Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:30])[CH2:16][N:17]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[CH2:35](Cl)Cl.CO>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:30][CH3:35])[CH2:16][N:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CN1CCN(Cc2ccccc2)CC1)Cn1c2ccccc2c2ccccc21
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CI
Product: COC(CN1CCN(Cc2ccccc2)CC1)Cn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 7 (0.200 g, 0.50 mmol) in 5 mL of THF are added NaH (0.068 g, 1.56 mmol) and methyl iodide (125 μL, 2.0 mmol). After 2 hr of stirring at rt the reaction is judged to be complete by tlc monitoring (SiO2, DCM:MeOH (100:3)) and is quenched with a saturated aqueous solution of Na2CO3 (5 mL). Extraction with DCM, drying over MgSO4, concentration in vacuo, flash chromatography on a 2.5×12 cm2 column of silica gel using DCM:MeOH (95:5) as eluting solvent and removal of the solvent in vacuo gives the title compound as an oil. Slow addition of HCl (4 eq, 1M in Et2O) into a solution of the above compound in EtOH (2 mL) gives the hydrochloride salt of the title compound (0.39 g) as white crystals in a 60% yield. M.p.: 272° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:20]([NH2:32])[CH2:21][C:22]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=1>C(O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH:32][CH2:20][CH2:21][C:22]4[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCO
Product: COc1ccc(CCN[C@H]2CC[C@H](Nc3ccnc4cc(Cl)ccc34)CC2)cc1OC
Product: Cl

Procedure:
275 mg 4-(7-chloroquinolin-4-ylamino)-cyclohexanone (see Example 124) and 181 mg of homoveratrylamine were boiled at reflux for 3 hours in 5 ml of ethanol in the presence of molecular sieve. The solution, which was cooled and freed from the molecular sieve, was concentrated to dryness. The residue was again taken up in 5 ml of ethanol and treated under argon at +5° C. with 37 mg of sodium borohydride. After 1 hour the mixture was concentrated and the residue was suspended in dichloromethane. The excess reducing agent was decomposed by the addition of 2 ml of 3N sodium hydroxide solution. The mixture was diluted with water and the dichloromethane was separated. The dried organic phase was concentrated. The residue was chromatographed on silica gel with dichloromethane/methanol (3:1). The free base obtained was crystallized as the dihydrochloride by treatment with 3N hydrochloric acid in methanol. Yield: 280 mg (54%) of white crystals, m.p. 210° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:12]=[CH:13][O:14][C:15]=1[CH2:16][CH2:17][NH:18][C:19](=[O:48])[C@H:20]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:21][C@H:22]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:51](=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[N:12]=[CH:13][O:14][C:15]=1[CH2:16][CH2:17][NH:18][C:19](=[O:48])[C@H:20]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[N:21]([C@H:22]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:51])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(OCc1ccccc1)c1ncoc1CCNC(=O)[C@H](Cc1ccccc1)N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN([C@@H](Cc1ccccc1)C(=O)NCCc1ocnc1C(=O)OCc1ccccc1)[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A mixture of 2.6 g of the compound obtained in Example 1, 0.4 ml of methyl iodide, 0.83 g of potassium carbonate and 3 ml of hexamethylphosphoric triamide was stirred at room temperature overnight. Then, ethyl acetate was added to the mixture, and the insolubles were removed by filtration. The filtrate was washed and dried, and then the solvent was removed. The residue was purified by silica gel column chromatography (solvent: chloroform:ethyl acetate=95:5) to obtain 1.81 g (Yield: 68%) of 4-benzyloxycarbonyl-5-(2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)-N-methyl-(L)-phenylalanyl]aminoethyl}oxazole as an oily product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>O.C(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:25]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:26]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59 %

