Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:11])([CH3:10])[CH3:9].C([Li])CCC.Cl[CH2:18][C:19]([OH:21])=[O:20].O>C1(C)C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([O:11][CH2:18][C:19]([OH:21])=[O:20])([CH3:9])[CH3:10]
Reactant: CC(C)(O)C1CC2C=CC1C2
Reactant: O=C(O)CCl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(OCC(=O)O)C1CC2C=CC1C2
Temperature: 25 °C
Yield: 31.4 %

Procedure:
2-(5-norbornen-2-yl)-2-propanol (15.20 g, 0.10 mole) (JSR Corp., Japan) and toluene (100 ml) were added to a three-necked 500 ml round bottomed flask equipped with a magnetic stirrer, an addition funnel, and a condenser with a nitrogen inlet. The addition funnel was charged with n-butyl lithium (1.6M in hexane, 62.50 ml, 0.10 mole). The n-butyl lithium was added drop wise while stirring at room temperature. An exothermic reaction occurred. Afterwards, chloroacetic acid (4.75 g, 0.05 mole) in toluene (100 ml) was added drop wise. The contents were heated to reflux for about 20 hours. After cooling to room temperature, water (200 ml) was added cautiously and stirred. The water phase was collected, washed with ether (100 ml) and neutralized with 2 molar hydrochloric acid solution. The cloudy solution was extracted twice with ether (100 ml) and the combined ether solutions was washed with brine (100 ml) and dried over anhydrous magnesium sulfate. The solvent was removed and the residue was recrystallized from a small amount of hexane to give 3.3 g of white crystalline material (Melting Point: 48.5-49.50° C.).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>CN(C=O)C.CCOC(C)=O>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: N#Cc1cccc(CCN)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(NCCc2cccc(C#N)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 8.7 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (150 mg, 0.525 mmol) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. 3-(2-Aminoethyl)benzonitrile (78 mg, 0.530 mmol) was added followed by TEA (53 mg, 0.525 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (18 mg, 56.3%). 1H NMR (500 MHz, CDCl3): δ 1.59 (d, 6H), 2.60 (t, 2H), 3.17 (q, 2H), 4.37-4.46 (m, 1H), 5.49 (bs, 1H), 6.88 (s, 1H), 7.02 (d, 1H), 7.30-7.34 (m, 1H), 7.47-7.57 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 20.38, 35.75, 44.70, 47.90, 107.72, 113.00, 118.70, 125.17, 129.19, 129.67, 130.36, 130.77, 131.95, 132.20, 133.23, 135.11, 139.03, 158.60; Mass Spectrum: M+H+ 396.1.
Reaction SMILES: [CH2:1]([N:5]1[CH2:14][CH2:13][C:8]2([CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:15]([O:17][CH:18]([O:27][CH2:28][CH3:29])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.CN(C)C=O>[CH2:28]([O:27][CH:18]([O:17][CH2:15][CH3:16])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:11]2[CH2:10][CH2:9][C:8]3([CH2:7][CH2:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:14][CH2:13]3)[CH2:12]2)=[CH:21][CH:20]=1)[CH3:29]
Reactant: CC(C)CN1CCC2(CCNC2)CC1
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CN2CCC3(CCN(CC(C)C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.5 %

Procedure:
To a 10% acetic acid-dimethylformamide (10 mL) solution of 8-isobutyl-2,8-diazaspiro[4.5]decane (600 mg) and 4-(diethoxymethyl)benzaldehyde (661 mg), sodium triacetoxyborohydride (1.30 g) was added. The reaction solution was stirred at room temperature for 14 hours. To the reaction solution, an aqueous 5N sodium hydroxide solution (10 mL) was added. The aqueous layer was extracted twice with dichloromethane (20 mL). The combined organic layer was washed with saturated sodium chloride solution (20 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol:28% aqueous ammonia=1:0:0→100:5:1→100:10:2) to obtain the title compound (730 mg) having the following physical properties.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.