Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([NH:13][C:14](=[O:30])[CH2:15][NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][CH:47]([C:50](Cl)=[O:51])[CH2:46][CH2:45]2)=[CH:40][CH:39]=1>C(Cl)Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[S:17]([NH:16][CH2:15][C:14]([NH:13][CH:4]([C:5]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:6])[CH2:3][NH:2][C:50]([CH:47]1[CH2:46][CH2:45][N:44]([C:41]2[CH:40]=[CH:39][N:38]=[CH:43][CH:42]=2)[CH2:49][CH2:48]1)=[O:51])=[O:30])(=[O:19])=[O:18]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: NCC(NC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
N-[2-Amino-1-(piperidinocarbonyl)ethyl]-2-(2-naphthalene-sulphonamido)acetamide hydrochloride salt (2.6 g) and triethylamine (3.18 ml) were added in turn to a stirred solution of 1-(4-pyridyl)piperidine-4-carbonyl chloride (1.54 g) in methylene chloride (20 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 89:10:1 mixture of ethyl acetate, methanol and ammonia as eluent. The material so obtained was triturated under diethyl ether to give 2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)-piperidin-4-ylcarbonylamino]ethyl}acetamide as a foam (1.9 g, 55%);
Reaction SMILES: [C:1](O)(=O)[C:2]([OH:4])=[O:3].[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3C=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:27](C(OC(C)(C)C)=O)[CH:26]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9].Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46]>>[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:1]=3[C:2]([O:4][C:25]([CH3:30])([CH3:26])[CH3:24])=[O:3])=[CH:27][CH:26]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9]
Reactant: O=C(O)C(=O)O
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3)c(C(=O)OC(C)(C)C)c1)C(C(=O)OCC)NCC2
Reactant: CCOC(=O)Cl
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)OCC)CC2
Yield: 169.1 %

Procedure:
The compound obtained in Example 62 (1.00 g) is treated in the same manner as in Example 64 with using ethyl chloroformate (0.27 g) instead of acetic anhydride to give ethyl 2-n-propyl-5-ethoxycarbonyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-4-carboxylate (0.82 g) as a white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>O>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(-c2ccccc2F)cc1

Procedure:
47.6 g (0.21 mol) of methyl 4-bromophenylacetate are introduced under argon into 400 ml of absolute tetrahydrofuran and, at room temperature, 320 ml of 1M sodium carbonate solution and 40 g (0.28 mol) of 2-fluorophenylboronic acid are added. Addition of 7.0 g (0.01 mol) of bis(triphenylphosphane)palladium(II) chloride is followed by heating under reflux for 18 h. Cooling is followed by dilution with 500 ml of water and extracted three times with 300 ml of ethyl acetate each time. The combined organic phases are washed with 400 ml each of saturated ammonium chloride solution, water and saturated sodium chloride solution, dried over magnesium sulfate and freed of solvent in vacuo. Example V is obtained after silica gel filtration (petroleum ether/ethyl acetate 10:1) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:9]
Reactant: Sc1ccccc1Br
Reactant: Fc1cc(Cl)ccc1I
Product: Fc1cc(Cl)ccc1Sc1ccccc1Br

Procedure:
Prepared from 4-chloro-2-fluoro-1-iodo-benzene and 2-bromo-benzenethiol.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[N:9]=[CH:10][N:11]2[C:16]=1[C:15](=[O:17])[N:14]1C=N[CH:20]=[C:13]1[C:12]2=[O:21].N[C@@H]1C[CH2:27][N:26]([CH:29]([CH3:49])[CH2:30][C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:25][C@H]1O>CN(C)C=O>[OH:21][C@H:12]1[C@H:13]([NH:14][C:15]([C:16]2[NH:11][CH:10]=[N:9][CH:8]=2)=[O:17])[CH2:20][CH2:27][N:26]([CH:29]([CH3:49])[CH2:30][C:31]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:32]([N:34]([CH3:35])[CH3:36])=[O:33])[CH2:25]1
Reactant: O=c1c2cncn2c(=O)c2cncn12
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2cnc[nH]2)[C@H](O)C1
Reaction time: 8 h
Yield: 23 %

