Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[NH:13][CH:12]([C:14]([O:16]C)=O)[CH2:11][S:10]1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[NH:13][CH:12]([C:14]([NH:27][CH2:24][CH2:25][CH3:26])=[O:16])[CH2:11][S:10]1
Reactant: COC(=O)C1CSC(Cn2cncn2)(c2ccc(Cl)cc2Cl)N1
Reactant: CCCN
Solvent: CO
Product: CCCNC(=O)C1CSC(Cn2cncn2)(c2ccc(Cl)cc2Cl)N1
Yield: 39.9 %

Procedure:
1.87 g of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl methyl)-4-methoxycarbonyl thiazolidine (Compound No. 24) prepared in the same manner as in Working Example 2 and 3.0 g of n-propylamine were dissolved in 20 ml of methanol and reacted at a temperature of 60° C. for 1 hour. After distilling off methanol under reduced pressure, the reaction product was purified by silica gel column chromatography using a solvent mixture of chloroform and ethyl acetate as the developer, whereby 0.8 g of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl methyl)-4-(n-propylaminocarbonyl)thiazolidine (Compound No. 46 in Table 1) was obtained.
Reaction SMILES: C(OC([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]1=[O:22])=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[NH2:8][N:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C:10]1=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(N)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A solution of (3S)-1,3-bis(tert-butoxycarbonylamino)-2-pyrrolidone (3.15 g) in methanol (10 ml) was combined with a 4N solution of hydrochloric acid in ethyl acetate (20 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the resultant residue was combined with dichloromethane (30 ml) and triethylamine (6.06 g), and then with di-tert-butyl dicarbonate (2.62 g) at 0° C. and stirred at room temperature for 1 hour. The reaction mixture was combined with an aqueous solution of sodium carbonate, extracted with dichloromethane, dried and concentrated. The residue obtained was washed with hexane to obtain (3S)-1-amino-3-(tert-butoxycarbonylamino)-2-pyrrolidone (1.89 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:18]2[O:32][C@H:31]([CH2:33][O:34]C(C3C(C)=CC=CC=3)=O)[C@@H:20]([O:21]C(C3C(C)=CC=CC=3)=O)[CH2:19]2)[C:4]2[C:9]([C:10]=1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[CH:8][C:7]([Cl:16])=[C:6]([Cl:17])[CH:5]=2.C[O-].[Na+].CO.C(Cl)(Cl)Cl>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:18]2[O:32][C@H:31]([CH2:33][OH:34])[C@@H:20]([OH:21])[CH2:19]2)[C:4]2[C:9]([C:10]=1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[CH:8][C:7]([Cl:16])=[C:6]([Cl:17])[CH:5]=2
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2c(Cl)c(-c3ccco3)c3cc(Cl)c(Cl)cc32)C[C@@H]1OC(=O)c1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)c(-c3ccco3)c3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
2,5,6-Trichloro-3-(2-furyl)-1-(3,5-di-O-toluoyl-2-deoxy-β-D-ribofuranosyl)indole (4.76, 142 mg, 0.22 mmol) was suspended in dry MeOH (10 mL) to which was added sodium methoxide (30 mg, 0.56 mmol). The suspension was stirred at room temperature for 45 min, until the solids were completely dissolved. The solvent was then removed under vacuum, and the residue suspended in brine (50 mL). The aqueous suspension was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over MgSO4, filtered and evaporated to yield a clear oil. The oil was dissolved in CHCl3 (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a pale yellow solid which was recrystallized from 10% MeOH/CHCl3 and hexane to yield 67 mg (75%) of 4.78 as a white crystalline solid: mp 140-141 C; Rf 0.5 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 6.88 (d, 1H), 6.68 (s, 1H), 6.47 (dd, 1H), 5.42 (d, 1H, D2O exch.), 5.23 (s, 1H, D2O exch.), 4.45 (d, 1H), 3.89 (d, 1H), 3.73 (s, 2H), 2.55 (m, 1H), 2.13 (m, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 146.54, 142.25, 132.30, 125.61, 124.39, 124.09, 122.64, 120.75, 114.98, 111.51, 106.91, 104.87, 87.25, 85.04, 69.98, 60.91, 38.97. HRMS (EI) m/z calcd. for C17H14Cl3NO4 400.9988. found 400.9986. Anal calcd for C17H14Cl3NO4.¼H2O: C, 50.15; H, 3.59; N, 3.44. Found: C, 50.17; H, 3.65; N, 3.43.
Reaction SMILES: C([O:3][C:4]([C:6]1([N:9]([CH2:52][CH3:53])[S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1([N:9]([CH2:52][CH3:53])[S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:43][CH:44]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:7][CH2:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1(N(CC)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Yield: 63.4 %

