Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24][C:23](=[O:25])[NH:22][CH:21]2[C:26](O)=[O:27])=[CH:16][CH:15]=1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:26]([CH:21]1[CH:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[S:24][C:23](=[O:25])[NH:22]1)=[O:27])([O-:7])=[O:6]
Reactant: COc1ccc(C2SC(=O)NC2C(=O)O)cc1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: COc1ccc(C2SC(=O)NC2C(=O)NCCO[N+](=O)[O-])cc1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 401 mg of N-(2-nitrooxyethyl)-amine nitrate and 500 mg of 5-(4-methoxyphenyl)-2-oxothiazolidine-4-carboxylic acid, to obtain 408 mg of the title compound as colorless crystals, melting at 142°-143° C. (after recrystallization from methylene chloride).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=O)([OH:3])=[O:2].Cl.[NH2:21]O.C([O-])=O.[Na+].O>C(O)=O>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[C:14]#[N:21])([OH:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccc(O)c(Sc2ccccc2C(=O)O)c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1ccc(O)c(Sc2ccccc2C(=O)O)c1

Procedure:
Reflux 91.3 g of the aldehyde of Step D, 27.4 g of hydroxylamine hydrochloride and 41.9 g of sodium formate in 900 ml of formic acid (98-100%) for 11/4 hours. Cool the mixture and pour into 21/2 1. of cold water. Separate the precipitate, wash with water and dry in vacuo at 75° C. (Yield: 82 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([Si](C)(C)C)=[CH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[C:10]([F:15])=[CH:9][CH:8]=2)[CH3:2].[F-].[Cs+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([F:15])=[C:11]2[F:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(F)c(F)ccc2cc1[Si](C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2ccc(F)c(F)c2c1

Procedure:
44.0 g (about 81.6 mmol) of (3-ethoxy-5,6-difluoronaphthalen-2-yl)trimethylsilane are stirred at 100° C. for 20 h together with 26.3 g (0.17 mol) of caesium fluoride in 300 ml of DMF. After cooling, the mixture is diluted with water and extracted a number of times with MTBE. The combined organic phases are washed with water and sat. sodium chloride soln., and the solution is dried using sodium sulfate. The brown oil remaining after removal of the solvent is purified by column chromatography (SiO2, toluene:ethyl acetate=9:1), giving 7-ethoxy-1,2-difluoronaphthalene as a brown oil.
Reaction SMILES: C[O-].[Na+].[C:4]([O:14]C)(=O)[CH2:5][S:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].Cl>C1COCC1>[CH3:12][O:11][C:9]([CH:8]1[C:4](=[O:14])[CH2:5][S:6][CH2:7]1)=[O:10]
Reactant: COC(=O)CCSCC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CSCC1=O
Temperature: 25 °C
Yield: 38.4 %

Procedure:
To a stirred slurry of sodium methoxide (1.68 g, 31.25 mmol) in dry THF (15 mL) was added a solution of dimethyl 3-thiahexanedioate (5 g, 26.03 mmol) in THF (10 mL) at rt for 5 min. The reaction mixture was heated at reflux for 2 h, cooled to rt and poured into ice cold water and acidified with dil. HCl. The solution was extracted with chloroform and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as pale yellow color oil (1.6 g, 39%).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH:16]1[CH2:19][N:18]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1)(=O)=O>CN(C=O)C>[C:21]1([C:20]([N:18]2[CH2:19][CH:16]([O:7][C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=3[CH3:8])[CH2:17]2)=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2ccccc2)C1
Reactant: Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1OC1CN(C(=O)c2ccccc2)C1
Temperature: 60 °C
Yield: 34.7 %

Procedure:
To a stirred solution of o-cresol (0.16 g, 1.51 mmol) in DMF (10 ml) was added 60% sodium hydride (0.063 g, 1.59 mmol) at room temperature. After 10 min 1-benzoylazetidin-3-yl methanesulfonate (0.50 g, 1.96 mmol) was added and the resulting reaction mixture was heated at 60° C. for 16 h. After this reaction mixture was cooled to room temperature, partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 80:20 to 50:50, heptane/ethyl acetate) to provide a white solid. Trituration of the solid with heptane/ethyl acetate and collection of the resulting solids by filtration provided phenyl(3-(o-tolyloxy)azetidin-1-yl)methanone (0.14 g, 35%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:28](=[O:29])[NH:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=1)[C:9]#[N:10]
Reactant: COc1ccc(N=C=O)cc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C(C#N)C(=O)c2cccn2C)cc1
Reaction time: 8 h