[NH2:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH2:14][NH:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[N:9]=[C:8]([C:19]([F:22])([F:20])[F:21])[CH:7]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCNCc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of crude 122 (1.522 g, 4.97 mmol) in MeOH (20 mL) was added a solution of tert-butyl 2-aminoethyl(methyl)carbamate (1.732 g, 9.94 mmol, E. Atherton et al, J. Chem. Soc. C, 1971, 3393-3396) in MeOH (5 mL) followed by acetic acid (1.1 mL, 20 mmol). The reaction was stirred at room temperature for 1 hour then sodium cyanoborohydride (0.625 g, 9.94 mmol) was added and the resulting mixture was stirred for 16 hours. After the usual work-up crude 123 (2.30 g, 4.95 mmol, 100% yield) was obtained as yellow oil. LRMS(ESI): (calc.) 464.5 (found) 465.2 (MH)+, 487.2 (MNa)+.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[C:10]1[CH:20]=[CH:19][C:13]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:12][CH:11]=1.Cl[C:24](=[N:30]O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[C:17]([C:16]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:30][O:15][C:14]=1[C:13]1[CH:19]=[CH:20][C:10]([C:9]([F:21])([F:22])[F:8])=[CH:11][CH:12]=1)#[N:18]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: N#CCC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1C#N
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
Triethylamine (0.98 mL, 7.0 mmol) was added to a −5° C. solution of 4-trifluoromethylbenzoylacetonitrile (1.5 g, 7.0 mmol) in ethanol (15 mL) and the mixture was stirred for 20 minutes. A solution of ethyl 2-chloro-2-(hydroxyimino)acetate (1.06 g, 7.0 mmol) in ethanol (5 mL) was added to the reaction over 15 minutes. After stirring at room temperature for 72 hours, the cream-colored solid which formed was collected by filtration, washed with cold water and dried in vacuo to obtain ethyl 4-cyano-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (1.84 g, 5.93 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]1[CH2:30][NH:29][CH2:28][CH2:27][C:16]21[O:20][N:19]=[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17]2.Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:29]2[CH2:28][CH2:27][C:16]3([O:20][N:19]=[C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:17]3)[CH:15]([CH3:14])[CH2:30]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CNCCC12CC(c1ccccc1)=NO2
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC1CN(C(=O)Nc2ccc(C(C)(C)C)cc2)CCC12CC(c1ccccc1)=NO2
Reaction time: 2 h

Procedure:
4-Tert-butylphenyl isocyanate [260 mg, 1.48 mmol, dissolved in abs. THF (1 ml)] was added to a solution of compound U (320 mg crude product, approx. 1.39 mmol) in abs. THF (20 ml) under argon at RT within 10 min. The mixture was stirred for two hours and then mixed with 2N HCl solution (10 ml). The acidic reaction mixture was stirred for 10 min and then extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. NaHCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. The residue obtained was purified by flash chromatography (mobile solvent:cyclohexane/EtOAc=7:3). 6-Methyl-3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylic acid-(4-tert-butylphenyl)amide was thus obtained as a diastereoisomer mixture (melting point from 65° C.) in a yield of 170 mg (30%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1.I[CH2:15][CH2:16][CH3:17]>CN(C=O)C>[F:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:15][CH2:16][CH3:17])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: CCCI
Reactant: O=c1[nH]c2ccc(F)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)oc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To 670 mg (16.74 mmol) of hexanes washed sodium hydride in 20 ml DMF was added a solution of 2.33 g (15.22 mmol) 6-fluoro-1,3-benzoxazolin-2(3H)-one in 40 ml DMF. The reaction was stirred for 10 minutes before 3.11 g (18.3 mmol) 1-iodopropane was added and then stirred for 3 hr at room temperature. After quenching onto 50 ml of ice/water, the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic layers were washed with water (1×100 ml), dried over Na2SO4 and evaporated to dryness in vacuo to give 2.2 g (75% yield) of the alkylated product as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1.[CH2:43]([O:45][CH2:46][CH2:47][C:48](Cl)=[O:49])[CH3:44]>>[CH2:43]([O:45][CH2:46][CH2:47][C:48]([NH:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:8]1)=[O:49])[CH3:44]