Procedure:
2.8 Parts of N,N-diethylethanamine were added to a solution of 1 part of 5H, 10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione in 36 parts of N,N-dimethylformamide. The thus obtained suspension was added dropwise to a stirred and heated (70° C.) solution of 3.95 parts of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide in 18 parts of N,N-dimethylformamide. Upon complete addition, stirring was continued overnight at 70° C. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:9:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was pulverised and evaporated again, yielding 1.13 parts (23%) of trans-3-hydroxy-4-[(1H-imidazol-5-yl)carbonylamino] -N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 155.0° C. (compound 43).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:24]=1[CH2:25]O>>[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: Cc1cccc(C)c1CO
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Product: Cc1cccc(C)c1COc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 24 with 2,6-dimethylbenzyl alcohol gave 2-(2-(3-(2,6-dimethylbenzyloxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.2 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.85-7.88 (m, 2H), 7.71-7.74 (m, 2H), 7.12-7.18 (m, 1H), 7.01-7.10 (m, 3H), 6.60 (dd, J=8.0, 1.8 Hz, 1H), 6.57 (s, 1H), 6.51 (dd, J=8.0, 1.8 Hz, 1H), 4.99 (s, 2H), 4.09-4.24 (m, 4H), 2.38 (s, 6H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[N:34]=[CH:33][C:32]=2[CH3:42])=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[NH:43]1[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44]1>CC(O)C.CCOC(C)=O>[OH:48][C@@H:45]1[CH2:46][CH2:47][N:43]([C:11]2[C:30]([C:31]3[N:35]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:34]=[CH:33][C:32]=3[CH3:42])=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=3)=[O:16])=[CH:13][N:12]=2)[CH2:44]1
Reactant: Cc1cnn(C2CCCCO2)c1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Reactant: O[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cnn(C2CCCCO2)c1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 140 °C

Procedure:
DIPEA (43.9 μL, 0.252 mmol) was added to a solution of 6-chloro-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 4.1, 55 mg, 0114 mmol) and (R)-pyrrolidin-3-ol (11.96 mg, 0.137 mmol) in iPrOH (114 μL) in a vial, which was sealed and heated at 140° C. for 18 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, EtOAc/MeOH 98:2) to afford 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide as an off-white foam. This intermediate (39 mg, 0.073 mmol) was dissolved in DCM (0.8 mL), treated with TFA (0.262 mL, 3.4 mmol) and stirred at RT for 3 h. The RM was poured into 25 mL Na2CO3 10% and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) to afford the title compound as an off-white powder. HPLC (Condition 4) tR=4.46 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=448.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.81 (m, 2H) 1.86 (s, 3H) 2.78-2.97 (m, 1H) 3.07-3.41 (m, 3H) 4.18 (br. s, 1H) 4.81 (br. s, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.58 (br. s, 1H) 7.85 (d, J=9.38 Hz, 2H) 7.93 (br. s, 1H) 8.73 (br. s, 1H) 10.14 (s, 1H) 12.63 (br. s, 1H).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cnc2c(C3CCN4CCCC4C3)c[nH]c2c1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2ncccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (more polar isomer) (22 mg, 0.091 mmol), 1-naphthalenesulfonyl chloride (38 mg, 0.18 mmol) and 1M NaN(TMS)2 (200 μL, 0.10 mmol) in THF (2.5 mL) at RT.
Reaction SMILES: CC[O-].[Na+].[Na].[C:6]1([CH2:12][O:13][C:14]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:28](Br)[C:29]#[CH:30]>C(O)C.C1(C)C=CC=CC=1>[C:6]1([CH2:12][O:13][C:14]([NH:16][C:17]([C:28]#[C:29][CH3:30])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: C#CCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC#CC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Yield: 41.9 %

