Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>O1CCCC1>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:31](=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 65.8 %

Procedure:
1,1′-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of acid 3 (200 mg, 0.66 mmol) in tetrahydrofuran (5 mL) and the mixture stirred for 4 hours. A solution of N-tert-butoxycarbonylpiperazine (148 mg, 0.79 mmol) in tetrahydrofuran (2 mL) was added and the reaction stirred for an additional 14 hours at room temperature. The solvent was then removed under vacuum and the residual oil purified by column chromatography (silica gel, gradient 99:1 to 95:5 dichloromethane/methanol, v/v) to afford 7 (204 mg, 66%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 12H), 1.41-1.51 (m, 21H), 1.56-1.66 (m, 5H), 2.32 (t, 2H, J=7.5 Hz), 3.08-3.11 (m, 2H), 3.38-3.41 (m, 2H), 3.56-3.59 (m, 2H), 4.51 (br, 1H); m/z (ESI) 470 [C25H47N3O5+H]+.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[OH:21][C:18]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: O=C1CCOCC1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(C2(O)CCOCC2)cc1
Reaction time: 1.5 h

Procedure:
Under inert conditions, 109 ml (218 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were added dropwise at −40° C. to a solution of 50.0 g (218 mmol) of 4-iodobenzonitrile in 1000 ml of anhydrous THF. After the mixture had been stirred at the same temperature for 1.5 h, a solution of 32.8 g (327 mmol) of tetrahydro-4H-pyran-4-one in 250 ml of anhydrous THF was added. After the addition had ended, the reaction mixture was stirred first at −40° C. for 10 min, then at 0° C. for 30 min and finally at RT for 60 min. Then approx. 20 ml of saturated aqueous ammonium chloride solution were added at −20° C. Subsequently, the solvent was substantially removed on a rotary evaporator. 1000 ml of water were added to the remaining residue, which was extracted three times with approx. 500 ml each time of dichloromethane. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The resulting crude product was purified by stirring with 10:1 cyclohexane/ethyl acetate. 19.3 g (43% of theory) of the title compound were obtained.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].COCCOCCN(CCOCCOC)CCOCCOC.[CH3:29][N:30]1[C:34]2[C:35]([CH2:39][OH:40])=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1>ClCCl>[CH3:29][N:30]1[C:34]2[C:35]([CH:39]=[O:40])=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1
Reactant: Cn1nnc2cccc(CO)c21
Agent: O=[Mn](=O)(=O)[O-]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: ClCCl
Product: Cn1nnc2cccc(C=O)c21
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a stirred mixture of 7.4 parts of potassium permanganate, 0.6 parts of 2-(2-methoxyethoxy)-N,N-bis[2-(2-methoxyethoxy)ethyl]ethanamine and 130 parts of dichloromethane was added dropwise a solution of 7.6 parts of 1-methyl-1H-benzotriazole-7-methanol in dichloromethane. Upon complete addition, stirring was continued for 2 hours. The reaction mixture was filtered over diatomaceous earth and washed with dichloromethane. The organic layer was washed with 30 parts of a hydrochloric acid solution 2N and then with a sodium carbonate solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.5 parts (46.6%) of 1-methyl-1H-benzotriazole-7-carboxaldehyde; mp. 126° C. (int. 18).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:28])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:27])[CH3:26])=[O:4].Cl>CO.O1CCCC1.[OH-].[Na+].O>[F:28][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:16]=1)[CH2:11][C:10]2([CH3:27])[CH3:26]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCCC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)O)cc(F)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 93.8 %

Procedure:
A mixture of afford 6-fluoro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.32 g, 0.81 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-fluoro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.28 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=369.3.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:13][C:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:17]([CH3:25])[N:16]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:35](=O)[O:36]C3C=CC=CC=3)=[CH:28][CH:27]=2)[N:15]=1>CN(C)C=O>[CH3:13][C:14]1[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:17]([CH3:25])[N:16]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][NH:34][C:35]([NH:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[O:36])=[CH:30][CH:31]=2)[N:15]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccccc3)cc2)c(C)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a stirred solution of benzenesulfonamide (40 mg, 0.26 mmol), sodium hydride (11 mg, 0.49 mmol) and N,N-dimethylformamide (2 mL) was added dropwise a solution of phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1, 100 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL) at room temperature. After 2 h, the mixture was poured into ice-water and extracted with dichloromethane. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by TLC with dichloromethane/methanol (10:1) to give 84 mg (73%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.89 (2H, d, J=8.2 Hz), 7.64-7.21 (12H, m), 6.33 (1H, br.s), 3.51-3.44 (2H, m), 2.84 (2H, t, J=6.8 Hz), 2.33 (3H, s), 2.24 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[O-:11][C:12]#[N:13].[Na+]>>[CH:6]([C:5]1[NH:13][C:12](=[O:11])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:4]=1)([CH3:9])[CH3:7]
Reactant: N#C[O-]
Reactant: COc1ccc(CN)cc1
Agent: [Na+]
Product: COc1ccc(Cn2cc(C(C)C)[nH]c2=O)cc1