Reactant: CCOCCC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(N)c2)cc1
Product: CCOCCC(=O)Nc1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Example 116b, 1.81 g of tert-butyl 3-(3-aminobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 118c) and 0.612 g of 3-ethoxypropionyl chloride are reacted. The title compound is obtained as a colourless oil. Rf=0.22 (1:1 EtOAc-heptane); Rt=5.77.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:8]([C:11]1[CH:12]=[CH:13][C:14]([OH:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:10])=[O:9]>ClCCl>[OH:21][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Piperidine (849 mg, 9.97 mmol) was added dropwise to methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (may be prepared as described in Description 60; 500 mg, 2.00 mmol) in dichloromethane (20 ml) at 25° C., and the mixture was allowed to stir at 25° C. for 2 h. The mixture was then concentrated in vacuo to yield the title compound as a crude product. 430 mg.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Br[C:31]#[C:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]#[C:31][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:34][CH:35]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Fc1ccc(C#CBr)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(F)cc2)CCN(C)C1
Temperature: 82.5 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1.00 mmol) was dissolved in toluene (5 mL). The mixture was stirred for 10 min, and copper sulfate (24.9 mg, 0.01 mmol) and 1,10-phenanthroline (36 mg, 0.2 mmol) were added, and the mixture further stirred for 10 min. To this was added 1-(bromoethynyl)-4-fluorobenzene compound (220 mg, 1.1 mmol) dissolved in toluene and the mixture purged with nitrogen. The reaction mixture was heated at 80-85° C. overnight. The progress of reaction was monitored by TLC and LCMS. The toluene was evaporated under reduced pressure and the crude product purified by column chromatography using silica (100-200 mesh) and 0-50% Ethylacetate:hexane as eluent. 1H NMR (DMSO, oxalate salt) δ (ppm): 7.70 (m, 2H), 7.55 (d, 1H), 7.30 (m, 3H), 7.20 (d, 1H), 4.30 (m, 2H), 3.16 (m, 4H), 2.90 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:10]([C:9]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][CH2:20]2)=[CH:7][CH:8]=1)(=[O:11])[NH2:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: NC(=O)c1ccc(NC(=O)CCl)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NC1CCN(CC(=O)Nc2ccc(C(N)=O)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(2-chloroacetamido)benzamide (0.57 g; 2.68 mmol), tert-butyl piperidin-4-ylcarbamate (0.55 g; 2.68 mmol) and DBU (0.40 mL; 2.68 mmol) in ACN (30 mL) is stirred at r.t. over night. Then the solvent is evaporated and the residue is dissolved in DCM. The solution is washed once with water, then with brine. The organic layer is dried and the solvent is evaporated. The residue is suspended in ether, filtered off with suction and dried to yield tert-butyl 1-(2-(4-carbamoylphenylamino)-2-oxoethyl)piperidin-4-ylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[O:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccco4)c3C2=O)C(=O)N1
Yield: 88.5 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added furan-2-carbonyl chloride (0.52 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. To the reaction mixture was added additional furan-2-carbonyl chloride (0.26 g, 2 mmol). The mixture was heated to reflux for an additional 8 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.65 g (88%) of product as an off-white solid: mp 299-301° C.; 1H NMR (DMSO-d6) δ 11.19 (s, 1H), 10.37 (s, 1H), 8.68 (dd, J=1.4 and 8.4 Hz, 1H), 8.06 (s, 1H), 7.90 (t, J=8.1 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.39 (d, J=3.5 Hz, 1H), 6.79 (dd, J=1.5 and 3.2 Hz, 1H), 5.19 (dd, J=5.1 and 12.5 Hz, 1H), 2.98-2.84 (m, 1H), 2.67-2.49 (m, 2H), 2.13-2.08 (m, 1H); 3C NMR (DMSO-d6) δ 172.66, 169.62, 168.44, 166.59, 155.71, 146.80, 146.34, 136.55, 136.23, 136.12, 131.30, 124.86, 118.54, 116.64, 113.06, 48.98, 30.90, 22.01; Anal. Calcd. For C11H13N3O6: C, 58.86; H, 3.57; N, 11.44. Found: C, 58.69; H, 3.54; N, 11.41.
