Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([N:11]1[C:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH:19]=2)[NH:14][C:13](=O)[C:12]1=[O:22])([CH3:10])([CH3:9])[CH3:8].P(Cl)(OCC)(OCC)=O.[F:32][C:33]1[CH:41]=[CH:40][C:36]([CH2:37][N+:38]#[C-:39])=[CH:35][CH:34]=1>C1COCC1>[C:7]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:39]=[N:38][C:37]([C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)=[C:13]2[C:12]1=[O:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]Cc1ccc(F)cc1
Reactant: CC(C)(C)N1C(=O)C(=O)NC2CCCC=C21
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)n1c(=O)c2c(-c3ccc(F)cc3)ncn2c2ccccc21
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1.0M in THF, 24.1 ml) is added to a mixture of 1-(tert-butyl)tetrahydroquinoxalin-2,3-dione (XXXI, 5.00 g) and THF (54.0 ml) at -20°. The mixture is allowed to warm to 0° over 30 min. After cooling to -40°, diethyl chlorophosphate (3.53 ml) is added and the solution is allowed to warm to 20°-25° over 40 min. After cooling to -78°, a solution of 4-fluorobenzyl isocyanide (3.62 g) and THF (5.0 ml) is added. Potassium tert-butoxide (24.1 ml) is then added dropwise over several min. The mixture is stirred at -78° for 30 min and is allowed to warm slowly to 20°-25° over 2 hr. Aqueous workup (ethyl acetate, magnesium sulfate) and purification by flash chromatography eluting with ethyl acetate/hexane (1/2), pooling the appropriate fractions and concentration gives the title compound, mp 135°-137°; IR (mineral oil) 2953, 2925, 2855, 1668, 1498, 1299 and 751 cm-1 ; NMR (CDCl3) 8.31, 8.22, 7.63, 7.55, 7.05-7.35 and 1.76 δ; MS (m/z) 335, 279.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].[CH2:10]([Mg]Br)[CH3:11].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>C(OCC)C.C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]1([NH2:7])[CH2:11][CH2:10]1
Reactant: CC[Mg]Br
Reactant: CC(C)(C)CCCC#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)CCCC1(N)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Titanium tetraisopropoxide (1.4 mL, 5.52 mmol) was added to a solution of 5,5-dimethyl-hexanenitrile (630 mg, 4.8 mmol) in diethyl ether (16 mL) and the resulting solution was stirred at room temperature for 10 minutes. The mixture was cooled to 0 ° C. and ethyl magnesium bromide (10 mL, 10 mmol of a 1 M solution in THF, 2.1 EQ) was added over a 20 minute period. The reaction mixture was warmed to room temperature and allowed to stir for 40 minutes after which TLC indicated complete consumption of the starting material. The solution was cooled to 0° C. and BF3.OEt2 (1.3 mL, 10.1 mmol) was added. The mixture was stirred at room temperature for 30 minutes after which aqueous HCl (2 mL of 1 N solution) and aqueous NaOH (3 mL of 3 N solution) were added. This mixture was then extracted with ethyl acetate (3×20 mL), the combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column (eluant methylene chloride/methanol/NH4OH, 99/1/0.1 to 90/10/1) to give 1-(4,4-dimethyl-pentyl)-cyclopropylamine. Retention time (min) =1.307, Method [1], MS (ESI) 186.2 (M+H).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9]([C:11]1[C:15]2[CH2:16][C:17](=[O:19])[CH2:18][C:14]=2[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=1)=O.[NH4+:27].[OH-]>O1CCOCC1>[CH2:20]([N:13]1[C:14]2[CH2:18][C:17](=[O:19])[CH2:16][C:15]=2[C:11]([C:9]([NH2:27])=[O:8])=[N:12]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [NH4+]
Reactant: O=C1Cc2c(C(=O)ON3C(=O)CCC3=O)nn(Cc3ccccc3)c2C1
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1nn(Cc2ccccc2)c2c1CC(=O)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the intermediate from step D (2.0 g, 5.25 mmol) in 1,4-dioxane (50 mL) was added NH4OH (14.8 N, 10.0 eq, 3.53 mL). A precipitate formed immediately. After stirring at room temperature for 15 minutes the reaction mixture was filtered through a fritted funnel and the precipitate washed with 1,4-dioxane. The filtrate was concentrated in vacuo to give a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.O>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](=[O:11])[NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:4]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)c1cc(Cl)ccn1
Reaction time: 20 h
Yield: 95.4 %

