Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:10]CP(O)(=O)O)[S:3]([C:6]([F:9])([F:8])[F:7])(=[O:5])=[O:4].C(N(CCC[P:32]([OH:35])(=[O:34])[OH:33])S(C(F)(F)C(F)(F)F)(=O)=O)C.CN(CCCP(O)(=O)O)S(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O.C(N(CCCP(O)(=O)O)S(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)C.C(N(CCCP(O)(=O)O)S(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)C.C(N(CCCCCCCCCCCP(O)(=O)O)S(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)C.CN(CCCCCCP(O)(=O)O)S(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O.CN(CCCP(O)(=O)O)S(C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F)(=O)=O>>[CH3:1][N:2]([CH2:10][P:32]([OH:35])(=[O:33])[OH:34])[S:3]([C:6]([F:7])([F:8])[F:9])(=[O:4])=[O:5]
Reactant: CN(CCP(=O)(O)O)S(=O)(=O)C(F)(F)F
Reactant: CCN(CCCP(=O)(O)O)S(=O)(=O)C(F)(F)C(F)(F)F
Agent: CCN(CCCCCCCCCCCP(=O)(O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCN(CCCP(=O)(O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCN(CCCP(=O)(O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CN(CP(=O)(O)O)S(=O)(=O)C(F)(F)F

Procedure:
2-(N-Methyltrifluoromethanesulfonamido)ethanephosphonic acid; 3-(N-Ethylperfluoroethanesulfonamido)propanephosphonic acid; 3-(N-Methylperfluorohexanesulfonamido)propanephosphonic acid; 3-(N-Ethylperfluorododecanesulfonamido)propanephosphonic acid; 3-(N-Ethylperfluorooctadecanesulfonamido)propanephosphonic acid; 11-(N-Ethylperfluorooctanesulfonamido)undecanephosphonic acid; 6-(N-Methylperfluorobutanesulfonamido)hexanephosphonic acid; 3-(N-Methyl-1,1-dihydroperfluorobutanesulfonamido)propanephosphonic acid; 3-(N-Methylperfluorocyclohexanesulfonamido)propanephosphonic acid; 3-(N-Methyl-1,2-dihydroperfluorobutanesulfonamido)propanephosphonic acid;
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=3)[CH:27]=[CH:26]2)[CH2:24][CH2:23]1.Cl.[O:40]=[C:41]1[O:45][N:44]=[C:43]([C:46]2[CH:47]=[C:48]3[C:58](=[CH:59][CH:60]=2)[O:57][C:51]2([CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][C:49]3=[O:61])[NH:42]1>CN(C=O)C.O.CCN(CC)CC>[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([N:54]4[CH2:55][CH2:56][C:51]5([CH2:50][C:49](=[O:61])[C:48]6[C:58](=[CH:59][CH:60]=[C:46]([C:43]7[NH:42][C:41](=[O:40])[O:45][N:44]=7)[CH:47]=6)[O:57]5)[CH2:52][CH2:53]4)=[O:36])[CH:32]=3)[CH:27]=[CH:26]2)[CH2:23][CH2:24]1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3noc(=O)[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4noc(=O)[nH]4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (58 μL), HOBT (32 mg) and WSC (40 mg) were added to a solution of 1-cyclopropyl-4-methoxy-1H-indol-6-carboxylic acid (40 mg) and 6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (70 mg) in DMF (4 mL), and stirred overnight at room temperature. Water was added to the reaction mixture, and the formed solid was collected by filtration. The solid was washed thoroughly with water and ether. This was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 12.91 (1H, brs), 8.20 (1H, d, J=4.0 Hz), 8.00 (1H, dd, J=8.0, 4.0 Hz), 7.36-7.26 (2H, m), 7.22 (1H, s), 6.57 (1H, s), 6.39 (1H, d, J=4.0 Hz), 4.20-4.00 (1H, m), 3.87 (3H, s), 3.46-3.40 (1H, m), 3.40-3.20 (3H, m), 2.89 (2H, s), 2.06-1.77 (4H, m), 1.07-1.03 (2H, m), 0.94-0.90 (2H, m); MS [M+H]+=515.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl>[F:15][C:16]([F:24])([F:25])[C:17]1[CH:18]=[CH:19][C:20]([NH:21][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])=[CH:22][CH:23]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
