Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[N:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].C1C(=O)N([Br:29])C(=O)C1.ClCCl.[Cl-].[Na+].O>ClCCl>[Br:29][C:15]1[CH:14]=[CH:13][C:12]([N:4]([C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[CH3:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1N(c1ccccc1)c1ccccc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1N(c1ccc(Br)cc1)c1ccccc1C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 2-methyl-N-phenyl-N-(o-tolyl)aniline (Compound 10) (8.2 g, 30 mmol) in dichloromethane (DCM) (100 mL), was added n-bromosuccinimide (NBS) (5.34 g, 30 mmol) at about 0° C. and stirred for about 4 hours. The resulting mixture was worked up with dichloromethane/brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1. The desired fraction was collected, and removal of solvent gave a white solid (Compound 11) (10.7 g, in 100% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[OH-:20].[K+]>O1CCCC1>[Cl:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(Cl)nc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
A solution of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (336.5 mg, 1.06 mmol) in tetrahydrofuran (6 mL) was treated with a 2N aqueous potassium hydroxide solution (6 mL). The reaction was warmed to 80° C. where it stirred overnight. At this time, the reaction was concentrated in vacuo. The resulting mixture was then carefully brought to pH ˜7 with a 2N aqueous hydrochloric acid solution, diluted with water (25 mL) and extracted with a 10% methanol/methylene chloride solution (2×25 mL). The combined organics were dried over magnesium sulfate, filtered and rinsed with methylene chloride and concentrated in vacuo onto Celite®. Flash chromatography (40 g silica gel column, 1-50% ethyl acetate/hexanes) afforded 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one as an off-white solid (53.7 mg, 16.9%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.08 (s, 9H) 0.82 (t, J=8.10 Hz, 2H) 3.50 (t, J=8.10 Hz, 2H) 5.42 (s, 2H) 6.53 (d, J=3.20 Hz, 1H) 7.26 (br. s., 1H) 12.98 (br. s., 1H). LC-MS calcd. for C12H19ClN3O2Si [(M+H)+] 300, obsd. 300.0.
Reaction SMILES: [OH-:1].[Na+].OO.[Cl:5][C:6]1[CH:7]=[C:8]([S:12]([N:15]2[CH2:20][CH2:19][C:18]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=O)([C:21]#[N:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.O>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([S:12]([N:15]2[CH2:20][CH2:19][C:18]3([N:23]=[C:24]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[NH:22][C:21]3=[O:1])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1
Reactant: [OH-]
Reactant: N#CC1(NC(=O)C2CCCCC2)CCN(S(=O)(=O)c2cccc(Cl)c2)CC1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)c1cccc(Cl)c1)CC2
Temperature: 25 °C
Yield: 52 %

Procedure:
A 6 M aqueous sodium hydroxide solution (0.74 mL) and a 30% aqueous hydrogen peroxide solution (0.25 mL) were added to a solution of cyclohexanecarboxylic[1-(3-chloro-benzenesulfonyl)-4-cyano-piperidin-4-yl]-amide (100 mg, 0.244 mmol) in ethanol (1.60 mL), and the mixture was heated under reflux for 4.5 hours. The reaction mixture was cooled to room temperature and water was then added, followed by concentration under reduced pressure. The residue was neutralized with a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=90:10) to give 8-(3-chloro-benzenesulfonyl)-2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a white solid (52 mg, 52%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[H-].[Na+].[CH3:12][CH2:13][O:14]C(C)=O>C1COCC1>[O:14]=[C:13]([CH3:12])[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]#[N:9]
Reactant: N#CCc1cccnc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(C#N)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Pyridin-3-yl)acetonitrile (7.00 g, 59.3 mmol) was dissolved in THF (100 ml). NaH (60% in oil) (5.93 g, 148 mmol) was slowly added and the reaction mixture was stirred at RT for 1 hour (continuous gentle gas evolution). EtOAc (1 ml) was added and the mixture was stirred until an exothermic reaction occurred. EtOAc (7 mL) was then added slowly to maintain gentle heating. The reaction was stirred at RT for 2 hours and then approximately 75% of the THF was removed in vacuo. The resulting mixture was partitioned between Et2O and water and the aqueous phase was washed with Et2O (2×50 mL). The aqueous phase was then acidified with 1M HCl and the product was extracted into EtOAc. A significant amount of solid gradually formed between the two layers. This material was filtered off and dried.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br.C(OCC)(=O)C>CC(C)=O.CN(C)C=O>[CH3:27][O:28][C:29]([CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:32]
Reactant: O=[N+]([O-])c1cccc(-c2nc(O)cc3cccnc23)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