Procedure:
To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rf 0.50.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)Cl>[C:25]1([C:23]2[N:24]=[C:20]([C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][NH2:10])=[CH:19][CH:18]=3)[S:21][CH:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(NCCOc1ccc(-c2nc(-c3ccccc3)cs2)cc1)OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: NCCOc1ccc(-c2nc(-c3ccccc3)cs2)cc1
Yield: 78 %

Procedure:
Benzyl-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethyl}-carbamate (396 mg, 0.92 mmol) was dissolved in methylene chloride (4.6 ml) and methanesulfonic acid (0.895 ml, 13.8 mmol) was added dropwise to give a homogenous yellow solution. The reaction mixture was allowed to stir for about sixteen hours, diluted with methylene chloride, and was brought to basic pH (12-13) with 1M sodium hydroxide. The mixture was then extracted with methylene chloride, and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride) to afford the product in 78% yield (213 mg). LRMS ([M+H]+)=297.2.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:24]=[CH:23]C(C(Cl)=O)=[CH:18][CH:17]=1>>[C:6]([NH:5][NH:4][C:1](=[O:3])[C:2]1[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)NNC(=O)c1ccccc1
Product: COc1ccc(C(=O)NNC(=O)c2ccccc2)cc1

Procedure:
Synthesis and isolation were same as 1-acetyl-2-benzoylhydrazine, using 1.5 g (11.2 mmol) of benzoylhydrazide, 1.9 g (11.1 mmol) of 4-methoxybenzoylchloride and 1.1 g of TEA. Yield was 2.9 g (97%). 1H NMR (200 MHz, d6-DMSO) δ 5.13 (s, 3H), 8.36 (d, 2H), 8.86 (m, 3H), 9.23 (d, 4H) 11.72 (d, 2H); MS (EI, m/e, relative intensity %) calcd for C15H14N2O3 270, found 270 (M+, 5.1); mp 201-202° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)OC(C)(C)C)=[C:8]([NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[CH:7]=1.Cl>CO.O1CCOCC1>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]=1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24]
Reactant: CCOC(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a stirred solution of tert-butyl ethyl (4-(thiophen-2-yl)-1,2-phenylene)dicarbamate (0.10 g, 0.28 mmol, 1.0 equiv.) in MeOH (2 mL) at 0° C. was added a 4M solution of HCl in dioxane (1.5 mL). The reaction was warmed to room temperature and stirred for 2 h, The reaction was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added. The obtained solid was filtered, washed with water and dried. The crude material was purified by column chromatography (silica gel, 15% EtOAc/hexanes) to give ethyl (2-amino-5-(thiophen-2-yl)phenyl)carbamate (0.05 g, 69% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](S(Cl)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[F:13][C:14]([F:32])([F:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=1>N1C=CC=CC=1>[F:32][C:14]([F:13])([F:31])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCCN3)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(N2CCCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 25 °C

Procedure:
582 mg of commercially available 4-cyano-benzenesulfonyl chloride were dissolved in 5 ml pyridine. Then 400 mg 6-(4-Trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline were added and the mixture was stirred at room temperature for thirty minutes. Then 290 mg of commercially available 4-cyano-benzenesulfonyl chloride were added and the mixture was stirred at room temperature for additional two hours. Then the solvent was removed in vacuo and the residue was purified by chromatography on silica gel to obtain 307 mg of 4-[6-(4-Trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-benzonitrile.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][C@@H:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([O:28][CH:29]([O:31][CH2:32][CH3:33])[CH3:30])[C:17]4([CH3:35])[CH3:34])=[CH:11][CH2:10]1)[CH3:8])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:32]([O:31][CH:29]([O:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@@H:7]([OH:6])[CH3:8])[CH2:10][CH:11]=4)[C:17]1([CH3:35])[CH3:34])[CH3:30])[CH3:33]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)O[Si](C)(C)C(C)(C)C)[C@@]1(C)CC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)O)[C@@]1(C)CC3
Yield: 89.7 %