A suspension of 2.1 g of 5-chlorosulfonyl-2-oxindole, 1.6 g of 4-trifluoromethylaniline and 1.4 g of pyridine in 20 mL of dichloromethane was stirred at room temperature for 4 hours. The precipitate which formed was collected by vacuum filtration, washed twice with 5 mL of water and dried under vacuum at 40° C. overnight to give 2.4 g of crude product containing some impurities by thin layer chromatography. The crude product was chromatographed on silica gel eluting with ethyl acetate:hexane (1:2) to give 1.2 g (37% yield) of 5-(4-trifluoromethylphenyl-aminosulfonyl)-2-oxindole.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[CH:27]([CH3:29])[CH3:28])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>CC(O)=O>[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:14]=1[CH:27]([CH3:29])[CH3:28])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc([N+](=O)[O-])c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 75 °C
Yield: 35 %

Procedure:
HNO3 (1.11 ml, 13.7 mmol) was added to a suspension of 2,4-bis-benzyloxy-1-isopropyl-benzene (3.8 g, 11.44 mmol) in AcOH (46 ml) and the reaction was heated to 70-80° C. for 40 minutes. The solution was cooled down to 0° C. and neutralized with aq. NaHCO3. The organic phase was extracted with AcOEt and the solvent was removed under reduced pressure. The crude reaction mixture was purified by flash chromatography (PE/AcOEt:95/5 to 90/10) and the title compound was obtained as a yellow solid.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1.C(O)C>C1(C)C(C)=CC=CC=1>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]2[C:4]=1[CH2:3][C@@H:2]([N:27]1[CH2:26][CH2:25][N:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=3)[CH2:29][CH2:28]1)[C@H:11]([OH:1])[CH2:10]2
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](N1CCN(c3cccc(C(F)(F)F)c3)CC1)C2
Yield: 36.7 %

Procedure:
A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 11.5 g of N-(α, α, α-trifluoro-m-tolyl)piperazine, and 2 ml of absolute ethanol in 100 ml of xylene is refluxed for 7 days. The reaction mixture is concentrated in vacuo, and the residue is triturated with ether to give 11.9 g of crude product. Recrystallization from ethyl acetate gives 8.0 g of the title compound, melting point 184°-187° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([CH2:14][OH:15])[CH:10]([OH:11])[CH:9]([OH:12])[CH:8]([OH:13])[CH2:7][NH:6]1.CO.C(N(CC)CC)C.[CH2:25]([O:31][C:32](Cl)=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O.C(OCC)(=O)C>[CH2:25]([O:31][C:32]([NH:3][CH2:4][C:5]1([CH2:14][OH:15])[CH:10]([OH:11])[CH:9]([OH:12])[CH:8]([OH:13])[CH2:7][NH:6]1)=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: NCC1(CO)NCC(O)C(O)C1O
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCOC(=O)NCC1(CO)NCC(O)C(O)C1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.3 g of 2-aminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine dihydrochloride (Example 11) are dissolved in 20 ml of water, and 30 ml of methanol and 8.4 ml of triethylamine are added. 7.8 ml of chloroformic acid hexyl ester, dissolved in 30 ml of ethyl acetate are added dropwise to this solution at 0°-5° C. After stirring the mixture at room temperature for three hours, it is concentrated. The evaporation residue is partitioned in water/ethyl acetate, the phases are separated and the ethyl acetate phase is washed 1× with water. The combined aqueous phases are stirred with 80 g of Amberlite IR A 400, OH- form for 1 hour, the mixture is filtered and the filtrate is concentrated. The evaporation residue is dissolved in a little methanol and the solution is discharged onto a column 120 cm long and 4 cm wide which contains cellulose as the stationary phase and acetone as the mobile phase. The column is washed with acetone. The substance is obtained by elution with 95% pure acetone. After concentrating the eluate, 2.4 g of an almost colourless yellow foam are obtained.