Procedure:
3-Methylbutan-2-one was brominated with bromine in methanol to give 1-bromo-3-methylbutan-2-one which was reacted with 4-methoxybenzylamine and cyclized with sodium cyanate to give 4-isopropyl-1-(4-methoxybenzyl)-1H-imidazol-2(3H)-one.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])C>CCO>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:11]2([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:26])=[O:5])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCCCC1(c2cccc(OC)c2)CCCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C2(CCCCC(=O)O)CCCCC2=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Solid KOH (0.090 g, 1.4 mmol) was added to a solution of the ester from Step A (0.132 g, 0.38 mmol) in EtOH (5 mL). After stirring at ambient temperature for 48 hr, the reaction mixture was partitioned between EtOAc (50 mL) and H2O (100 mL), the aqueous layer acidified, then extracted with EtOAc (2×100 mL), the organic layer washed with H2O (50 mL), dried (Na2SO4), filtered, and concentrated to dryness to give the title compound. Mp 89-91° C. MS 318.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:28][OH:29]>O.CO>[OH:29][N:28]=[C:2]([CH3:4])[CH2:1][C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cccc(C2=C(CC(C)=NO)C(=O)NCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The mixture of 7.0 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 3.88 g of potassium carbonate, 3.55 g of hydroxylamine hydrochloride, 5 ml of water and 60 ml of methanol is refluxed for 5 hours and then stirred at room temperature overnight. 80 ml of water are added, the precipitate collected and washed with ethanol and diethyl ether, to yield the 3-(2-hydroxyiminopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, melting at 155°-158°.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][C:14]([C:16]([F:19])([F:18])[F:17])=C)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].CSC.C[OH:24]>>[CH2:1]([C:3]1([CH2:13][C:14](=[O:24])[C:16]([F:19])([F:18])[F:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CO
Reactant: C=C(CC1(CC)CCCc2ccccc21)C(F)(F)F
Solvent: CSC
Product: CCC1(CC(=O)C(F)(F)F)CCCc2ccccc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
1-Ethyl-1-[2-(trifluoromethyl)-2-propen-1-yl]-1,2,3,4-tetrahydronaphthalene (Intermediate 12) (120 mg, 0.447 mmole) was dissolved in methanol (25 ml) and cooled to −78° C. Ozone was bubbled through the solution for 5 min followed by oxygen for 10 min then nitrogen for 10 min. Dimethyl sulphide (4 ml, 54 mmole) was added and the dry-ice bath was removed to bring the mixture to room temperature. Stirring was continued for 30 min then volatiles were removed in vacuo. The residue was purified on a 10 g silica SPE cartridge eluting with cyclohexane (200 ml), cyclohexane:ethyl acetate 80:20 (100 ml) and ethyl acetate (100 ml) to give the title compound (31 mg, 26%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH:10]=[CH2:11])(=[O:7])[OH:6].[H][H]>O.[Pd]>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])[OH:7]
Reactant: [H][H]
Reactant: C=CCCP(=O)(O)CCCN
Agent: [Pd]
Solvent: O
Product: CCCCP(=O)(O)CCCN

Procedure:
A solution of 1 g of 3-aminopropyl(but-3-enyl)phosphinic acid in 25 ml of water is treated with 0.1 g of 5% palladium on charcoal and hydrogenated at room temperature until hydrogen uptake ceases. The catalyst is removed by filtration of the reaction mixture through celite and the filtrate evaporated to dryness, to afford 3-aminopropyl(butyl)phosphinic acid, m.p.231°-234° (dec.) 31 -NMR (D2O): δ+44.6 ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[S:4]/[C:3]/1=[N:11]\[CH3:12].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])(=[O:26])=[O:25])[CH:18]=[CH:17]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([CH2:27][CH2:28][C:29]([N:31]1[CH2:32][CH2:33][N:34]([C:8]([C:5]3[S:4]/[C:3](=[N:11]\[CH3:12])/[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:10])[CH2:35][CH2:36]1)=[O:30])(=[O:26])=[O:25])[CH:18]=[CH:17]2
Reactant: O=C(CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: C/N=c1\sc(C(=O)O)c(C)n1C
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/N=c1\sc(C(=O)N2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)c(C)n1C
Yield: 8.9 %