Procedure:
xvi)—A solution of (3β,5α,20S)-20-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-diene (16; 7.40 g) in a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (42 ml) was stirred at room temperature for 24 h. The reaction mixture was poured into water and the product was extracted into ethyl acetate. The combined organic phases were washed with brine and concentrated under reduced pressure. Column chromatography afforded (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-dien-20-ol (compound 17; 5.21 g).
Reaction SMILES: C(O)(=O)C(O)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[NH2:19])=[CH:10][CH:9]=1.C1CCN2C(=NCCC2)CC1.[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[NH:19][S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])=[CH:12][CH:13]=1
Reactant: NC1CCCC1c1ccc(Cl)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(4-chloro-phenyl)-cyclopentylamine oxalate salt (200 mg, 0.70 mmol), methylene chloride (5.0 mL) and the solution was cooled to 0° C. DBU (0.84 mL, 5.60 mmol) and isopropylsulfonyl chloride (0.47 mL, 4.20 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 116 mg (55%) of the purified title compound. The nmr was consistent with the assigned structure.
Reaction SMILES: [CH:1]([C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1)=O.[CH3:26][NH2:27]>ClCCl.CO.C(O)C>[CH3:26][N:27]=[CH:1][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1
Reactant: O=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reactant: CN
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CN=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reaction time: 24 h

Procedure:
2.0 g (5.9 mmol) of 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine is dissolved in 100 ml of a 1:1 mixture of dichloromethane-methanol, mixed with 40 ml of a 33% solution of methylamine in ethanol and allowed to stand for 24 hours at room temperature. Then, the solvent is drawn off, and the residue is boiled with 25 ml of ethanol. After filtration, 1.95 g (93%) of the title compound with a melting point of 245-247° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH2:14][CH2:13][N:12](S(C2C=CC(C)=CC=2)(=O)=O)[N:11]=1.[O-]CC.[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1
Reactant: COc1ccccc1NC1=NN(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1Nc1cc[nH]n1

Procedure:
The product of step (a) (7.5 g) was added to a solution of sodium ethoxide (60 ml, prepared from 0.6 g sodium), at a temperature of 60°. The mixture was refluxed for 10 minutes, cooled, added to water, extracted with ethyl acetate, dried and evaporated to give the sub-title compound as a purple oil, ms 189 (M+).
Reaction SMILES: [C:1]([NH:3][C:4](=[NH:12])OC1C=CC=CC=1)#[N:2].[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.NC(=N)O.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([NH:3][C:4](=[NH:12])[NH:23][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)#[N:2]
Reactant: N#CNC(=N)Oc1ccccc1
Reactant: NC1CCCc2ccccc21
Agent: N=C(N)O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N#CNC(=N)NC1CCCc2ccccc21
Reaction time: 30 h