Procedure:
The suspension of 2.0 g of the 1-methyl-β-oxo-2-pyrrolpropionitrile in 50 ml of toluene and 1.6 g of triethylamine is treated with 2.1 g of p-methoxyphenylisocyanate. The mixture is warmed gently until all is dissolved and allowed to stand overnight at room temperature. It is evaporated, the residue is taken up in methanol and combined with 10 ml of 10% aqueous sodium hydroxide and 250 ml of water. The alkaline solution is filtered, acidified with 5 N hydrochloric acid and the precipitate formed collected. It is washed with water, dried, triturated with warm methanol-ethyl acetate, and recrystallized from ethyl acetate, to yield the 1-methyl-β-oxo-α-(p-methoxyphenylcarbamoyl)-2-pyrrolpropionitrile melting at 192°-193°.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[N:25]#[C:26]Br.O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][C:26]([NH2:25])=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH2:23][CH3:24]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(N)=NC2=N1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A partial solution of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.1 g), cyanogen bromide (0.33 g), and sodium acetate trihydrate (0.42 g) in 50% aqueous ethanol (44 ml) was stirred at room temperature for 2 hours then allowed to stand overnight. The stirred mixture was then heated in a water bath (temperature 65° C.) for 3 hours, extra cyanogen bromide (0.05 g) added, and the mixture heated for a further 2 hours. The suspension was subjected to partial evaporation under reduced pressure then ammonium hydroxide was added to pH 5. The crude product was collected by filtration and recrystallised from acetonitrile to give the pure title compound, 0.6 g, m.p. 322-335° C. dec. (after melting about 200° C.). NMR (DMSO-d6; 250 MHz) δ: 0.9 (3H, t) ; 1.6 (2H, m) ; 3.9 (2H, t); 6.8 (2H, s); 6.8 (2H, s); 6.9-7.1 (2H, m); 7.3-7.5 (3H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[H-].[Na+]>CN(C=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C=O)c3ccccc32)cc1
Yield: 109.3 %

Procedure:
Using analogous procedure as those described to prepare intermediate I-38b, 1H-Indole-3-carbaldehyde (10 g, 68.96 mmol) was reacted with 1-(chloromethyl)-4-methoxybenzene (11.26 mL, 82.75 mmol) and 60% NaH (5.5 g, 137.92 mmol) in DMF (140 mL) at room temperature for 1 hour to afford 20 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
A mixture of methyl 4-[({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)methyl]benzoate (step 1, 154 mg, 0.37 mmol), tetrahydrofuran (2 mL), methanol (2 mL), and 2 N sodium hydroxide (2 mL) was stirred at room temperature for 4 h. The mixture was poured into 1N hydrochloric acid (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by TLC [dichloromethane/ethyl acetate (1:2)] to give 98 mg (66%) of the title compound as white solids: 1H-NMR (DMSO-d6) δ 9.13 (1H, t, J=6.0 Hz), 8.29 (1H, dd, J=2.6, 1.5 Hz), 8.22 (1H, dd, J=2.6, 1.5 Hz), 7.88 (2H, d, J=8.1 Hz), 7.47 (2H, d, J=8.1 Hz), 7.29–7.26 (4H, m), 4.60 (2H, d, J=6.0 Hz); MS (ESI) m/z 401 (M+H)+, 399 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[N+:9]([O-:12])([OH:11])=[O:10].[N+:13]([O-])([O:15]C(=O)C)=[O:14].C(OC(C)C)(C)C.[N+]([O-])([O-])=O>C(#N)C>[N+:9]([O-:12])([OH:11])=[O:10].[O:1]([CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[N+:13]([O-:15])=[O:14]
Reactant: CC(=O)O[N+](=O)[O-]
Reactant: OCC1CCNCC1
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: O=[N+]([O-])OCC1CCNCC1
Reaction time: 3 h

Procedure:
5.8 g. 4-Hydroxymethylpiperidine are dissolved in 100 ml. acetonitrile and cooled to -25° C. By the addition of 3.1 ml. 100% nitric acid, the base is converted into the nitric acid salt. To this solution is added a freshly prepared acetyl nitrate solution (prepared from 9.5 ml. acetic anhydride and 4.2 ml. 100% nitric acid in 40 ml. acetonitrile at -25° C.) and the reaction mixture then stirred for 3 hours at this temperature. The reaction solution is diluted with 300 ml. diisopropyl ether. The crystals obtained are filtered off with suction and washed with diethyl ether. There are obtained 9.5 g. (82% of theory) of the nitrate of the title compound; m.p. 64°-65° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH:3]=1.C([O-])(=O)C.[Na+].[I:30]Cl>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:3]=1[I:30]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)c(I)c(N)c2F)c1F
Temperature: 80 °C
Yield: 42.3 %