Procedure:
(2Z)-3,4-Dimethyl-2-methylimino-2,3-dihydro-1,3-thiazole-5-carboxylic acid (0.6 g) was dissolved in dichloromethane (30 mL), and triethylamine (0.14 mL) was added thereto. With ice cooling, 1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.0 g), HOBt (0.42 g) and WSC (0.57 g) were added thereto, and the mixture was mixed at room temperature for 16 hours. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (0.13 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C@@H:28]1[CH2:30][C@H:29]1[C:31]([NH:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)=[O:32]>C1(C)C=CC=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:31]([C@@H:29]2[CH2:30][C@H:28]2[CH3:27])=[O:32])=[CH:41][CH:40]=1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 79 %

Procedure:
Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.94 g, 2.2 mmol) with a solution of (±)-trans-4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamine (0.899 g, 4.403 mmol) in anhydrous toluene (22 mL) and anhydrous dioxane (5.8 mL). Purify by chromatography on silica gel to afford (±)-trans-7-chloro-6-{4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.834 g, 79%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:16]3[N:20](C)[N:19]=[N:18][N:17]=3)[CH:9]=2)=[CH:4][CH:3]=1.COC(C1SC(C2C=CC(F)=CC=2)=CC=1C1N(C)N=NN=1)=O.[OH-].[Li+]>CO.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1nnnc1-c1cc(-c2ccc(F)cc2)sc1C(=O)O
Agent: COC(=O)c1sc(-c2ccc(F)cc2)cc1-c1nnnn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccc(F)cc2)cc1-c1nnn[nH]1
Yield: 90 %

Procedure:
5-(4-Fluoro-phenyl)-3-(1-methyl-1H-tetrazol-5-yl)-thiophene-2-carboxylic acid (DNM-143) A solution of 5-(4-fluoro-phenyl)-3-(1-methyl-1H-tetrazol-5-yl)-thiophene-2-carboxylic acid methyl ester (28 mg, 0.088 mmol) and lithium hydroxide (10.5 mg, 0.44 mmol) in 3 mL of methanol, 4.5 mL of THF and 2 mL of H2O was stirred overnight at room temperature. The solvent was removed, and the residue was redissolved in 5 mL of H2O. After being acidified with 1N HCl, the precipitate formed was collected by suction filtration, washed with H2O, and dried under vacuum overnight. 24 mg (90%) of product was obtained as a white solid, mp: 270.0-272.0° C. (decomposed); 1H NMR (DMSO, 500 MHz) δ 7.89 (m, 2H), 7.77 (s, 1H), 7.36 (m, 2H); 13C NMR (DMSO, 125 MHz) δ 163.76, 161.79, 161.46, 150.48, 147.83, 132.96, 128.94, 128.49, 128.45, 128.39, 127.03, 116.56, 116.39, 34.12.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][C:14]([CH2:19][C:20]([OH:22])=O)=[CH:13][CH:12]=2.ClC(OCC)=O.[CH3:29][NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1>[N:37]1([C@@H:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]2[N:30]([CH3:29])[C:20](=[O:22])[CH2:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]([CH3:8])=[C:17]3[CH3:18])[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: Cc1[nH]c2ccc(CC(=O)O)cc2c1C
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(CC(=O)N(C)[C@@H]3CCCC[C@H]3N3CCCC3)cc2c1C
Reaction time: 0.08 h
Yield: 55.5 %