Procedure:
A solution of 2-trifluoromethylaniline (3 mL), triethylamine (3.5 mL) and CH2Cl2 (30 mL) was stirred at room temperature under N2 and added dropwise with cyclohexanecarbonyl chloride (3.34 mL). After 2.5 h stirring at room temperature, the mixture was poured into H2O and alkalinized with 1 N NaOH. The organic phase was dried on anhydrous Na2SO4 and the crude was crystallized from EtOH to give 3.82 g (59%) of the title compound. M.p. 153-154° C.
Reaction SMILES: [CH3:1][C@H:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)OC(=O)[NH:3]1.[H][H]>CO.CC(O)=O.[Pd]>[NH2:3][C@@H:2]([CH3:1])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: C[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](N)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A suspension of (S)-4-methyl-5,5-diphenyl-2-oxazolidinone (11) (3.52 g, 13.90 mmol) in MeOH/AcOH and a 10% Pd (148 mg, 1.39 mmol) on activated carbon was shaken for 45 h under 4–5 atm pressure of hydrogen at room temperature. The catalyst was filtered off over Hyflo Super Cell and organic solvents were evaporated under reduced pressure. The resulting residue was treated with HCl (2M, 100 ml), stirred overnight at room temperature, made basic with NaOH pellets, and saturated with K2CO3. The organics were then extracted into diethyl ether (3×100 ml), dried over MgSO4/K2CO3 and concentrated under reduced pressure to obtain a crude product. Impurities were washed with AcOEt over silica gel by means of dry-flash column chromatography, and then further elution with a mixture of MeOH and AcOEt, ranging from 5% up to 30%, gave the title compound (12) (1.90 g, 65%) as a white solid. m.p. 76–77° C. [α]D25=−19.32 (c, 0.10765 in CHCl3). δH 1.04 (3H, d, 3J=6.30 Hz, CH3), 1.31 (2H, broad s, NH2), 3.55 (1H, d, J=9.90 Hz, CH—Ph2), 3.73 (1H, dq, 3J=6.30 and 10.20 Hz, CH—NH2), 7.10–7.40 (10H, m, Ar—H). δC 22.4 (CH3), 50.3 (CH—NH2), 62.4 (CH—Ph2), 126.5, 126.8, 128.2, 128.5, 128.7 and 129.0 (o-, m- and p-Ar), 143.3 and 143.7 (α-Ar). Anal. Calcld for C15H17NO: C 85.26; H 8.11; N 6.63. Found: C 85.10; H 8.08; N 6.36. ir 3343 (NH2). m/e (CI—NH3) 212 (MH+, 100%).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.ClS([N:19]=[C:20]=O)(=O)=O>CN(C=O)C>[C:20]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1)#[N:19]
Reactant: COc1ccc2ccn(C3CC3)c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(C#N)cn(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of 1-cyclopropyl-6-methoxylindole (3.29 g, 17.6 mmol) in dry DMF (30 mL), at 0° C., is added chlorosulfonyl isocyanate (3.11 g, 1.91 mL, 22.0 mmol). After the addition, the mixture is stirred at room temperature for 2 h, followed by aqueous work-up. Chromatography (silica gel, hexanes/EtOAc, 9/1) furnishes 3-cyano-1-cyclopropyl-6-methoxyindole (3.05 g, 82%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.ClCCl.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.O.CC(OC)(C)C>[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13]
Reactant: CC(C)(C)OC(=O)C(C)(C)C(=O)O
Reactant: CC(C)(C)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)COC(=O)C(C)(C)C(=O)OC(C)(C)C

Procedure:
To a mixture of 2,2-dimethylmalonic acid mono-t-butyl ester (10 g), 2,2-dimethyl-1-propanol [CAS No. 75-84-3] (5.15 g), DMAP (1.3 g), and dichloromethane (100 mL), WSC (12.2 g) was added with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 days. TBME and water were added to the mixture, and the resulting mixture was extracted. The organic layer was sequentially washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain 2,2-dimethylmalonic acid t-butyl ester(2,2-dimethylpropyl)ester (12 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]([Cl:22])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC1(c2ccc(F)cc2)CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCC1(c2ccc(F)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(1-(4-fluorophenyl)cyclohexyl)propanoic acid (Preparation 42A, 209 mg, 0.835 mmol) in dichloromethane (3 mL) at 0° C. was added oxalyl chloride (0.146 mL, 1.670 mmol) followed by a couple of drops of N,N-dimethylformamide, and the mixture was stirred at the same temperature for 20 mins and warmed up to room temperature. The volatiles were evaporated off and the residue was used for next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])C.CN(C)[CH:21]=[O:22]>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:14]2[CH2:15][CH2:16][CH:21]([OH:22])[CH2:18][CH2:17]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CN2CCC(O)CC2)cc1
Reaction time: 16 h