Reaction SMILES: C([N:3](C([O-])=O)[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)C.O=[S:29](Cl)Cl>>[CH3:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C:5]1[N:4]=[N:3][S:29][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCN(N=C(Cc1ccc(OC)cc1)c1ccc(OC)cc1OC)C(=O)[O-]
Product: COc1ccc(-c2snnc2-c2ccc(OC)cc2OC)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
Acylhydrazone 15 (4.32 g, 11.6 mmol) was added to SOCl2 (50 ml) at 0° C. The reaction was allowed to warm to room temperature. The reaction was complete (by TLC) after 3 hours. SOCl2 was removed under reduced pressure and the crude brown oil was chromatographed on 350 g SIO2, eluting with 4:1, CH2Cl2 :Hexane to afford 13 (1.7 g, 44.7%), m.p. 90-91.5.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>CC#N>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidine (3.89 g, 54.8 mmol) is added to a mixture of 8.40 g (36.5 mmol) of 1-(2-bromoethyl)-4-nitrobenzene and 6.14 g (73.0 mmol) of NaHCO3 in 60 mL of CH3CN at 0° C. The mixture is stirred for 0.5 h at 0° C. and then at 25° C. overnight. The reaction is filtered, the insoluble material is washed with CH3CN and the filtrate and wash were combined. Darco is added, the solution is dried (MgSO4) and evaporated to a viscous red oil. Stirring this material with Et2O caused crystallization of the product. It is collected, washed with Et2O and dried in vacuo to give 7.60 g (95%) of a tan hygroscopic solid. 1H NMR (DMSO-d6) δ 8.22 (d, 2H, J=6.57 Hz), 7.62 (d, 2H, J=6.57 Hz), 3.47 (m, 2H), 3.25 (m, 2H), 3.10 (m, 4H), 1.94 (m, 4H); MS (ESI) m/z 221.2 (M+1).
Reaction SMILES: OO.[C:3]([OH:7])([CH3:6])([CH3:5])[CH3:4].[OH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1.N=O>O>[OH:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([O:17][CH2:4][C:3]([OH:7])([CH3:6])[CH3:5])[C:11]([CH3:19])([CH3:18])[CH2:10]1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: N=O
Agent: OO
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 47.5 °C

Procedure:
A solution of 9.4 g (140 mmol) of 50% aqueous hydrogen peroxide mixed with 20 mL of tert-butyl alcohol is added over four hours at 45-50° C. to a mixture of 3.44 g (20.0 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 0.125 g (0.77 mmol) of anhydrous ferric chloride, 30 mL of tert-butyl alcohol and 10 mL of water. The temperature is then maintained at 45-50° C. for 19 hours. Analysis by gas chromatography shows less than 1% of the starting nitroxyl compound is present.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:15][C:16]1[C:21]([OH:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26].CCN(CC)CC>C(Cl)Cl>[F:15][C:16]1[C:21]([O:22][S:2]([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)(=[O:4])=[O:3])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of methyl 4-(chlorosulfonyl)benzoate (Preparation 2, 606 mg, 2.1 mmol, 1 eq) in DCM (35 ml) was added pentafluorophenol (412 mg, 2.2 mmol, 1.1 eq) and Et3N (540 mg, 5.4 mmol, 2.5 eq) and the reaction mixture stirred at room temperature until all of the starting material was consumed. The solvent was evaporated in vacuo and the residue redissolved in ethyl acetate (10 ml), washed with water (10 ml), saturated sodium hydrogen carbonate (10 ml), dried over sodium sulphate, filtered and evaporated to yiled the title compound as a white solid (690 mg, 1.8 mmol, 85%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]1)(C)(C)C.