Procedure:
A mixture of 237 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl](ethyl)sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 0.5 mL of a 5.0 M aqueous sodium hydroxide solution, and 2.4 mL of ethanol was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and to the residue were added water, citric acid, dichloromethane, and THF in this order. The organic layer was separated and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol). The obtained crude product was washed with diethyl ether to obtain 142 mg of 4-{2-[4-({[2-({3-[(1-carboxycyclopropyl)(ethyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid as a pale yellow crystal.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C@H:2]([C:17](O)=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[BH4-].[Na+]>>[NH:1]([C:20]([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21])[C@H:2]([CH2:17][OH:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(NCCC[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21)OCc1ccccc1

Procedure:
Commercially available Fmoc-Orn(Z) was converted to the alcohol by reduction of its mixed anhydride with sodium borohydride. After crystallization from EtOAc, the compound was thereafter used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[BrH:12].BrBr>C(O)(=O)C>[Br:12][CH2:10][C:9]([C:6]1[CH:7]=[N:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: CNc1ccc(C(C)=O)cn1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CNc1ccc(C(=O)CBr)cn1
Yield: 63.8 %

Procedure:
380 mg (2.53 mmol) of 1-(6-methylaminopyrid-3-yl)ethanone, 416 μl (2.53 mmol) of hydrobromic acid, 130 μl (2.53 mmol) of bromine and 5 mL of glacial acetic acid were used in the reaction. After precipitation with ethyl ether and filtration, the precipitate is taken up in water. The solution is basified with saturated NaHCO3 solution. The precipitate formed is filtered off, washed with water and then dried under vacuum. 370 mg of 2-bromo-1-(6-methylaminopyrid-3-yl)ethanone are obtained, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][Br:13])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc(Br)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: COC(=O)c1ncc(Br)cc1CBr
Yield: 92.5 %