Procedure:
1.0 g (0.00989 mol) of 4-hydroxypiperidi,ne was dissolved in 50 ml of dimethylformamide and cooled to 0°. 2.56g (0.001186 mol) of 4-nitro-benzyl bromide and 2.78 ml (0.0198 mol) of triethylamine were added and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was taken up in dichloromethane. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (9:1) as the eluent. 0.836 g (36%) of 1-(4-nitro-benzyl-piperidin-4-ol was obtained as beige crystals; m.p. 114°-115°.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[CH2:15][C:16]([OH:18])=[O:17]>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[CH2:15][C:16]([OH:18])=[O:17])=[O:4]
Reactant: O=C(O)CC1C=CC=CC1=NO
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Product: O=C(O)CC1C=CC=CC1=NOC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a mixture of methylene chloride (45 ml) and dichloroacetyl chloride (10 ml) was added portionwise with stirring 2-hydroxyiminophenylacetic acid (synisomer) (5g) in portions over about fifteen minutes. The reaction mixture became solid, and was stirred for one hour at room temperature after the addition was complete. The reaction was diluted with petroleum (b.p. 40°-60°), filtered, and the solid washed several times with petroleum spirit to remove residual acid chloride. The solid was dried under vacuum, giving 2-dichloroacetoxyiminophenylacetic acid (syn-isomer)(8.0g; 96%), m.p. 115°, νmax. (CHBr3) 3470 and 1750 (-CO2H), 1765 cm.-1 (ester), τ (CDCl3) values include 2.0 - 2.7 (multiplet; aromatic protons), 3.85 (singlet; -CHCl2).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([CH:7]1[CH2:11][C:10](=[O:12])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:8]1)=O.O>C(O)C>[OH:4][CH2:5][CH:7]1[CH2:8][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH2:11]1
Reactant: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2CC(CO)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH4 (15 g, 0.081 mol) was added in portions to ester 79 in ethanol (600 mL) at room temperature. After 4.5 hours water (˜200 mL) was carefully added to the reaction and the solution stirred at room temperature overnight. The resultant solid was removed by filtration and the filtrate concentrated to give alcohol 80 as an oil. 15.33 g, 81%. MS, m/z (relative intensity): 235 [M+H, 100%].
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:14])[S:8][C:7]2=[N:9][CH:10]=[CH:11][N:6]2[C:5]1=[N:12][OH:13].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>O1CCCC1>[CH3:3][C:4]1([CH3:14])[S:8][C:7]2=[N:9][CH:10]=[CH:11][N:6]2[C:5]1=[N:12][O:13][C:17](=[O:18])[N:16]([CH3:20])[CH3:15]
Reactant: CN(C)C(=O)Cl
Reactant: CC1(C)Sc2nccn2C1=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)ON=C1n2ccnc2SC1(C)C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 330 mg (13.6 mmol) of sodium hydride in 150 ml of dry tetrahydrofuran was added 2.50 g (13.6 mmol) of 2,2-dimethyl-3-hydroxyimino-2,3-dihydroimidazo-[2,1-b]thiazole. The reaction mixture was stirred at 25° for 1 hour and cooled in an ice bath before 1.54 g (14.3 mmol) of dimethylcarbamoyl chloride was added. After stirring for 12 hours at 25°, the solvent was removed in vacuo and the residue washed with hexane, dissolved in methylene chloride. The methylene chloride solution was washed with water, dried (MgSO4), and concentrated in vacuo to give 2.94 g (85%) of desired product. m.p. 99°-102.5°.
Reaction SMILES: [C:1]([CH2:4][C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=[O:6])([OH:3])=O.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:46]([O:48][C:49]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50])[CH3:47]>C(Cl)Cl.C(OCC)(=O)C>[CH2:46]([O:48][C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:1]([CH2:4][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[O:6])=[O:3])[CH2:55][CH2:56]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)CC(=O)Nc2ccc3ccccc3c2)CC1
Reaction time: 0.08 h
Yield: 62.5 %

Procedure:
To a solution of 2-((carboxy)methylcarbonylamino)naphthalene (1.2 g, 5.2 mmol) in CH2Cl2 (40 mL) was added triethylamine (2.2 mL, 15.6 mmol) and 1-hydroxybenzotriazole (HOBT) (0.84 g, 6.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.2 g, 6.2 mmol). After 5 minutes, 1-ethoxycarbonylpiperazine (0.84 mL, 5.3 mmol) was added and the reaction was stirred overnight. The reaction mixture was evaporated in vacuo to afford an oil, which was dissolved in ethyl acetate, and washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated in vacuo to afford 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl]aminonaphthalene (1.2 g), as a solid that was used without further purification.
Reaction SMILES: [NH:1]([C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([N+:17]([O-])=O)=[C:10]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27].[H][H]>[Pd].C.CO>[ClH:27].[ClH:27].[NH2:14][C:13]1[C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:10]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:11]([NH2:17])[CH:12]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccccc2)nc1Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cc(N)c(Nc2ccccc2)nc1Nc1ccccc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 181.8 %