Procedure:
Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (600 mg, 1.682 mmol) was dissolved in acetic acid (5.6 mL). Sodium acetate (1.5 g, 18.50 mmol) was added followed by iodine monochloride (2.2 g, 13.45 mmol). An exotherm of approximately 10° C. was observed during the addition. The reaction mixture was heated at 80° C. for 20 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with water, satd aq NaHCO3 solution, dried (MgSO4) and then concentrated to dryness. The residue was applied to a silica gel column (80 g) then eluted (0-70% acetone-hexanes gradient) to give an orange solid (343 mg, 42%): mp 134-135° C.; 1H NMR (400 MHz, acetone-d6) δ 7.41 (dd, J=8.5, 1.6 Hz, 1H), 7.33 (dd, J=8.5, 6.8 Hz, 1H), 6.29 (s, 2H), 5.29-5.14 (septet, 1H), 3.98 (d, J=1.1 Hz, 3H), 1.37 (d, J=6.3 Hz, 6H); EIMS m/z 396.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:1][C:2]2[CH:18]=[CH:17][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=3)=[CH:4][CH:3]=2)=[O:28])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (52.3 kg, 215 mol) is suspended in ethyl acetate (146 kg) and the suspension is heated to approx. 40° C. 4-Chloro-3-trifluoromethylphenyl isocyanate (50 kg, 226 mol), dissolved in ethyl acetate (58 kg), is then added to such a degree that the temperature is kept below 60° C. After cooling to 20° C. within 1 h, the mixture is stirred for a further 30 min and the product is filtered off. After washing with ethyl acetate (30 kg), the product is dried under reduced pressure (50° C., 80 mbar). 93 kg (93% of theory) of the title compound are obtained as colorless to slightly brownish crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=[C:5]2[C:4]1=O)[CH3:2].[BH4-].[Li+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([CH2:16][OH:17])[N:15]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn2c(n1)c(=O)n(CC)c1ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCN1Cc2nc(CO)cn2-c2ccccc21
Reaction time: 20 h
Yield: 76.7 %

Procedure:
A mixture of 3.13 g of ethyl 4,5-dihydro-5-ethyl-4-oxo-imidazo-[1,2-a]-quinoxaline-2-carboxylate, 0.5 g of lithium borohydride and 80 ml of anhydrous tetrahydrofuran was refluxed with stirring for 20 hours and the resulting suspension was poured into dilute hydrochloride acid. The mixture was stirred for 10 minutes to break the boron complex and the pale yellow clear solution was made alkaline with sodium carbonate addition. The mixture was extracted with ethyl acetate and the organic phase was evaporated to dryness to obtain 1.93 g of 4,5-dihydro-5-ethyl-imidazo-[1,2-a]-quinoxaline-2-methanol in the form of a buff crystalline solid which was crystallized from ethanol to obtain shiny white plates melting at 160°-165° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[N:5]=[C:4]([OH:12])[N:3]=1.[H][H]>CO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([OH:12])=[N:5][C:6]=1[CH3:11]
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nc(O)nc(C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
Compound 1 (1.0 g), 5% Pd—C (131 mg) were suspended in methanol (60 mL). Evacuation and replacement with hydrogen were repeated three times. Subsequently, the suspension was vigorously stirred at room temperature (20 to 30° C.) for 8 hours under hydrogen atmosphere. After the reaction was completed, the mixture was filtered through Celite and the filtered product was washed with methanol. The filtrate was evaporated under reduced pressure to give 853 mg of a crude desired product of Compound 3 as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]([N:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH3:19])(=[O:17])[CH3:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N:18]([C:15](=[O:17])[CH3:16])[CH3:19])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Amino-1-benzylpiperidine (3.63 ml, 17.8 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (4.00 g, 16.2 mmol) prepared in Preparative Example 12 and sodium acetate (2.65 g) in ethanol (40 ml). The obtained mixture was stirred at room temperature for 4 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-(1-benzyl-4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless viscous oil. This oil was dissolved in 4N aqueous hydrochloric acid and the obtained solution was heated under reflux for 3 hours. The resulting mixture was concentrated to give a solid residue. This residue was recrystallized from ethyl acetate to give the title compound as a white crystal (highly hygroscopic one) (5.80 g, overall yield of two steps: 80%). m.p. (°C.): amorphous (highly hygroscopic)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[CH3:19][N:20]([CH3:37])[CH2:21][CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]([CH2:22][CH2:21][N:20]([CH3:37])[CH3:19])[C:24]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc2ccccc2n1CCN(C)C
Reactant: OC(c1ccccc1)c1ccc(OCCCl)cc1
Product: CCOC(=O)c1c(C(c2ccccc2)c2ccc(OCCCl)cc2)c2ccccc2n1CCN(C)C
Yield: 81.3 %

