Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C@@H:9]2[CH2:11][O:10]2)[CH:2]=1.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:17][CH:16]=1>>[OH:10][C@H:9]([CH2:8][O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:19][CH:20]=1
Reactant: c1cncc(OC[C@@H]2CO2)c1
Reactant: NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1
Product: O=S(=O)(Nc1ccc(CCNC[C@H](O)COc2cccnc2)cc1)c1ccccc1

Procedure:
In a manner analogous to that of Example 7, the title compound was prepared from the epoxide from Example 162 and N-[4-(2-aminoethyl)phenyl]benzenesulfonamide (Example 6). Purification by preparative thin layer chromatography on silica gel (eluant 90:10:2 methylen chloride/methanol/30% ammonium hydroxide) gave the title compound. 1H NMR (400 MHz, CD3OD) δ8.23 (d, 1H, J=4Hz), 8.12 (dd, 1H, J=2.4Hz), 7.71(d, 2H, J=8Hz), 7.52 (m, 1H), 7.40-7.48 (m, H), 7.35 (m, 1H), 7.09 (d, 2H, J=10Hz), 7.00 (d, 2H, J=10Hz), 3.95-4.08 (m, 3H), 2.69-2.90 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[OH:9]O>CO>[C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccncc1
Reactant: OO
Solvent: CO
Product: N#Cc1cc[n+]([O-])cc1
Reaction time: 24 h

Procedure:
This example illustrates the use of catalytic activity of the product obtained in Example 1. A typical oxidation of substituted pyridine to substituted pyridine N-oxide was carried out as follows. 0.5 g. of the material obtained according to example 1, (x=0.064) were added to a mixture containing 10.0 g 4-Cyano pyridine and 40 ml methanol under stirring. The temperature of this reaction mixture was kept at 60° C. and then 19.8 g. of H2O2 (30%) were added drop wise to the reaction mixture under stirring. The progress of the reaction followed by Thin Layer Chromatography. Then this reaction was carried out for 24 hours. Once the reaction was complete the catalyst was removed by filtration and the solvent was distilled off under vacuum. The isolated product by this procedure contained, exclusively the corresponding N-oxide is observed from the 1HNMR and mass spectra. 4-Cyanopyridne gave 9.6 g of coresponding 4-Cyanopyridine N-oxide without any trace of byproduct.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:15]([C:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: OC1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: OC1(Cc2ccccc2)CCNCC1

Procedure:
A mixture of N-benzyl-4-benzyl-4-piperidinol (2.0 g, 7.1 mmol) and 10% palladium on charcoal catalyst (0.5 g) in absolute ethanol (100 ml), was stirred vigorously at 40° C. under a balloon of hydrogen for 5 h. The reaction mixture was then filtered through a pad of Celite and the filtrate concentrated in vacuo to a grayish solid. This material was dissolved in methanol and filtered a second time through Celite and the filtrate concentrated in vacuo to the product, a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:6][C:7](=[O:24])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][CH:20]=[N:19][CH:18]=2)=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:9])([CH3:5])[CH3:4].[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.ClCCl>[CH3:23][O:22][C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][CH2:25][C:26]2[CH:33]=[CH:32][C:29]([CH3:30])=[CH:28][CH:27]=2)=[O:24])[CH:16]=[CH:15][C:14]=1[C:17]1[O:21][CH:20]=[N:19][CH:18]=1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CN)ccc1-c1cnco1
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CNCc2ccc(C)cc2)ccc1-c1cnco1