Procedure:
Triethylamine (139 μl, 1 mmol) was added to a solution of 2,3-dimethyl-1H-indole-5-acetic acid (203 mg, 1 mmol) in tetrahydrofuran (10 ml) at -15° C., with vigorous stirring. Ethyl chloroformate (96 μl, 1 mmol) was added, and the mixture stirred for five minutes. A solution of trans-(±)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine (182 mg, 1 mmol) in tetrahydrofuran (2 ml) was added, and stirring continued for 30 minutes at -15° C., then 30 minutes at room temperature. The reaction was evaporated to small volume, the residue taken into ethyl acetate (50 ml), and washed with saturated sodium bicarbonate solution (3×50 ml). The organic extract was dried (MgSO4), evaporated under reduced pressure and recrystallized from ethyl acetate to yield the amide (204 mg, 56%); VmaxC=0 1615 cm-1.
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=C1NS(=O)(=O)c2ccccc21
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
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;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14](Cl)(=[O:24])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23]>O1CCOCC1>[N+:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:1][C:14](=[O:24])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:10]=1)[C:5]([OH:7])=[O:6])([O-:13])=[O:12]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: COCCOCCOCC(=O)Cl
Solvent: C1COCCO1
Product: COCCOCCOCC(=O)Nc1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
A mixture of 14.6 g. of 3-amino-5-nitrobenzoic acid and 17.1 g. of 3,6,9-trioxadecanoic acid chloride in 200 ml. of dioxane was heated at reflux for 24 hours. The reaction mixture was concentrated to remove the solvent. The residue was dissolved in dilute sodium hydroxide and then acidified with hydrochloric acid. The resulting product (13.6 g., m.p. 130° C.) was recrystallized from acetonitrile to give 3-nitro-5-(3,6,9-trioxadecanamido)benzoic acid as a beige solid, m.p. 136°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:20]([O-:22])=[O:21])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O[Si](C)(C)C)([C:13]#[N:14])[CH2:8][CH2:7][CH2:6]2.C(Cl)(C)=O>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([N+:20]([O-:22])=[O:21])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]#[N:14])=[CH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCCC2(C#N)O[Si](C)(C)C
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: COc1ccc2c(c1[N+](=O)[O-])CCC=C2C#N
Yield: 100 %

Procedure:
A solution of 6-methoxy-5-nitro-1-trimethylsilyloxy-l,2,3,4-tetrahydronaphthalene-1-carbonitrile (1.3 g, 4.0 mmol) and AcCl (1.0 ml) in 20 ml AcOH was stirred for 2 h at 80°-100° C. The resulting reaction mixture was concentrated in vacuo to yield the desired product as a colorless oil (0.86 g, 4.0 mmol, 96% for two steps), which was subjected to the following step without any further purification. 1H NMR (300 MHz, CDCl3):δ 2.48 (dt, 2H, J=2.3, 6.7 Hz), 2.78 (t, 2H, J=8.9 Hz ), 3.89 (s, 3H), 6.82 (t, 1H, J=2.3 Hz), 6.92 (d, 1H, J=8.9 Hz), 7.53 (d, 1H, J=8.9 Hz).
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.Cl[CH2:14][C:15]([N:17]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:16].O>CN(C)C=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([N:17]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:15](=[O:16])[CH2:14][N:6]2[C:2](=[O:12])[C:3]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]3[C:5]2=[O:7])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CCl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
tert-Butyl 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido] acetate may be prepared in the following manner: phthalimide potassium salt (7.5 g) is added to a solution of tert-butyl 2-[2-chloro-N-(3-methoxyphenyl)acetamido]acetate (6.3 g) in dimethylformamide (100 cc). The mixture is stirred at a temperature in the region of 100° C. for 5 hours and then poured into water (1000 cc). The insoluble product is separated by filtration, washed with water (3×60 cc) and dried in the air. After recrystallisation in diisopropyl ether, tert-butyl 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido]acetate (6.7 g), m p 138° C. is obtained.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=O.C[O-].[Na+].[Na].C(Cl)(=O)C.[CH:14]([NH:16][CH2:17][C:18]#[CH:19])=[O:15]>CN(C)C(=O)C.CO>[CH:14]([NH:16][CH2:17][C:18]1[O:3][N:1]=[C:4]([CH3:5])[CH:19]=1)=[O:15]
Reactant: CC[N+](=O)[O-]
Reactant: C#CCNC=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CC(=O)Cl
Product: Cc1cc(CNC=O)on1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A stirred solution of nitroethane (17.9 ml, 0.25 mol) in N,N-dimethylacetamide (DMA) (250 ml) was added dropwise at 25°-30° C. to a solution of sodium methoxide, prepared by dissolving sodium (5.75 g) in dry methanol. The reaction mixture was cooled to 5° C. and acetyl chloride (18.5 ml, 0.26 mol) was added at 5°-10° C. Then was added a solution of 3-formylaminopropyn (17 g, 0.20 mol) in DMA (15 ml), and stirring was continued at room temperature overnight. The solvent was removed in vacuo and the residue was extracted with ether (300 ml). The ether was evaporated leaving an oily residue from which the title compound was isolated by distillation (120°-140° C./0.3 mmHg); 1H-NMR (CDCl3) 2.21 (s,3H), 4.35 (d,2H), 5.97 (s,1H), 7-8 (br, 1H), 8.13 (s,1H). (Compound 15).