[ClH:25]>CCOCC.O1CCOCC1>[ClH:25].[NH2:7][CH2:8][C:9]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14]1
Reactant: CC(=O)N1CCC(CNC(=O)OC(C)(C)C)(c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)N1CCC(CN)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1-acetyl-4-phenylpiperidin-4-ylmethyl)carbamic acid tert-butyl ester in ether is added 4 N HCl in 1,4-dioxane. The reaction mixture is stirred at room temperature for 1 h, and concentrated in vacuo. The resulting solid is washed with ether to give the title compound, which is directly used for the next reaction without further purification.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[C:6]([CH3:12])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)=O.[CH:14]1([CH:17]([CH:25]2[CH2:27][CH2:26]2)[N:18]([CH2:22][CH2:23][CH3:24])[C:19]([NH2:21])=[S:20])[CH2:16][CH2:15]1.NC(N)=S>>[CH3:11][C:8]1[CH:7]=[C:6]([CH3:12])[C:5]([C:3]2[N:21]=[C:19]([N:18]([CH:17]([CH:25]3[CH2:27][CH2:26]3)[CH:14]3[CH2:15][CH2:16]3)[CH2:22][CH2:23][CH3:24])[S:20][C:2]=2[CH3:13])=[CH:10][N:9]=1
Reactant: CCCN(C(N)=S)C(C1CC1)C1CC1
Reactant: Cc1cc(C)c(C(=O)C(C)Br)cn1
Agent: NC(N)=S
Product: CCCN(c1nc(-c2cnc(C)cc2C)c(C)s1)C(C1CC1)C1CC1

Procedure:
This compound was prepared according to the process described in Example 1, Step A, using 2-bromo-1-(2,4-dimethyl-5-pyridyl)-1-propanone (Compound 27) as the ketone and N-(dicyclopropylmethyl)-N-propylthiourea (Compound 66) as the thiourea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[C@H:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C@:8]2([OH:12])[O:47][CH2:46][C:45]([CH3:49])([CH3:48])[NH:44][C@H:9]2[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: C[C@@H](O)C(=O)c1cccc(F)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1cccc(F)c1
Yield: 38.3 %

Procedure:
Compound 4c was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-fluorophenyl)-2-hydroxypropan-1-one (10c, 3.94 g, 0.024 mol), Proton sponge (6.0 g), triflic anhydride (4.6 mL, 25.8 mmol), and 2-amino-2-methyl-1-propanol (4.6 g, 0.052 mol) in acetonitrile (50 mL). After purification, 2.2 g (39%) of the free base 4c was isolated and converted to the hemi-D-tartrate salt, which had >99% ee: mp 131-132° C.; [α]20D +20.4° (c 1.0, CH3OH); 1H NMR (methanol-d4) δ 7.45-7.41 (m, 2H), 7.35-7.31 (m, 1H), 7.11-7.09 (m, 1H), 4.33 (s, 1H), 4.26 (d, 1H, J=12.0 Hz), 3.56-3.45 (m, 2H), 1.59 (s, 3H), 1.34 (s, 3H), 1.06 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 178.1, 165.4, 162.1, 144.8, 130.8, 123.2, 116.3 (d), 114.3 (d), 96.2, 74.5, 67.0, 54.3, 23.6, 20.8, 13.7; LCMS (ESI) m/z 240.0 [(M-tartrate)+, M=C15H21FNO5]; Anal. (C15H21FNO5.0.5H2O) calcd: C, 55.72; H, 6.86; N, 4.33. found: C, 55.61; H, 6.89; N, 4.33.