A suspension of 6-hydroxy-8-(3-nitrophenyl)-1,7-naphthyridine (107 mg, 0.40 mmol; produced according to the preceeding example, optionally without further purification), potassium carbonate (55 mg, 0.40 mmol) and bromoacetic acid methyl ester (37 μl, 0.4 mmol) is stirred for two hours in acetone-dimethylformamide (2 ml, 1:1) at ambient temperature. Ethyl acetate is added and the organic phase is washed with 2N NaOH. the solvent is removed in vacuo and the crude product is purified by preparative thin-layer chromatography to give the title compound. Mass M+H 340; mp 160-162° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[C:16](=[N:29][NH2:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O=O.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:17]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:29][NH:30][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: FC(F)(F)C(F)(F)Oc1ccc(Br)cc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: FC(F)(F)C(F)(F)Oc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a dry 2 L round bottomed flask fitted with an overhead mechanical stirrer, nitrogen inlet, thermometer, and reflux condenser were added 1 bromo-4-(perfluoroethoxy)-benzene (100 g, 344 mmol), benzophenone hydrazone (74.2 g, 378 mmol), and (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (BINAP, 4.28 g, 6.87 mmol), and the mixture was suspended in anhydrous toluene (500 mL). To exclude oxygen, argon was sparged into the mixture for ten minutes (min) prior to and during the addition of palladium (II) acetate (Pd(OAc)2, 1.54 g, 6.87 mmol) and sodium tert-butoxide (NaOtBu, 49.5 g, 515 mmol), which was added in portions. The argon sparge was halted and the brown mixture was warmed to 100° C. and stirred for 3 h. The reaction was cooled to RT and poured into water (500 mL) and the aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water, washed with saturated aqueous NaCI, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure on a rotary evaporator. The crude product was purified by flash column chromatography using 0-100% (v/v) EtOAc/hexanes as eluent to give the title compound as a red oil (123.3 g, 88%): 1H NMR (400 MHz, CDCI3) δ 5 7.63-7.56 (m, 4H), 7.55 (t, J=1.5 Hz, 1H), 7.51 (d, J=4.7 Hz, 1H), 7.36-7.26 (m, 5H), 7.13-7.04 (m, 4H); 19F NMR (376 MHz, CDCI3) 5-85.94, −87.84; 13C NMR (101 MHz, CDCI3) δ 145.23, 143.46, 141.24, 138.06, 132.53, 129.74, 129.41, 129.03, 128.30, 128.23, 126.57, 122.82, 113.45.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.O>C(Cl)Cl.C(N(CC)CC)C>[Br:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:4]
Reactant: CNCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Br)CBr
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Reaction time: 0.08 h
Yield: 104.6 %

Procedure:
To a solution of bromoacetyl bromide (30 g) in methylene chloride (20 ml) at 0° was added a solution of N-methyl-4-nitrobenzenemethanamine (8.3 g; G. I. Wilson, J. Chem. Soc., 1926, 2461) in methylene chloride (10 ml) and triethylamine (12 ml). The reaction was stirred 5 min. at 0° and then water (20 ml) was added. The methylene chloride layer was dried and evaporated in vacuo. The residue was purified by column chromatography eluting with methylene chloride/methanol (97:3) to give the title compound (15 g) as an oil. NMR includes signals at d 3.1(3H,s,N--CH3); 3.9(2H,s,CH2Br); 4.55(2H,s,Ph--CH2 --N); 7.0-8.3(4H,m,aromatics).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[F:29])[CH2:41][CH2:40]1)=[O:16]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 75.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (533 mg, 1.39 mmol, 75%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5][C:6](=[O:14])[C@@H:7]([C:9]([CH2:12][OH:13])([CH3:11])[CH3:10])[OH:8].Cl>CO.[OH-].[Na+]>[C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])[C@@H:7]([C:9]([CH2:12][OH:13])([CH3:10])[CH3:11])[OH:8]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](O)C(C)(C)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CO)[C@@H](O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 18 h
Yield: 97.8 %

Procedure:
To a solution of pantoylphenylalanine methyl ester (0.85 g, 2.7 mmol) in methanol, 3.85 ml of 1.00M sodium hydroxide was added very slowly, with stirring. The progress of the hydrolysis was monitored by TLC. After 18 h, the reaction mixture was acidified by the addition of 3.9 ml of 1.00M hydrochloric acid to pH 3.2, concentrated on a rotary evaporator, and diluted with ethyl acetate. The phases were separated, and the aqueous solution was extracted with additional ethyl acetate. The combined organic extracts were dried voer anhydrous sodium sulfate, gravity filtered, the solvent removed on a rotary evaporator. The resulting white solid was dried in a vacuum oven (65° C., 0.2 mm Hg, 24 h), to yield pantoylphenylalanine (0.78 g).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].C(=O)C(C)C.[C:12]([O:21]CC)(=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)(C)(C)C.C(O)C.[Pd]>[CH2:1]([CH:14]([CH2:13][C:12]([OH:21])=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]([CH3:5])[CH3:3]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: CC(C)C=O