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12]>ClC1C=CC=CC=1>[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[N:12]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(N)cc1C
Solvent: Clc1ccccc1
Product: Cc1ccc(N(c2ccccc2)c2ccccc2)cc1C

Procedure:
An improved process for producing triarylamines directly from an aniline is to react an arylchloride with an aniline compound in the presence of a suitable catalyst. For example, 3,4-dimethylaniline can be rapidly reacted with chlorobenzene to form 3,4-dimethyl-N,N-diphenylaniline using palladium acetate ligated with 2,4,6-trioxa-1,3,5,7-tetramethyl-8-phosphaadamantane, which is manufactured as Cytop-216 (Cytec Industries), and sodium t-pentoxide base. This reaction proceeds rapidly, in about 4 to 8 hours to produce the desired triarylamine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([NH:14][C:12]1[C:11]([C:19]([F:21])([F:20])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH:37]=[N:36][CH:35]=[N:34]4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {5-(isobutyl-amino)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M130) (0.43 g, 0.77 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (270 mg, 61%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]=[CH:9][C:10](=[CH2:12])[CH3:11]>O1CCCC1>[CH3:11][C:10]1[CH2:12][CH:2]2[CH:3]([CH2:8][CH:9]=1)[C:4](=[O:5])[O:6][C:1]2=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CC(=C)C
Solvent: C1CCOC1
Product: CC1=CCC2C(=O)OC(=O)C2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5-L round bottom reaction flask fitted with a condenser was charged with maleic anhydride (C2H2(CO)2O) (500 g) and tetrahydrofuran (THF) (3 L) and isoprene (CH2═C(CH3)CH═CH2) (400 g) was then added at room temperature. The reaction was mildly exothermic. The reaction mixture was stirred at room temperature for about 2 hours till the Gas Chromatography (“GC”) analysis showed the consumption of maleic anhydride. The resulting mixture containing crude 5-methyl-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione was used directly in the next step.
Reaction SMILES: COCC(O[CH:7]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[CH:31]=[C:30]2[CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:8]([CH:24]([CH3:26])[CH3:25])[CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O.C(CN)O>C(O)C.[Pd]>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[C:27]([CH2:7][CH:8]([CH:24]([CH3:25])[CH3:26])[CH2:9][CH:10]3[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:28]=2)[N:32]([CH3:36])[CH:31]=1
Reactant: COCCCc1cn(C)c2ccc(C(OC(=O)COC)C(CC3COC(C)(C)N3C(=O)OC(C)(C)C)C(C)C)cc12
Agent: [Pd]
Solvent: CCO
Solvent: NCCO
Product: COCCCc1cn(C)c2ccc(CC(CC3COC(C)(C)N3C(=O)OC(C)(C)C)C(C)C)cc12

Procedure:
A solution of 2.80 g of tert-butyl 4-(2-{(2-methoxyacetoxy)-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-yl]-methyl}-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (diastereomer mixture) in 140 ml of ethanol is hydrogenated at 0° C. in the presence of 0.294 ml of ethanolamine and 3.34 g of 10% Pd/C over 3.5 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.48 (1:1 EtOAc-heptane). Rt=29.41 (gradient II).
