooling, 5 ml of concentrated hydrochloric acid are slowly added dropwise, and then 4.9 g (0.05 mol) of potassium cyanate, dissolved in 30 ml of water, are added dropwise. The precipitated solid is filtered off with suction and recrystallized from toluene/ethyl acetate. Yield: 3.8 g (42% of theory), Melting point: 139°-141° C. Elemental analysis: C9H15N3O (181.24) calculated: C 59.6 H 8.3 N 23.2 0 8.8 found: C 59.2 H 8.2 N 22.8 0 9.1
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[NH:10][C:11]2[CH2:12][O:13][CH2:14][C:15]([F:41])([F:40])[C@:16]([C:19]3[CH:24]=[C:23]([N:25]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=[CH:21][C:20]=3[F:39])([CH3:18])[N:17]=2)=CC=1>ClCCl.O1CCOCC1.Cl>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([F:39])=[C:19]([C@:16]2([CH3:18])[C:15]([F:40])([F:41])[CH2:14][O:13][CH2:12][C:11]([NH2:10])=[N:17]2)[CH:24]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reaction time: 1 h

Procedure:
To a solution of crude (R)-N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-(diphenylmethyleneamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (1.2 mmol) in dichloromethane (20 ml) was added at 22° C. trifuoroacetic acid (2.6 ml) and stirring was continued for 1 h. The mixture was diluted with 1,4-dioxane (40 ml) and aqueous hydrochloric acid (1 M, 33 ml) and vigorous stirring of the emulsion at 22° C. was continued for 16 h. The mixture was evaporated and the residue partitioned between saturated aqueous NaCl and ethyl acetate, the aqueous layer was separated, the pH was adjusted to 14 using saturated aqueous Na2CO3 solution and extracted with ethyl acetate. The organic layer was dried, evaporated and the residue purified by chromatography on silica-NH2 using dichloromethane to give (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine as a colorless oil. MS (ISP): m/z=274.3 [M+H]+.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].OS(O)(=O)=O.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[O:17]>[N+]([O-])(O)=O>[CH3:15][C:16]([C:18]1[CH:19]=[C:20]([Cl:24])[CH:21]=[CH:22][C:23]=1[N+:6]([O-:9])=[O:7])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 55.8 %

Procedure:
65% HNO3 (80 ml) was stirred at −5° C.±1° C. and 98% H2SO4 (10 mix 10) was added dropwise. To the stirring solution of HNO3/H2SO4 was added 3-chloroacetophenone (54) (12.0 g, 77.6 mmol). The mixture was stirred at −5□±1□ for 3 h and poured into crushed ice, and extracted with CH2Cl2. The extract was dried over MgSO4 and evaporated. The crude product was purified by column chromatography (silica gel, n-hexane/EtOAc=15:1) to give 55 as yellow solid (9.3 g, 46.6 mmol). Yield: 55.8%; mp 47-49° C.; 1H-NMR (CDCl3, 200 MHz): δ 2.48 (s, 3H), 7.32 (d, J=2.4 Hz, 1H), 7.49 (dd, J=8.8, 2.2 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 198.27, 143.78, 141.05, 139.44, 130.55, 127.36, 125.91, 30.06; Anal. Calcd for C8H6ClNO3: C, 48.14; H, 3.03; N, 7.02.
Reaction SMILES: CO[C:3](=[O:21])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[NH2:5].[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:14]([O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:29](=[S:30])[N:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]1=[O:21])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: S=C=Nc1ccccc1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Product: O=C(NCCCCC1NC(=S)N(c2ccccc2)C1=O)OCc1ccccc1