Procedure:
30 mg (0.09 mmol) of N-(2-amino-1,1-dimethyl-ethyl)-N′-(3-methoxy-4-oxazol-5-yl-phenyl)-oxalamide, 11.3 mg (0.095 mmol) of 4-methylbenzaldehyde and 30 mg (0.14 mmol) of sodium triacetoxyborohydride were dissolved in 2 ml of a 5% acetic acid dichloromethane mixture for 16 hours. The reaction mixture was then diluted with 8 ml of dichloromethane and washed with water, saturated sodium hydrogen carbonate and brine. The resulting organic solution was then dried with magnesium sulphate, filtered and evaporated to give N-[3-methoxy-4-(5-oxazolyl)phenyl-N′-[2-(4-methylbenzylamino)-1,1-dimethylethyl]oxalamide as a yellow solid MS: m/e 437.3 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].[CH3:8][CH2:9][Mg+].[Br-].B(F)(F)F.CCOCC.[OH-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([NH2:7])[CH2:9][CH2:8]1
Reactant: N#Cc1ccco1
Reactant: CC[Mg+]
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1(c2ccco2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-furonitrile (5 g, 53.71 mmol, 1.0 eq) in dry THF under an argon atmosphere was added slowly titanium isopropoxide (18.9 ml, 64.4 mmol, 1.2 eq) at r.t. The reaction mixture was stirred for 15 min. A 1M solution of EtMgBr in THF (129 ml, 129 mmol, 2.4 eq) was added slowly via syringe to the mixture at 0° C. After addition, the reaction mixture was allowed to warm to r.t. and stirred at r.t. for 2 hour. BF3.Et2O (10.4 ml) was then added slowly to the mixture at 0° C. After the completion of addition, the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was added with ice, and then with 10% NaOH solution slowly till the reaction mixture becomes basic. The mixture was extracted with EtOAc. The organic was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 35% EtOAc/Pet ether as eluent. Yield: 2.5 g (crude).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[C:8]([C:13]([NH2:15])=[O:14])=[N:9][CH:10]=[CH:11][N:12]=1.[N+:16]([O-])([O-:18])=[O:17].[K+].[OH-].[Na+]>O>[OH:6][C:7]1[C:8]([C:13]([NH2:15])=[O:14])=[N:9][C:10]([N+:16]([O-:18])=[O:17])=[CH:11][N:12]=1
Reactant: NC(=O)c1nccnc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1nc([N+](=O)[O-])cnc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.4 %

Procedure:
Into 1.2 L of 97% sulfuric acid was added and dissolved 208.0 g of 3-hydroxy-2-pyrazinecarboxamide, while keeping the solution at 10-25° C. by cooling it with ice. To the solution thus obtained was added 185.0 g of potassium nitrate at 30-35° C., and the mixture thus obtained was stirred at room temperature for 15 hours and then at 40° C. for 2 hours. After cooling the reaction mixture to 20° C., it was poured into 6 L of ice water and stirred at room temperature for one hour, and the deposited matter was collected by filtration and washed with two 500 mL portions of water. The solid product thus obtained was suspended in 1 L of water, pH was adjusted to 1.5 with 5 mol/L aqueous solution of sodium hydroxide, and then the solid matter was collected by filtration. The solid was washed successively with 500 mL of water and 500 mL of acetone to obtain 180.0 g of 3-hydroxy-6-nitro-2-pyrazinecarboxamide as a solid product.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].C(=O)(O)[O-].[Na+].[CH3:17][CH:18](O)[CH3:19]>Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH:18]([CH3:19])[CH3:17])=[O:10]
Reactant: O=C(O)Cc1ccccn1
Reactant: CC(C)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)OC(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In a solution of 355 mg of 2-pyridylacetic acid hydrochloride in 5 ml of 2-propanol, hydrogen chloride was saturated at 0° C., and the solution was stirred for 10 hours at room temperature. Sodium bicarbonate was added to the reaction mixture to make alkaline, and the solution was extracted with 50 ml of diethyl ether. The ethereal layer was washed successively with water and a suturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 305 mg of isopropyl 2-pyridylacetate as an oil.
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>C(O)C(F)(F)F>[ClH:1].[I:2][C:3]1[C:4]2[NH:9][C:16]3[CH2:17][CH2:18][NH:13][CH2:14][C:15]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1I
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O
Product: Ic1cccc2c3c([nH]c12)CCNC3
Reaction time: 3 h
Yield: 84.8 %