Reaction SMILES: [CH:1]([O:6]C)(OC)[O:2][CH3:3].C([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)(O)=O>C1(C)C(S(O)(=O)=O)=CC=CC=1.CO>[CH3:3][O:2][C:1]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[O:6]
Reactant: COC(OC)OC
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Yield: 95.9 %

Procedure:
A glass reaction vessel fitted with a reflux condenser and magnetic stir bar was charged with trimethyl orthoformate (34.28 grams), 4-carboxybenzenesulfonamide (50.00 grams), toluenesulfonic acid (2.5 grams) and methanol (197 mL). The mixture was heated to 70° C. for 16 hours. The cooled mixture was concentrated on a rotary evaporater. Diethyl ether (200 mL) was added to the concentrate and stirred. The resulting solid was filtered to afford 51.3 grams of the desired 4-methoxycarbonyl benzenesulfonamide. In a glass reaction vessel fitted with a reflux condenser, a thermometer, a pressure-equalizing addition funnel, and a nitrogen inlet was placed a 60 weight percent dispersion of NaH in mineral oil (16.22 grams). The dispersion was washed three times with heptane by stirring the mixture for several minutes, allowing the mixture to stand, and using a pipette to decant the supernatant heptane. NMP (50 grams) was added to the flask and the mixture was stirred. To this stirred mixture was added a solution of camphoric anhydride (14 grams), 4-methoxycarbonyl benzenesulfonamide (15 grams), and NMP (61 grams) slowly via the addition funnel. The resulting mixture was stirred at room temperature for approximately 1 hour, poured into a beaker of deionized water that was vigorously stirred. The basic mixture was acidified with 1.0N HCl and subsequently extracted with EtOAc. The volatile components were removed using a rotary evaporator to afford a solid intermediate. This intermediate was combined with THF (111 grams), acetic anhydride (8.54 grams), and triethylamine (23.3 grams) and stirred for 1 hour at 60° C. The mixture was poured into aqueous 1N HCl and the resultant solid isolated by filtration. The solid was combined with methanol and this mixture was heated to boiling, cooled to room temperature, filtered, and washed sequentially with methanol and diethyl ether. The solid was dried overnight in a vacuum oven at room temperature and 67 Pa (0.5 mm Hg) to give the desired product.
Reaction SMILES: NC1C=CC(C#N)=CC=1[N+]([O-])=O.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH2:22])[CH:16]=1)#[N:14].[Cl:23][C:24]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:25]=1[CH:26]=O>>[Cl:23][C:24]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:25]=1[C:26]1[NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][C:17]=2[N:22]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: N#Cc1ccc(N)c([N+](=O)[O-])c1
Product: N#Cc1ccc2[nH]c(-c3cc([N+](=O)[O-])ccc3Cl)nc2c1

Procedure:
4-Amino-3-nitrobenzonitrile was reduced to 4-cyano-1,2-phenylenediamine as for compound 19. This was reacted with 2-chloro-5-nitrobenzaldehyde as described in route 1 step 4 to give 2-(2-chloro-5-nitro-phenyl)-1H-benzoimidazole-5-carbonitrile.
Reaction SMILES: [C:1](Cl)(=O)C.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1>CO>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:1])=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of MeOH (25 mL) was added slowly acetyl chloride (3.5 mL). After 30 min, 2-(6-chloropyridin-3-yl)acetic acid (2.5 g) was added and the resulting reaction mixture stirred at room temperature for 2 hr. Solvents were then removed. The residue was dissolved in EtOAc and washed with 10% NaHCO3. The organic phase was dried and concentrated to afford the product (2.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].O>C1C=CC=CC=1>[CH2:11]([N:13]([CH2:14][CH3:15])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[CH3:12]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCNCC
Solvent: O
Solvent: c1ccccc1
Product: CCN(CC)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a 50 ml flask fitted with a stirrer, condenser, drying tube and an addition funnel is added m-fluorobenzoyl chloride (15.9 g, 0.10 mole) and benzene (100 ml). Then a solution of diethylamine (14.6 g, 0.20 mole) in benzene (100 ml) is added dropwise over 1 hour and the reaction mixture allowed to stir at room temperature overnight. Water (150 ml) is then added rapidly and after trituration for a few minutes, the benzene layer is decanted and washed repeatedly with water (5×150 ml), dried (anhyd. Na2SO4) and the solvent removed under vacuum to afford 18 grams of N,N-diethyl-3-fluorobenzamide as a yellow oil. Elemental analysis calculated for C11H14FNO: C, 67.70; H, 7.22; F, 9.72; N, 7.16; Found: C, 66.40; H, 7.08; F, 9.65; N, 6.92