Procedure:
Using an analogous procedure to Example 1 Nε-benzyloxycarbonyl-L-lysine methyl ester may be reacted with phenyl isothiocynate to give the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:24])[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1.FC(F)(F)C(O)=O.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)Cl>[CH3:12][C:13]1([CH3:24])[C:22](=[O:9])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C=Cc2cc(F)ccc2O1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Oc2ccc(F)cc2CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40.6 g (0.2 mol) of m-chloroperbenzoic acid are added, while stirring at from 15° to 20°, to a solution of 17.8 g (0.1 mol) of 2,2-dimethyl-6-fluoro-2H-chromene in 300 ml of trichloromethane. 17.1 g (0.15 mol) of trifluoroacetic acid are added rapidly to the resulting suspension at room temperature. The reaction mixture is then stirred at room temperature for 2 hours and then an aqueous solution of sodium sulfite/sodium hydrogen carbonate (1:1) is added thereto. The organic phase is separated off, washed in succession with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The resulting residue is subjected to bulb tube distillation under a high vacuum at 160°. The distillate is dissolved in diethyl ether and the solution is washed in succession with sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and again concentrated by evaporation in vacuo. The resulting oily residue is chromatographed on 500 g of silica gel (0.040- 0.063 mm) with toluene as eluant, yielding 7.76 g (40% of the theoretical yield) of 2,2-dimethyl-6-fluoro-3-oxo-chroman in the form of a light-yellow oil.
Reaction SMILES: [CH:1]1([C:6](=O)[CH2:7][N+:8]([O-:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(O)(O)(=O)=O.[NH2:17][OH:18]>C1(C)C=CC=CC=1.C(O)C>[CH:1]1([C:6](=[N:17][OH:18])[CH2:7][N+:8]([O-:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C[N+](=O)[O-])C1CCCC1
Reactant: NO
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])CC(=NO)C1CCCC1
Yield: 88.7 %

Procedure:
9.90 g (63 mmol) of 1-cyclopentyl-2-nitro-ethanone (example II) and 20.688 g (126 mmol) of hydroxylamine sulfate are heated under reflux, for 4 hours, in 310 ml of a toluene/ethanol mixture (1:1). The solvent is removed in vacuo and the residue is taken up in ethyl acetate; the organic phase is washed 2 times with water and dried over sodium sulfate and the solvent is removed in vacuo. 9.62 g (74%) of pale yellow solid are obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][CH3:21])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2[C:4]3[CH:3]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=1)[CH3:21]
Reactant: CCc1nc2c(N)nc3ccc(Br)cc3c2n1CC(C)C
Reactant: OB(O)c1ccccc1
Product: CCc1nc2c(N)nc3ccc(-c4ccccc4)cc3c2n1CC(C)C

Procedure:
8-Bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (5%-7% methanol in CH2Cl2 gradient) afforded 2-ethyl-1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 233-235° C.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:18].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([F:18])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with (S)-N-BOC-proline, 24e, (215.3 mg, 1.00 mmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15° C. and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 148.0 mg of 25e as a faintly yellow oil. FTIR (neat) 1850 cm−1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]=[C:26]=[O:27]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:10][C:26]([NH:25][CH3:24])=[O:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN=C=O
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Temperature: 120 °C
Yield: 34 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionamide (126 mg, 0.37 mmol) and methyl isocyanate (211 mg, 3.70 mmol) in toluene (2 mL) was heated under reflux (120° C.) for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting yellow oil was treated with a small amount of a 1/1 mixture of hexanes/ethyl acetate, and a precipitate started to form. The material was further cooled in the freezer for 2 h to facilitate additional precipitation. The solid was collected by filtration and then dried in vacuo to afford 1-[3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionyl]-3-methyl-urea (50 mg, 35%) as a pale yellow solid: mp 241-242° C.; FAB-HRMS m/e calcd for C17H23N3O6S (M+H)+398.1386, found 398.1399.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.O.[NH2:16][NH2:17]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:16][NH2:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)c(Cl)nn1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(N2CCOCC2)c(Cl)nn1
Yield: 73.6 %