Procedure:
1-(2-Iodophenyl)hydrazine hydrochloride (1.67 g, 6.2 mmol) and 4-piperidone monohydrate hydrochloride (0.952 g, 6.2 mmol) were dissolved in trifluoroethanol (15 mL) and concentrated hydrochloric acid (5 mL) and heated at 87° C. and stirred for 3 h. The solid was filtered, washed with cold isopropyl alcohol (50 mL), and dried to give 6-iodo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (1.76 g, 85%) as a tan solid. 1H NMR (CD3OD, 300 MHz) δ 7.49 (d, 1H, J=7.7 Hz), 7.43 (d, 1H, J=8 Hz), 6.82 (t, 1H, J=7.7 Hz), 4.40 (s, 2H), 3.60 (t, 2H, J=6.25 Hz), 3.18 (t, 2H, J=5.85 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH2:25]([NH-:29])[CH2:26][CH2:27][CH3:28]>>[CH2:25]([NH:29][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[CH2:26][CH2:27][CH3:28]
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Reactant: CCCC[NH-]
Product: CCCCNC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride is reacted with butyl amide to produce 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl amide, m.p. 178° C.; and
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[Na].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Nc1nc(N)nc(OCc2ccccc2)n1
Temperature: 130 °C

Procedure:
2,4-Diamino-6-chloro-s-triazine (2.25 g, 15.0 mmol) was added to a solution of sodium (0.43 g, 18.8 mmol) in benzyl alcohol (30 mL) under argon. The suspension was heated in a 130° C. oil bath for 3.5 h. The excess benzyl alcohol was removed under vacuum and the resulting solid was collected with the aid of benzene, and washed with water (100 mL): yield, 1.83 g (56%); mp 184-185° C. (lit. 186-188° C.; Wakabayashi et al. Nippon Dojo-Hiryogaku Zasshi, 41, 193-200 (1970) ); UV (pH 1) λmax 233 nm (sh) (ε=0.589×104); (pH 6.9) 238 (sh) (0.111×104); (pH 13) 240 (sh) (0.073×104); 1H NMR δ 5.25 (s, 2H, ArCH2), 6.63 (s, 4H, NH2, exchange with D2O), 7.30-7.42 (m, 5H, ArH); MS (EI) calcd. m/z for C10H11N5O 217.0963, found 217.0955.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of maleic acid (0.58 g) in 2-propanol (35 ml) with stirring at room temperature. The mixture is stirred for 3 hours at room temperature and concentrated at vacuum to give the title compound.
Reaction SMILES: [Li+].[CH3:2]CC[CH2-].[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]([CH3:2])=[CH2:6])[CH:10]=1
Reactant: [CH2-]CCC
Reactant: CC(=O)c1cccc(Br)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Methyltriphenylphosphonium bromide (35.7 g, 97.9 mmoles, 1.3 equiv) is suspended in tetrahydrofuran (100 mL) and cooled to 0° C. N-Butyllithium (2.5M in hexanes, 27.0 g, 97.7 mmoles, 39.2 mL, 1.3 equiv) is added slowly to the mixture via an addition funnel. The resulting solution is stirred for 1 h at 0° C. A solution of 3-bromoacetophenone (15.0 g, 75.3 mmoles, 10.0 mL, 1.0 equiv) in tetrahydrofuran (50 mL) is added slowly via an addition funnel. The resulting mixture is warmed to room temperature and stirred for 3 h. The reaction is cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution. The layers are partitioned in a separatory funnel and the aqueous phase is extracted with hexanes. The combined organic phase is dried over anhydrous sodium sulfate, filtered, and allowed to stand overnight at room temperature. The organic phase is decanted from a precipitate and concentrated under reduced pressure. The resulting solid is diluted with hexanes and filtered. The precipitate is washed with hexanes. The filtrate is concentrated and the resulting mixture is purified by silica gel flash column chromatography (hexanes) to give the title compound (83% yield): 1H NMR (CDCl3, 400 MHz) δ 7.59 (t, 1H, J=1.72 Hz), 7.40-7.36 (m, 2H), 7.18 (t, 1H, J=8 Hz), 5.36 (s, 1H), 5.12-5.10 (m, 1H), 2.13-3.11 (m, 3H).
Reaction SMILES: [C:1]([CH:3]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].N>CO.[OH-].[OH-].[Pd+2].[Ni]>[NH2:2][CH2:1][CH:3]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C#N)c2ccc(C(F)(F)F)cc2)CC1
Agent: [Ni]
Agent: [Pd+2]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(CN)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
A solution of Intermediate (51.1) (2000.0 mg; 5.46 mmol; 1.00 eq.) in 50 ml of methanol was surged on H-Qube through 20% Pd(OH)2 cartridge at 1.5 ml/min and RT for one cycle. LCMS showed a clean product as tert-butyl 4-(cyano(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carboxylate. 10 ml of 7.0N NH3 in methanol was added to the above solution and the solution was then placed on H-Qube through Raney Ni column as cartridge at 1.5 ml/min and 45° C. for one cycle. LCMS showed clean reaction of reducing nitrile. The reaction mixture was concentrated to afford tert-butyl 4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)-piperidine-1-carboxylate, which was added 10 ml of 4.0M HCl in dioxane and stirred at RT for 4 hr. The precipitate was collected by filtration to yield the title compound as white solid (1600 mg, yield 77.7%). LC-MS: (M+1=273, obsd.=273).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([NH:13][C:14](=[O:33])[C@@H:15]([C@H:18]3[C@@H:23]([OH:24])[C@@H:22](/[CH:25]=[CH:26]/[C:27]([CH3:30])([CH3:29])[CH3:28])[O:21]C(C)(C)[O:19]3)[O:16][CH3:17])[CH2:8][CH2:7][C:6]=2[CH:34]=1.[OH-].[Na+]>C1COCC1.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([NH:13][C:14](=[O:33])[C@H:15]([O:16][CH3:17])[C@H:18]([OH:19])[C@@H:23]([OH:24])[C@H:22]([OH:21])/[CH:25]=[CH:26]/[C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:8][CH2:7][C:6]=2[CH:34]=1
Reactant: CO[C@@H](C(=O)NC1CCc2cc(Br)ccc2NC1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)NC1CCc2cc(Br)ccc2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C