Reaction SMILES: [C:1]([C@:3]1([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[C@H:5]([O:16][C:17](=[O:19])[CH3:18])[C@@H:4]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:2].[OH-].[Na+].C(O)(=O)C.CS(Cl)(=O)=O>CO.C(OCC)(=O)C.O>[C:1]([C@:3]1([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[C@@H:5]([O:16][C:17](=[O:19])[CH3:18])[C@@H:4]1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)#[CH:2]
Reactant: C#C[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: C#C[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 15 (2.30 g, 4.69 mmol) was dissolved in methanol (90.0 ml), and a 1 N aqueous solution of sodium hydroxide (10.0 ml) was added to the solution, followed by stirring for two hours at room temperature. The reaction mixture was neutralized with acetic acid and then brought to dryness under reduced pressure. The residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and brought to dryness under reduced pressure. The residue was concentrated by co-boiling with a small amount of pyridine three times. The product was dissolved in pyridine (50.0 ml), and methanesulfonyl chloride (0.73 ml, 9.41 mmol) was added to the solution under cooling, followed by stirring for three hours. A small amount of water was added to the reaction mixture, and the mixture was brought to dryness under reduced pressure. The residue was dissolved in ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate and then brought to dryness under reduced pressure. The residue was dissolved in tetrahydrofuran (30.0 ml), and a 1 N aqueous solution of sodium hydroxide (50.0 ml) was added to the solution, followed by refluxing for one hour. After the reaction mixture was neutralized with acetic acid, the target compound was taken up through extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The organic layer was brought to dryness under reduced pressure, and the residue was purified by means of silica gel column chromatography (silica gel 250 ml, eluent; n-hexane:ethyl acetate=1:2), to thereby yield a white powder compound (Compound 16; 1.54 g, 3.43 mmol, 73.1%).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:13])[CH2:11][NH2:12]>C(O)C>[CH:1](=[N:12][CH2:11][CH2:10][N:13]=[CH:1][C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=Cc1ccccc1O
Reactant: NCCN
Solvent: CCO
Product: Oc1ccccc1C=NCCN=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of salicylaldehyde (12.21 g/10.62 mL) in 70° C. ethanol (100 mL) was added ethylenediamine (3.01 g/3.33 mL). A yellow crystalline material immediately formed, and the reaction mixture was allowed to cool to room temperature with stirring. The solution was filtered, and the crystals were washed with cold ethanol. The ethanol layers were combined and reduced to approximately 20 mL and allowed to stand at 0° C. overnight. The resulting crystals were collected by vacuum filtration and washed with water. The collected solids were dried in vacuo to obtain 13.15 g (98%) N,N′-bis(salicylidene)ethylenediamine as yellow platelets with a melting point of 126° C. (literature value (24) 127-128° C.). 1H NMR (DMSO-d6) δ 8.57 (s 2H, HC=N), 7.42 (d, 2H aromatic, J=7.3 Hz), 7.31 (t, 2H, aromatic, J=9.0 Hz), 6.88 (t, 4H, aromatic, J=8.3, 16.1 Hz), 3.89 (s, 4H, CH2). 13C NMR (DMSO-d6) δ 166.94 (2C, CO−), 160.57 (2C, HC+N), 132.38 (2C, aromatic), 131.69 (4C, aromatic), 118.59 (2C, aromatic), 116.51 (2C, aromatic), 58.88 (2C, CH2).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]([CH3:19])([CH:16]([CH3:18])[CH3:17])[C:14]#[N:15]>C(Cl)Cl>[C:14]([C:13]([NH:12][C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])([CH3:19])[CH:16]([CH3:18])[CH3:17])#[N:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)C(C)(N)C#N
Solvent: ClCCl
Product: CC(C)C(C)(C#N)NC(=O)c1ccccc1C(=O)O
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a stirred boiling mixture of 28.1 g (0.189 mole) of phthalic anhydride in 28 ml methylene chloride is added dropwise 23.6 g (0.21 mole) of 2-amino-2,3-dimethylbutyronitrile in 57 ml methylene chloride. After the addition, heating is continued for 3 hours. The mixture is cooled and the precipitate removed by filtration, washed with methylene chloride and air-dried to give 44.2 g (90%) of N-(1-cyano-1,2-dimethylpropyl)phthalamic acid, melting point 154°-155° C.