Procedure:
Substantially the same procedure as in Reference Example 5 was repeated using 4-(2-chloroethoxy)benzhydrol (17.66 g, 67.2 mmol) and ethyl 1-(2-dimethylaminoethyl)indole-2-carboxylate (19.2 g, 73.9 mmol) to give 27.6 g (yield: 81%) of the title compound.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[C@H:69]12[CH2:75][C@@H:72]([CH2:73][CH2:74]1)[C@@H:71]([C:76]1[NH:80][C:79]3[CH:81]=[C:82]([C:85]4[CH:97]=[C:96]5[C:88]([C:89]6[CH:90]=[CH:91][C:92]([C:100]7[NH:104][C:103]([C@@H:105]8[CH2:109][CH2:108][CH2:107][N:106]8[C:110](=[O:121])[C@@H:111]([NH:116][C:117](=[O:120])[O:118][CH3:119])[C@H:112]([O:114][CH3:115])[CH3:113])=[N:102][CH:101]=7)=[CH:93][C:94]=6[C:95]5([F:99])[F:98])=[CH:87][CH:86]=4)[CH:83]=[CH:84][C:78]=3[N:77]=1)[NH:70]2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:70]1[C@H:71]([C:76]2[NH:80][C:79]3[CH:81]=[C:82]([C:85]4[CH:86]=[CH:87][C:88]5[C:89]6[C:94](=[CH:93][C:92]([C:100]7[NH:104][C:103]([C@@H:105]8[CH2:109][CH2:108][CH2:107][N:106]8[C:110](=[O:121])[C@@H:111]([NH:116][C:117]([O:118][CH3:119])=[O:120])[C@H:112]([O:114][CH3:115])[CH3:113])=[N:102][CH:101]=7)=[CH:91][CH:90]=6)[C:95]([F:99])([F:98])[C:96]=5[CH:97]=4)[CH:83]=[CH:84][C:78]=3[N:77]=2)[C@H:72]2[CH2:75][C@H:69]1[CH2:74][CH2:73]2)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@H]6N[C@@H]7CC[C@@H]6C7)[nH]c5c4)ccc2-3)[nH]1)[C@@H](C)OC
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6[C@@H]7CC[C@H](C7)N6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)[nH]1)[C@@H](C)OC

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (2S,3R)-1-((S)-2-(5-(7-(2-((1R,3S,4R)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 913.69 [M+H]+. (93 mg, 57%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[O:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][OH:35].Cl.NO>O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[OH:35][NH:34][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12])=[O:21]
Reactant: O=C(O)CCCCCNC(=O)c1ccc2ccccc2c1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCCCNC(=O)c1ccc2ccccc2c1)NO
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
(Method J5C) A solution of 6-[(naphthalene-2-carbonyl)amino]hexanoic acid (4/53) (0.618 g, 2.17 mmol) in dry tetrahydrofuran (6 ml) was cooled in ice bath under argon atmosphere and 1,1′-carbonyldiimidazole (0.422 g, 2.6 mmol) was added. The mixture was stirred for 30 min. and a solution of hydroxylamine (4.35 mmol) in dry dimethylformamide (3 ml) [the solution of hydroxylamine was made from hydroxylamine hydrochloride (0.302 g, 4.35 mmol) and triethylamine (0.61 ml) in dimethylformamide (3 ml) and filtered] was added. After stirring overnight the reaction mixture was diluted with saturated NaH2PO4 (30 ml) and extracted with ethyl acetate (3×30 ml). The organic phase was evaporated under reduced pressure by adding several times of benzene to remove traces of water. The crude product was crystallized successively from ethyl acetate and acetonitrile to give of the title compound (0.260 g, 40%), m.p. 96-98° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.21-1.45 (2H, m); 1.46-1.73 (4H, m); 1.89-2.05 (2H, m); 3.25-3.37 (2H, m); 7.65-7.81 (2H, m); 7.86-8.04 (4H, m); 8.42 (1H, s); 8.56-8.72 (2H, m); 10.32 (1H, s). HPLC analysis on Symmetry C8 column: impurities <1% (column size 3.9×150 mm; mobile phase 40% acetonitrile +60% 0.1% H3PO4; detector UV 220 nm; sample concentration 0.145 mg/ml). Anal. Calcd, %: C, 67.98; H, 6.71; N, 9.33. Found, %: C, 68.29; H, 6.97; N, 8.99.