Agent: [K+]
Solvent: CCO
Solvent: CC(C)(C)O
Product: CCOC(=O)C(CC(=O)O)CC(C)C

Procedure:
49.4 g of potassium tert.butoxide in 350 ml of tert.butanol were stirred and heated under reflux under nitrogen. A mixture of 36.4 ml of isobutyraldehyde and 83.2 ml of diethyl succinate was added over a period of 0.25 hour and the mixture was heated under reflux for 1.5 hours. The solution was evaporated to a small volume, acidified with 2N hydrochloric acid and the evaporation was continued. The residue, diluted with water, was extracted three times with 300 ml of diethyl ether each time and the ether solutions were combined, washed with water and extracted three times with 200 ml of 10% potassium carbonate solution each time. The basic solution was acidified with concentrated hydrochloric acid and the product was extracted into diethyl ether, washed with water, dried over anhydrous magnesium sulfate and evaporated to give an oil. This oil was dissolved in 400 ml of ethanol and the solution was hydrogenated for 2 hours in the presence of 5 g of 5% palladium/carbon. After filtration and evaporation of the filtrate there were obtained 69.8 g of crude 1-ethyl hydrogen 2(RS)-isobutylsuccinate.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])[N:5]=[CH:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][C@@H:21]2[CH2:23][C@@H:19]([C:20]2([CH3:25])[CH3:24])[C@H:18]1[CH3:26].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][C@@H:21]2[CH2:23][C@@H:19]([C:20]2([CH3:24])[CH3:25])[C@H:18]1[CH3:26]
Reactant: CCOC(=O)C(C)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C(=O)O)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Yield: 158.3 %

Procedure:
Ethyl 2-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoate (149 mg, 0.349 mmol) in 1,4-dioxane (1 mL) was stirred with 1 M aqueous sodium hydroxide (0.698 mL, 0.698 mmol) at room temperature for 5.5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (220 mg, quant.).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][CH2:10][N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13][C:14]([O:16]C)=O)=[CH:7][CH:6]=1>>[OH:2][NH:1][C:14](=[O:16])[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:33][CH:32]=1)[S:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[NH:31][N:30]=[N:29][N:28]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: NO
Reactant: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(-c2nnn[nH]2)cc1
Product: COc1ccc(CCN(CCC(=O)NO)S(=O)(=O)c2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Freshly prepared NH2OH solution (1 M in MeOH) (1.5 mL) was added to methyl 3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)-benzenesulfonyl)-amino]-propionate (112 mg, 0.25 mmol). After stirring at room temperature for 18 h, the reaction mixture was partitioned between 1 N HCl solution (20 mL) and ethyl acetate (30 mL). Two phases were separated and the aqueous layer was extracted with another 30 mL of ethyl acetate. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give N-hydroxy-3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)benzene-sulfonyl)amino]-propionamide (52 mg, 0.12 mmol). NMR (360 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.74 (br s, 1H), 8.22 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H), 6.81 (d, J=8.2 Hz, 2H), 3.69 (s, 3H), 3.42 (t, J=7.5 Hz, 2H), 3.31 (t, J=7.9 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.25 (t, J=7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH:21]=[CH:22][CH:23]=2)(O)[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH:21]=[CH:22][CH:23]=2)=[CH2:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1cccc(C(C)(O)c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(c1cccc(-c2ccccc2OC)c1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Yield: 40.1 %

Procedure:
A solution of crude 22 (2.66 mmol) in toluene (60 mL) was treated with para-toluenesulfonic acid (20 mg) and refluxed under a Dean-Stark trap for 1.5 hrs. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (100 mL) and water (100 mL). The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (40 g) with hexane (2 L) and 1% ethyl acetate in hexane (2 L) to afford pure 23 (0.12 g) and impure 23 (0.50 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1.CC(C)CCN1C2(CCN(C3CCCCC3=O)CC2)C(=O)NC1>>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:23][CH2:24]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCC1O)CC2
Agent: CC(C)CCN1CNC(=O)C12CCN(C1CCCCC1=O)CC2
Product: O=C1CCCCC1N1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
The title compound was prepared from (rac,trans) 8-(2-hydroxy-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one in analogy of the procedure described for the synthesis of rac-1-(3-methyl-butyl)-8-(2-oxo-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one (Example 73d). rac-8-(2-Oxo-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one was obtained as yellow solid, MS (ISP): 328.4 MH+.