Procedure:
A 500 ml Parr bottle was twice charged with 2,6-dianilino-3,5-dinitropyridine (13.5 g, 0.0385 mole), 300 ml of methanol containing HCl (10 g) and 5% Pd/Charcoal catalyst (1.1 g). The mixture was placed under 55 psig. hydrogen pressure and kept at 25°-40°C until no further uptake of hydrogen was observed. The combined reduction mixtures were cooled, precipitated product and catalyst filtered under nitrogen, and the filter cake washed with 10% HCl in isopropyl alcohol. The filter cake was added to 500 ml of warm (55°C) conc. HCl, stirred well for 5 minutes, filtered and the insolubles washed with conc. HCl. The clear filtrate was cooled (0°C), diluted with 500 ml cold (-15°C) isopropyl alcohol with good stirring to precipitate product. The solid was filtered, washed with 10% HCl in isopropyl alcohol and vacuum dried over P2O5 to afford 3,5-diamino-2,6-dianilinopyridine dihydrochloride (25.5 g, 92%). Anal. Calcd. for C17H17N5.2HCl: C, 56.0; H, 5.2; N, 19.2; Cl, 19.5. Found: C, 54.0; H, 5.4; N, 19.4; Cl, 20.0.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[O-:11][C:12]#[N:13].[K+]>C(O)(=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH:4][C:12]([NH2:13])=[O:11]
Reactant: COc1ccc(F)c(N)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(F)c(NC(N)=O)c1
Temperature: 19 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of 2-fluoro-5-methoxyaniline (35.15 g, 249 mmol) in acetic acid (99 mL) and water (177 mL) at 35° C. was added potassium cyanate (40 g, 0.49 mol) in water (170 mL) over 20 minutes under N2. The mixture was stirred at 40° C. for 20 min and at 18 to 20° C. for 2 h, and then quenched into water (500 mL). The crude product was filtered, washed with water (1.2 L), heptane (50 mL) and slurred in a mixture of tert-butylmethylether (100 mL) and ethyl acetate (5 mL) for 5 minutes at ambient temperature. The product was filtered, washed with tert-butylmethylether (30 mL) and dried in vacuo at 40° C. to give N-(2-Fluoro-5-methoxyphenyl)urea (31.75 g, 69%) as a light-brown solid.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][N:3]=1.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.ClCCl>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: Brc1n[nH]c2ccncc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Brc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccncc12
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
To a solution of 4.69 g of 3-bromo-1H-pyrazolo[4,3-c]pyridine in 72 mL of dimethylformamide was added 1.42 g of sodium hydride at room temperature and stirred for 15 minutes, and then added with 6.6 g of trityl chloride and stirred at this temperature for a day. The solution was diluted with dichloromethane, and the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The precipitated crystals were washed with ethyl acetate, the filtrate was evaporated, and the residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:3), an the resultant product was combined with the above crystals, to afford 5.28 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]2[C:16]([O:18][CH3:19])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20]OS([O-])=O.[K+].[K+].S(=O)(=O)([O-])[O-].[K+].S([O-])(OO)(=O)=O.[K+].[OH2:40]>CO.ClCCCl>[C:1]1([S:7]([CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]2[C:16]([O:18][CH3:19])=[O:17])(=[O:20])=[O:40])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CC(Sc2ccccc2)C1C(=O)OC
Reactant: O
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])OO
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)C1CC(S(=O)(=O)c2ccccc2)C1C(=O)OC
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a vigorously stirred solution of 1.05 g (3.75 mmol) of dimethyl 3-(phenylthio)cyclobutane-1,2-dicarboxylate from Step A in 20 mL of methanol, was added slowly a suspension of 3.46 g (11.25 mmol) of OXONE (a commercially available mixture of sulfuric acid potassium salt and potassium hydrogen peroxymonosulfate) in 20 mL of water. The resultant cloudy suspension was stirred for 0.5 h then diluted with 50 mL of water and 100 mL of 1,2-dichloroethane. The phases were allowed to separate and the aqueous phase was extracted with 20 mL of 1,2-dichloroethane. The combined organic layers were washed with 2×50 mL of dilute aqueous sodium bicarbonate solution, 2×50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate and concentrated to give 1.10 g (94% yield) of the title compound as a viscous oil; EI-MS, m/e (relative intensity): 281 (M+ -OCH3, 9), 171 (100), 139 (24), 111 (47); 1H NMR (CDCl3) δ 2.48 (m, 1H), 2.76 (m, 1H), 3.23 (q, 1H), 3.52 (s, 3H), 3.74 (s, 3H), 3.80 (m, 1H), 3.92 (q, 1H), 7.58 (m, 2H), 7.68 (m, 1H), 7.89 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([C:28](Cl)=[O:29])[CH:23]=1>C1(C)C=CC=CC=1>[CH3:31][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[C:28]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:29]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Yield: 65 %

Procedure:
1.0 g (0.00532 mol) of 1-benzyl-4-hydroxypiperidine and 0.72 ml (0.00532 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.7 ml (0.00532 mol) of m-toluoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3→1:2). 1.07 g (65%) of 1-benzyl-piperidin-4-yl 3-methyl-benzoate were obtained as a yellow solid: m.p. 45°-46°.