Procedure:
Methyl 5-bromo-3-methylpyridine-2-carboxylate (800 mg, 3.5 mmol)(Combi-Blocks Cat. No. SS-3016) in methylene chloride (15 mL) was treated with N-bromosuccinimide (620 mg, 3.5 mmol) and AIBN [2,2′-azobis(isobutyronitrile)] (14 mg, 0.087 mmol). The mixture was stirred and irradiated with a 250W tungsten halogen lamp overnight. LCMS showed most starting material was consumed. The mixture was concentration under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (1.0 g). LCMS (M+H)+=309.9.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:3]1.[C:17]1([CH:23]([N:30]=[C:31]=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH:23]([NH:30][C:31]([N:7]1[CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:3][CH:2]1[CH3:1])=[O:32])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1CN(CC2CCN(C)CC2)CC(C)N1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC1CN(CC2CCN(C)CC2)CC(C)N1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
To a solution of 3,5-dimethyl-1-((1-methylpiperidin-4-yl)methyl)piperazine (0.2 g, 1 mmol) dissolved in methylene chloride (5 ml) was added diphenylmethyl isocyanate (0.227 g, 1.09 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.12 g of desired product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH2:8](Br)[CH2:9][CH3:10].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:8]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])[CH2:9][CH3:10]
Reactant: CCCBr
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCNCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
A suspension of glycine methyl ester HCl (5.0 g, 39.8 mmol) in acetonitrile (100 mL) was treated with propyl bromide (3.7 mL, 39.8 mmol), and diisopropylethylamine (13.9 mL, 79.6 mmol). After stirring at room temperature for 1 hour, the mixture was heated at reflux overnight. Solution occurred at reflux temperature. The solvent was removed under reduced pressure and the residue triturated with Et2O/EtOAc. Filtering and removal of the solvent under pressure left 1.13 g of the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (98:2) gave 0.53 g (10.2% yield) of the product as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][CH:9](OC(=O)C)[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[NH:36]1[CH:44]=[C:42]([CH3:43])[C:40](=[O:41])[NH:39][C:37]1=[O:38].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C@@H:9]([N:36]2[CH:44]=[C:42]([CH3:43])[C:40](=[O:41])[NH:39][C:37]2=[O:38])[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of the anomeric mixture 33 (736 mg, 1.51 mmol) and thymine (381 mg, 3.03 mmol) in anhydrous acetonitrile (14.5 cm3) was added N,O-bis(trimethylsilyl)-acetamide (2.61 cm3, 10.6 mmol). The reaction mixture was stirred at reflux for 1 h, then cooled to 0° C. Trimethylsilyl triflate (0.47 cm3, 2.56 mmol) was added dropwise under stirring and the solution was stirred at 65° C. for 2 h. The reaction was quenched with a cold saturated aqueous solution of sodium hydrogen carbonate (15 cm3) and extraction was performed with dichloromethane (3×10 cm3). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogencarbonate (2×10 cm3) and brine (2×10 cm3), and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 34 as a white solid material (639 mg, 76%). δH (CDCl3) 8.98 (1 H, br s, NH), 7.39-7.26 (11 H, m, Bn, 6-H), 6.22 (1 H, d, J 5.3, 1′-H), 5.42 (1 H, t, J 5.4, 2′-H), 4.63-4.43 (5H, m, 3′-H, Bn), 4.41 (1 H, d, J 12.2, 5′-Ha), 4.17 (1 H, d, J 12.1, 5′-Hb), 3.76 (1 H, d, J 10.2, 1″-Ha), 3.51 (1 H, d, J 10.4, 1″-Hb), 2.09 (3 H, s, COCH3), 2.03 (3 H, s, COCH3), 1.53 (3 H, d, J 0.9, CH3). δC (CDCl3) 170.8, 170.4 (C═O), 163.9 (C-4), 150.6 (C-2), 137.4 (C-6) 137.4, 136.1, 128.9, 128.8, 128.4, 128.2, 127.9 (Bn), 111.7 (C-5), 87.2, 87.2, 86.1 (C-1′, C-3′, C-4′), 77.6 (C-2′), 74.8, 73.9, 71.1, 63.8 (Bn, C-1″, C-5′), 20.9, 20.8 (COCH3), 12.0 (CH3). FAB-MS m/z 553 [M+H]+. Found: C, 62.7; H, 5.9; N, 4.7; C29H32N2O9 requires C, 63.0; H, 5.8; N, 5.1%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]2[NH:18][C:19]([S:21][CH2:22][C:23]3[N:28]=[C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=[CH:25][N:24]=3)=[N:20][C:16]=2[CH:15]=1.N>ClCCl>[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]2[NH:18][C:19]([S:21]([CH2:22][C:23]3[N:28]=[C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=[CH:25][N:24]=3)=[O:9])=[N:20][C:16]=2[CH:15]=1
Reactant: COc1ccc2[nH]c(SCc3nccc(N4CCCCC4)n3)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(N4CCCCC4)n3)nc2c1
Yield: 90.2 %

Procedure:
A solution of m-chloroperbenzoic acid (1.69 g) in dichloromethane (25 ml) was added to a stirred solution of 5-methoxy-2-[4-piperidino-2-pyrimidinylmethylthio]-(1H)benzimidazole (3.48 g) in dichloromethane (75 ml) cooled to between -30° and -35°. After 1.5 hours at -20° a further quantity of m-chloroperbenzoic acid (0.34 g) was added. After a further 30 minutes ammonia was passed through the reaction mixture and the precipitated solid filtered off. The filtrate was washed with aqueous sodium carbonate, which was back washed with chloroform. The combined organic phases were dried (K2CO3) stripped and the residue purified by column chromatography (silica gel, 2% MeOH-NH3 /CHCl3) to give 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole (3.28 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 156.7 %