Procedure:
A mixture of 4-(3,6-dichloropyridazin-4-yl)morpholine (5 g, 21.3 mmol) and hydrazine hydrate (7.0 ml, 141 mmol) in 1,4-dioxane (100 ml) was stirred and heated at reflux for 20 hours. Upon cooling the 1,4-dioxane was removed in vacuo. The residue was then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous layer was further extracted with dichloromethane (×2). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol/aqueous ammonia (91:8:1) to give 6-chloro-5-(morpholin-4-yl)pyridazin-3-ylhydrazine (3.6 g, 74%): 1H NMR (250 MHz, d6-DMSO) δ3.17-3.37 (4H, m), 3.72-3.77 (4H, m), 4.31 (2H, br s), 6.58 (1H, s), 7.97 (1H, br s); MS (ES+) m/e 230, 232 [MH+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: NCCCOCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1-c1ccc(CNCCCOCc2ccccc2)cc1

Procedure:
A solution of 6.0 g (22 mmol) of 4-bromomethyl-2'-cyanobiphenyl, 5.8 g (35 mmol) of 3-benzyloxypropylamine and 3.6 g of triethylamine in 50 ml of 1,4-dioxane is heated to boiling under reflux for 18 hours. After working up analogously to Example 23a), an oil is obtained which, after flash-chromatographic purification (ethanol:ethyl acetate: 1:4), gives the title compound (TLC system B7; Rf value 0.39).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 2,4-difluoroaniline (10 g, 77 mmol) and triethylamine (12.95 mL, 93.00 mmol) in THF (50 mL) was added ethyl 2-chloro-2-oxoacetate (9.05 mL, 81.0 mmol) drop wise at 0° C. A white solid precipitated instantly. The reaction mixture was stirred at rt for 1 h. The solvent was evaporated, and Et2O was added. The solution was washed with 1N HCl (20 mL), saturated NaHCO3 and then brine, then the organic layer dried over MgSO4, filtered and concentrated to give Intermediate 11A (15.8 g, 68.9 mmol, 89.0% yield) as a white crystalline solid. HPLC/MS (Method L) RT=1.58 min, [M+H]+ 230.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Nc1cccnc1
Product: COC(=O)C(=CNc1cccnc1)C(=O)c1ccc(C)c(C)c1

Procedure:
1g (4.02 mmol) of the crude 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester and 0.38 g (4.02 mmol) of 3-aminopyridine were heated neat at 100° C. for 2 h. The product crystallized upon cooling the reaction to rt to yield 1.12 g of 2-(3,4-Dimethyl-benzoyl)-3-(pyridin-3-ylamino)-acrylic acid methyl ester as brown crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:62][N:63]([NH2:74])[C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65]>CN(C=O)C>[CH3:62][N:63]([NH:74][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:18][CH:17]=1)[C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CN(N)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Yield: 100.9 %

Procedure:
In a similar manner to Example 9, starting material step (a), 4-t-butoxycarbonylaminomethylbenzoic acid (300 mg), HBTU (460 mg), HOBT (190 mg), diisopropylethylamine (0.62 ml), DMF (3 ml) and benzyl 2-methylcarbazate (190 mg) were reacted to give benzyl 2-methyl-3-(4-t-butyoxycarbonylaminomethylbenzoyl)carbazate (440 mg) as a foam; NMR Spectrum (DMSO-d6) 1.39 (9H, s), 3.13 (3H, s), 4.17 (2H, d), 5.08 (2H, s), 7.42 (8H, m), 7.78 (2H, m), 10.73 (1H, br); Mass Spectrum m/Z 414 (M+H)+. In the NMR spectrum, ancillary signals attributable to rotamers were observed.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.FC(F)(F)C([O-])=[O:16].[Na+].O>FC(F)(F)C(O)=O>[OH:16][C:9]1[C:4]2[C:3](=[O:10])[NH:2][S:1](=[O:11])(=[O:12])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NS(=O)(=O)c2cccc(O)c21
Yield: 18.5 %

Procedure:
4.6 g (25 mmol) of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide (Saccharin®) were dissolved in 30 ml of trifluoroacetic acid and mixed with 4 g of sodium trifluoroacetate. The solution was electrolysed analogously to Example 1. After a charge quantity of 0.4 Ah had been used up the solution was added to water. It was extracted with chloroform and worked up as in Example 1. In addition to 3.3 g of starting material, 0.92 g of 4-hydroxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide were obtained after recrystallisation from water. This corresponds to a yield of 61% based on the starting material reacted;