Procedure:
150 mg of 12 (258 μmol) in 1.4 ml of THF and 2.78 ml of 1N hydrochloric acid are introduced into a 25 ml round-bottomed flask, with agitation and under argon. The agitation is maintained for 4.5 h at AT. The medium is neutralized with NaOH (1N), to pH 7, and extracted with 2 times 3 ml of EtOAc. The combined organic phases are dried over MgSO4, filtered and evaporated to dryness. The crude is chromatographed on a silica cartridge (10 g), elution being carried out with CH2Cl2/MeOH (as an MeOH gradient of 1 to 10%). 65 mg of expected product Ex3 are recovered. 40 mg of Ex3 are separated by preparative chiral HPLC (Chirapad AD-H 5 μm 250×4.6 mm, flow rate 1 ml/min, mobile phase: 50% heptane-50% EtOH, 0.1% TEA), to give 9 mg of Ex3a (tr=7.48 min) and 20 mg of Ex3b (tr=9.71 min).
Reaction SMILES: FC(F)(F)C1C=CC=CC=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6].Cl.FC(F)(F)C1N=CC(N[C@H]2CCC[C@@H]2N)=NC=1.[CH:48]1([C:51]2[C:52](C(O)=O)=[N:53][CH:54]=[CH:55][CH:56]=2)[CH2:50][CH2:49]1>>[CH:48]1([C:51]2[C:52]([C:5]([NH:7][C@H:8]3[CH2:12][CH2:11][CH2:10][C@@H:9]3[NH:13][C:14]3[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)=[O:6])=[N:53][CH:54]=[CH:55][CH:56]=2)[CH2:50][CH2:49]1
Reactant: O=C(O)c1ncccc1C1CC1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1C(F)(F)F
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1C1CC1