Reaction SMILES: C([O:4][CH:5]1[CH:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31](O)(C)[CH3:32]>[Ni]>[Cl:18][C:14]1[C:15]([Cl:17])=[CH:16][C:11]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:31]([CH3:32])=[N:19][C:12]=2[CH:13]=1
Reactant: CC(C)O
Reactant: CC(=O)OCC1CC(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])C(OC(C)=O)C1OC(C)=O
Agent: [Ni]
Product: Cc1nc2cc(Cl)c(Cl)cc2n1C1CC(CO)C(O)C1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (1.00 g, 2.16 mmol), Raney nickel (Aldrich, slurry in water, 100 mg wet), and isopropanol (200 mL) were shaken under hydrogen (50 psi) for 1.25 hours. Catalyst was filtered off with Celite and the filtrate-wash evaporated to dryness. The residual yellow oil was dissolved in triethylorthoaceate (20 mL) with 1 drop of methanesulfonic acid and the solution stirred at ambient temperature for 18 hours. Volatiles were removed in vacuo and the residue stirred in dioxane (20 mL)-1N sodium hydroxide (10 mL) for 5 hours at ambient temperature. The pH was then adjusted to 1 with concentrated hydrochloric acid and stirring continued for 15 minutes, at which point TLC (silica gel, developed with 20% methanol-chloroform) showed one UV-absorbing spot at Rf 0.25. The solution was neutralized with sodium hydroxide and volatiles evaporated in vacuo. The residue was chromatographed on a silica gel column and title compound eluted with 10-15% methanol-chloroform. Crystallization from ethanol-methanol-water gave (±)-(1R*, 2S*, 3S*, 5S*)-5-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as fine white crystals (0.482 g, 67%), m.p. 222°-226° C.; 1 H-NMR(DMSO-d6)δ: 8.30 and 7.72 (both s, 2, 2 aromatic CH), 5.0-4.8 (m, 3, 2 OH and NCH), 4.56 (t, J=5.1 Hz, 1, CH2OH), 4.2-4.1 (m, 2, 2 OCH), 3.8-3.5 (m, 2, CH2O), 2.58 (s, 3, CH3), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m, 2, CH2); mass spectrum (CI): 332 (M +1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][C:12]=2[F:24])[CH2:7][CH2:6]1)[CH3:2].[Cl:26]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[C:12]([F:24])=[CH:13][C:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:15][C:16]=2[Cl:26])[CH2:9][CH2:10]1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)OC(C)(C)C)cc2F)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2c(F)cc(C(=O)OC(C)(C)C)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
To a solution of 0.50 g of N-(4-tert-butoxycarbonyl-2-fluorophenyl)isonipecotic acid ethyl ester in 5 ml of DMF, 0.21 g of N-chlorosuccinimide was added, and the mixture was stirred at room temperature for 1 day. After the evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=5:1˜1:1) to obtain 0.51 g of N-(4-tert-butoxycarbonyl-2-chloro-6-fluorophenyl)isonipecotic acid ethyl ester.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C)(=[O:8])=[O:7]>C(Cl)Cl.O>[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])(=[O:7])=[O:8]
Reactant: COc1ccccc1S(C)(=O)=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1O
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
m-Chloroperbenzoic acid (280 mg, 1.62 mmol) was added to a cold (0-4° C.) solution of 1-methoxy-2-methylsulfanyl-benzene (100 mg, 0.64 mmol) in DCM (3 mL) and stirring was continued for 1 hr. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 110 mg (91.6% Yield) of 1-methanesulfonyl-2-methoxy-benzene. Boron tribromide (370 mg, 1.47 mmol) was added to a cold solution (−70° C.) solution of 1-methanesulfonyl-2-methoxy-benzene (10 mg, 0.591 mmol) in DCM (2 mL) and stirring was continued for 10 minutes. After which the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 65 mg (64.35% Yield) of 2-methanesulfonyl-phenol. 2-Methylsulfonyl-phenol was converted to 4-(2-methanesulfonyl-phenoxy)-piperidine hydrochloride according to Step 1 of the General Scheme).