Procedure:
Tert-butyl N-{1-(3-nitrobenzyl)piperidin-4-yl}carbamate (30.0 g, 89.5 mmol, 1.0 eq)) was dissolved in 300 mL of TFA:DCM (1:10) and the resulting solution stirred at 30° C. overnight. The reaction mixture was then concentrated under vacuum to provide crude 1-(3-nitrobenzyl)piperidin-4-amine (33 g, TFA salt) as a white solid.
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:20]([O:27][C:28]([CH:30]([CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:31]P(C)(=O)OCC1C=CC=CC=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH2:1]([P:5]([CH2:31][CH:30]([C:28]([O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29])[CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])(=[O:6])[OH:7])[CH2:2][CH2:3][CH3:4]
Reactant: CP(=O)(CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CCCC[PH](=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCP(=O)(O)CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
Butylphosphinic acid (2.0 g, 16mmol) in 80 mL of dry dichloromethane was cooled to 0C under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture was stirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate (2)(6.4 g, 20 mmol) in 20 mL of dichloromethane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 5% hydrochloric acid. The dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine. The organic layer was dried (MgSO4) and evaporated to give a clear light golden liquid. The liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3,R=n-butyl, R1=H) (2.9 g, 40w) as a clear and colorless oil. Rf 0.12 (3:1, Hex./EtOAc 5% AcOH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-])=O.C(O)C.O.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19]1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCN(Cc2ccccc2)CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1S(=O)(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of 75.0 g (0.2 mol) of 2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide in 2.0 1 ethanol was added dropwise, at room temperature, a solution of 174.0 g (0.828 mol) of sodium dithionite-dihydrate in 700 ml of water. After the heat of the exothermic reaction had died away the mixture was refluxed for 4.5 hours, then the ethanol was distilled off and the aqueous phase remaining was extracted thoroughly with dichloromethane. The combined dichloromethane extracts were dried over sodium sulphate and evaporated down, the residue remaining was purified by column chromatography over silica gel using dichloromethane/methanol/conc. ammonia 80/20/0.25 (v/v/v) as eluant. 6.5 g (8.6% of theory) of a highly viscous oil were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27](O)=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:67][C:68]([F:78])([F:77])[CH2:69][CH2:70][N:71]1[C:75](=[O:76])[CH2:74][NH:73][CH2:72]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:31])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([N:73]4[CH2:74][C:75](=[O:76])[N:71]([CH2:70][CH2:69][C:68]([F:67])([F:77])[F:78])[CH2:72]4)=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C1CNCN1CCC(F)(F)F
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)c3ccccc23)CN1CCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N,N-dimethylformamide (10 mL), 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]naphthalene-1-carboxylic acid (70 mg, 0.14 mmol, 1.00 equiv), HATU (74 mg, 0.19 mmol, 4.00 equiv), DIEA (218 mg, 1.69 mmol, 4.00 equiv), 3-(3,3,3-trifluoropropyl)imidazolidin-4-one (31 mg, 0.17 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC. This resulted in 32 mg (34%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]naphthalen-1-yl)carbonyl]-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a light brown solid. (ES, m/z): 693 [M+41]+; (300 MHz, CD3OD, ppm): δ 8.98-8.95 (m, 1H), 8.04-7.96 (m, 3H), 7.92-7.85 (m, 2H), 7.74-7.65 (m, 3H), 5.26 (s, 1H), 4.88-4.52 (m, 2H), 4.36-4.29 (m, 2H), 3.82 (s, 1H), 3.73 (t, J=6.6 Hz, 1H), 3.50 (t, J=7.5 Hz, 1H), 2.68-2.60 (m, 1H), 2.43-2.37 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]=1[N+:25]([O-:27])=[O:26].[CH:28]1([CH:31]([NH2:34])[CH2:32][CH3:33])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:34][CH:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][CH3:33])[C:12]=1[N+:25]([O-:27])=[O:26]
Reactant: COc1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1C
Reactant: CCC(N)C1CC1
Product: CCC(Nc1nccc(-c2cc(C)c(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 47 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.22 g, 0.51 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine (0.17 g, 1.29 mmol) were treated substantially as described in Part C of Example 19a to produce 90 mg (47%) of crude [4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (EI) m/z 376.18 [(M+H)+, 100].
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(#N)C>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18](=[O:23])[CH2:17][N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[N:4][N+:1]([O-:3])=[O:2]
Reactant: CC(C)(C)C(=O)CCl
Reactant: O=[N+]([O-])N=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)CN1CCNC1=N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A mixture of 2.6 g of 2-nitroimino-imidazolidine, 3.0 g of anhydrous potassium carbonate and 30 ml of dry acetonitrile was stirred at room temperature for 30 minutes. Then, 2.7 g of 1-chloro-3,3-dimethyl-2-butanone were added to the mixture under stirring at room temperature. The reaction mixture was heated and refluxed for 1 hour. The acetonitrile was distilled off under a reduced pressure, and the residue was admixed with water. The aimed product was separated by filtration. The crystalline product was washed in ether and dried. 3.5 g of 1-(3,3-dimethyl-2-butanon-1-yl)-2-nitroimino-imidazolidine were obtained. mp. 158°-159° C.