Procedure:
Prepared according to the procedure for 2-(trifluoromethyl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 62) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.30 mmol) and 3-cyclopropylpyridine-2-carboxylic acid (Intermediate 16; 50 mg, 0.31 mmol) to afford the title compound.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[C:40]1[C:49]2[C:44](=[CH:45][C:46]([S:50](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:52])=[O:51])=[CH:47][CH:48]=2)[CH:43]=[CH:42][N:41]=1>C1COCC1.[Cl-].[NH4+].C(Cl)Cl.C(O)(C(F)(F)F)=O.CO>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=1[C:40]1[C:49]2[C:44](=[CH:45][C:46]([S:50]([NH:6][C:7]3[S:11][N:10]=[CH:9][N:8]=3)(=[O:51])=[O:52])=[CH:47][CH:48]=2)[CH:43]=[CH:42][N:41]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (50.3 mg, 0.200 mmol) and THF (1 mL) to give a clear, light-orange solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a suspension. Lithium bis(trimethylsilyl)amide (1M in THF) (200 μl, 0.200 mmol) was added dropwise. After about 5 min, a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (INTERMEDIATE LLL; 100 mg, 0.182 mmol) in THF (0.5 mL with a 0.25 mL syringe/vial wash) was added drop wise. After another 2 min, the flask was placed in an ice-water bath. The mixture was stirred for another 20 min, then diluted with saturated aq ammonium chloride and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g column, 10 to 50% EtOAc/Heptane). The desired product was collected with some of the excess amine to give a white foam. The solid was taken up in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with methanol and concentrated. The crude product was purified by chromatography on silica gel (12-g column, 0 to 10% MeOH/DCM) to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (56.9 mg, 0.122 mmol, 67.0% yield) as a white powder: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.73 (d, J=5.7 Hz, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.51 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.89 (dd, J=1.9, 8.9 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 7.61-7.43 (m, 3H), 3.75 (s, 3H). m/z (ESI) 467.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[C:5]=1[CH3:16].[N+:17]([O-])([OH:19])=[O:18].C(=O)([O-])O.[Na+]>>[CH3:2][NH:3][C:4]1[C:9]([N+:17]([O-:19])=[O:18])=[C:8]([CH3:10])[C:7]([O:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[C:5]=1[CH3:16]
Reactant: CNc1cc(C)c(OC(C)=O)c(C)c1C
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1c(C)c(C)c(OC(C)=O)c(C)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.3 g of N-methyl-4-acetoxy-2,3,5-trimethylaniline hydrochloride [prepared as described in step (h) above] were added to ice-cooled concentrated aqueous nitric acid, and the resulting mixture was stirred, whilst ice-cooling, for 10 minutes and then at room temperature for 10 minutes. At the end of this time, the reaction mixture was poured into ice-water and the aqueous mixture was neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, after which 50 ml of diisopropyl ether and 50 ml of hexane were added to the residue. The mixture was then agitated ultrasonically for 5 minutes. Insoluble precipitates were triturated with a 1:1 by volume mixture of diisopropyl ether and hexane. The resulting crystals were collected by filtration, after which they were washed with a 1:1 by volume mixture of diisopropyl ether and hexane to give 2.76 g of the title compound, melting at 143°-146° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[S:25][C:24]([CH3:26])=[N:23][C:22]=4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[Na+].[I-:34]>CC(C)=O.C(Cl)Cl>[I:34][CH2:12][C:13]12[CH2:20][CH2:19][C:16]([C:21]3[S:25][C:24]([CH3:26])=[N:23][C:22]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:17][CH2:18]1)[O:15][CH2:14]2
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Temperature: 85 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A mixture of (1-(2-Methyl-4-phenylthiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (125 mg, 0.266 mmol) and NaI (120 mg, 0.799 mmol) in acetone (5 mL) was stirred in a seal tube at 85° C. for 18 h. The reaction was cooled to rt, diluted with DCM (5 mL), and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 (0-30% EtOAc:hexanes) to afford the title compound (100 mg, 88% yield) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.45-7.34 (m, 5H), 3.79 (s, 2H), 2.96 (s, 2H), 2.66 (s, 3H), 2.12-2.00 (m, 2H), 1.90-1.78 (m, 2H), 1.71-1.51 (m, 4H).