Procedure:
A mixture of 1.3 g of N-cyano-O-phenylisourea and 1.2 g of 1,2,3,4-tetrahydro-1-naphthylamine in 5 ml of chloroform was heated at reflux in an oil bath. Disappearance of the isourea was monitored by thin layer chromatography analysis. After 30 hours, the resulting thick solution was treated with 5 ml of toluene and allowed to stand at room temperature which resulted in the crystallization of the desired product. The supernatant solution was withdrawn and the product washed with toluene (10 ml). Upon drying under vacuum, 0.91 g of the desired compound was obtained. A second crop of crystals was collected after concentrating the mother liquor slightly. Total yield of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)guanidine was 1.29 g, mp 153°-155° C.
Reaction SMILES: [Na].[SH:2][C:3]1[NH:4][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[CH2:18](I)[CH2:19][CH3:20]>CO>[CH2:18]([S:2][C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=1)[CH2:19][CH3:20]
Reactant: CCOC(=O)c1nc(S)[nH]c1C(=O)OCC
Reactant: CCCI
Agent: [Na]
Solvent: CO
Product: CCCSc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (0.253 g, 11 mmol) was dissolved in anhydrous methanol (150 mL) with ice-bath cooling. The ice-bath was removed after all the sodium had reacted and diethyl 2-mercapto-4,5-imidazoledicarboxylate prepared in accord with the second paragraph of Example XI (2.44 g, 10 mmol) was added. The appropriate n-propyl iodide (11 mmol) was added and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 hour. A second aliquot of n-propyliodide (3.52 mmol) was added and the solution was stirred for an additional 3 hours. The reaction mixture was concentrated to dryness in vacuo. The residue was partitioned between dichloromethane-water (5:1). The organic layer was separated, dried (sodium sulfate), filtered and concentrated to dryness in vacuo to give the captioned product as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[N:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Nc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-acetamide I-5a (58.6 mg, 0.34 mmol) and piperazine-1-carboxylic acid tert-butyl ester (636 mg, 3.42 mmol) in ethanol (2 mL) was stirred at reflux for 24 h. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with 0.1M HCl (3×35 mL), brine, dried (Na2SO4), filtered, and evaporated to dryness. The crude residue was purified by preparative TLC using ethyl acetate as the eluant to afford the title compound I-5b (36.9 mg).
Reaction SMILES: [C:1](Cl)(=[O:17])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na].[CH3:20][N:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH:24]([OH:29])[CH2:23][C:22]1([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[C:1](=[O:17])([O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:29][CH:24]1[CH2:23][C:22]([CH3:30])([CH3:31])[N:21]([CH3:20])[C:26]([CH3:28])([CH3:27])[CH2:25]1
Reactant: CCCCCCCCCCCCCCOC(=O)Cl
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)OC1CC(C)(C)N(C)C(C)(C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
27.7 g (0.1 mol) of tetradecyl chlorocarbonate are added slowly to a solution of 19.3 g (0.1 mol) of the sodium salt of 1,2,2,6,6-pentamethyl-4-piperidinol in 150 ml of toluene, maintaining the temperature at 0° C. After the end of the addition, the mixture is stirred for 2 hours at ambient temperature, washed with water, dried over Na2SO4 and evaporated. The residue is distilled in vacuo. The product obtained has a boiling point of 172°-174° C./0.3 mbar and solidifies with melting point 32°-34° C.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.C[N:29](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:26])([F:27])[F:25])(=[O:16])=[O:17])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:29])=[O:13])=[CH:8]2
Reactant: CN(C)C=O
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 98 %

Procedure:
To a mixture of 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carboxylic acid (2.65 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (1.3 g) and N,N-dimethylformamide (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.7 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with ethyl acetate-hexane to give the title compound (2.6 g, yield 98%) as colorless crystals. MS: 398(MH+). melting point: 223-224° C.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23]O)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CCOP([O-])OCC
Reactant: CCCC[C@@H](CO)NS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[C@@H](CP(=O)(OCC)OCC)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
Diethyl phosphite (8.9 ml., 69 mmole) is dissolved in dry tetrahydrofuran (125 ml.) under argon in a 250 ml. round-bottomed flask equipped with a condenser. Sodium hydride (2.4 g.) is added in small portions with frothing and bubbling. When the evolution of hydrogen ceases, the reaction mixture is heated to reflux for 45 minutes. It is then cooled to room temperature, and a solution of (S)-2-[[(4-methylphenyl)sulfonyl]amino]-1-hexanol, 4-methylbenzenesulfonate ester (18.1 mmole) is added dropwise over 5 minutes. A white solid precipitates. The mixture is then heated to reflux for 3.5 hours. It is cooled and partitioned between ethyl acetate and 5% potassium bisulfate. The ethyl acetate layer is washed with 5% potassium bisulfate, saturated sodium bicarbonate, and brine, and then concentrated in vacuo. The resulting gum is triturated with hexane to give 6.45 g. of beige solid (S)-[2-[[(4-methylphenl)sulfonyl]amino]hexyl]phosphonic acid, diethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH:15]([C:18]1[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24](Cl)=O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16].N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54]>C(OCC)(=O)C>[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54].[CH:15]([C:18]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:23]/[C:24]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:27][CH:28]=1)([CH3:17])[CH3:16]
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: CC(C)c1ccc(C=CC(=O)Cl)cc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and 4-isopropylcinnamoyl chloride (Perkin, W. H. J. Chem. Soc., 1877, 31, 388) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[CH:8][C:7]([CH3:15])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:2])=[O:16]
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 1D and 3B. MS m/z 477 (M+1).