Procedure:
A solution of sodium ethylate previously prepared from 500 mg of sodium in 20 ml of ethanol is added to 6 g of diethyl 2-[[(phenylmethoxy)carbonyl]amino]-propanedioate (prepared according to Bladon. C. M. J.Chem. Soc. Perkin. Trans I 9, 1151-1158 (1990) in 30 ml of ethanol then, after 30 minutes, 3 g of propargyl bromide at 80% in toluene is added and the reaction mixture is heated under reflux for 1 hour. The reaction mixture is then brought back to ambient temperature followed by evaporation under reduced pressure, taking up in dichloromethane, washing and drying. After evaporation under reduced pressure 6 g of the expected product is obtained which is purified by chromatography, eluting with a Cyclohexane/Ethyl acetate mixture 85/15. 2.82 g of purified product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][NH:9]1.F[C:20](F)(F)S(OC)(=O)=O>>[CH3:20][N:9]1[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12](=[O:13])[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2C)c1=O
Product: CCOC(=O)c1cn(C)n(-c2ccccc2C)c1=O
Yield: 66 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.1 g, 12 mmol) and methyl trifluoromethanesulfonate (2.5 mL) as starting materials, the title compound (2.1 g, 66%) was obtained as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2cc(F)cc(F)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
Methyl 2-(3,5-difluorobenzyl)piperidine-4-carboxylate (7.082 g, 26.30 mmol) was dissolved in DCM (170 mL) and DIPEA (5.50 mL, 31.56 mmol), then methyl carbonochloridate (2.88 mL, 36.58 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then additional methyl carbonochloridate (0.7 mL, 8.89 mmol) was added. The solution was stirred for 30 min then washed with 0.1 M HCl and satd NaHCO3. The organic phase was dried and concentrated to give dimethyl 2-(3,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.55 g, 99%). MS m/z 328 (M+H)+
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+].O>CN(C)C=O.C(Cl)(Cl)Cl>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: BrCCCCCCBr
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: BrCCCCCCN1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Phenothiazine (5.0 g, 0.025 mol) and 1,6-dibromohexane (10.0 g, 0.065 mol) were dissolved in 100 mL of DMF (dimethyl formamide), and NaOH (sodium hydride, 0.98 g, 0.041 mol) was slowly added at room temperature. The resulting mixture was stirred at room temperature for 8 hr. After completion of the reaction, work-up was implemented in a solvent mixture of water and CHCl3 at 1:1. Thereafter, the organic layer was separated using an extraction method, and the solvent was removed under reduced pressure, followed by silica gel column chromatography (chloroform:hexane, 1:5), affording a transparent liquid product (4.5 g, 49.7%).
Reaction SMILES: [OH:1][CH:2]([CH2:37][NH:38][CH:39]1[CH2:44][C:43]([CH3:46])([CH3:45])[N:42]([CH3:47])[C:41]([CH3:49])([CH3:48])[CH2:40]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:36])[CH2:23][NH:24][CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([CH3:33])[C:27]([CH3:35])([CH3:34])[CH2:26]3)=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.C(O[C:54](=[O:56])[CH3:55])(=O)C>C1C=CC=CC=1>[C:2]([O:36][CH:22]([CH2:23][N:24]([CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([CH3:33])[C:27]([CH3:34])([CH3:35])[CH2:26]1)[C:54](=[O:56])[CH3:55])[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([O:1][C:17](=[O:20])[CH3:16])[CH2:37][N:38]([CH:39]3[CH2:40][C:41]([CH3:49])([CH3:48])[N:42]([CH3:47])[C:43]([CH3:46])([CH3:45])[CH2:44]3)[C:5](=[O:4])[CH3:6])=[CH:6][CH:7]=2)([CH3:12])[CH3:13])=[CH:19][CH:18]=1)(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(C)(C)CC(NCC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CNC4CC(C)(C)N(C)C(C)(C)C4)cc3)cc2)CC1(C)C
Solvent: c1ccccc1
Product: CC(=O)OC(COc1ccc(C(C)(C)c2ccc(OCC(CN(C(C)=O)C3CC(C)(C)N(C)C(C)(C)C3)OC(C)=O)cc2)cc1)CN(C(C)=O)C1CC(C)(C)N(C)C(C)(C)C1

Procedure:
A mixture of 1 g of 2,2-bis[4-{2-hydroxy-3-[(1,2,2,6,6-pentamethyl-4-piperidyl)amino]propoxy}phenyl]propane, obtained as described in Example 4, and 1 g of acetic anhydride in 10 ml of benzene was reacted in a similar manner to that described in Example 8, giving the desired compound in the form of a white powder. The compound had an Rf value of 0.70 on thin layer chromatography on silica gel developed with a 9:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]=[CH:23][N:24]([CH2:26][CH2:27][N:28]([CH2:36][CH2:37][O:38][CH3:39])C(=O)OC(C)(C)C)[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]=[CH:23][N:24]([CH2:26][CH2:27][NH:28][CH2:36][CH2:37][O:38][CH3:39])[CH:25]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)=[O:43])[CH2:3][CH2:2]1
Reactant: COCCN(CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
To a solution of 252 (1 g, 1.63 mmol) in DCM (50 mL) was added TFA (15 mL) and the reaction mixture was stirred for 1.5 h then concentrated, diluted with water and 4M NaOH to pH 11 and extracted with DCM/MeOH. The extract was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 253 (800 mg, 1.56 mmol, 96% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.69 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 7.91 (d, J=1.2 Hz, 1H), 7.75 (d, J=0.8 Hz, 1H), 7.72 (dd, J=2.4 and 13.6 Hz, 1H), 7.66 (s, 1H), 7.36 (t, J=8.8 Hz, 1H), 7.21-7.16 (m, 1H), 6.57 (d, J=2.85 Hz, 1H), 6.54 (d, J=5.6 Hz, 1H), J=6.4 Hz, 2H), 3.36 (t, J=5.6 Hz, 2H), 3.22 (s, 3H), 2.89 (t, J=6.4 Hz, 2H), 2.67 (t, J=5.6. Hz, 2H), 2.58-2.53 (m, 1H), 0.68-0.61 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 511.56 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:22])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2/[CH:19]=[CH:20]/[CH3:21])[CH:7]=[CH:8][CH:9]=1.[H][H]>C1COCC1.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][OH:1])[C:5]2=[O:22])=[C:11]([CH2:19][CH2:20][CH3:21])[CH:12]=1
Reactant: C/C=C/c1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cc(N)ccc1-n1cccc(CCO)c1=O

Procedure:
520 mg (1.73 mmol) of the compound from Example 46A are dissolved in 10 ml of THF. 30 mg of palladium on carbon are added, and the mixture is hydrogenated at RT in a hydrogen atmosphere under atmospheric pressure. The mixture is then filtered through kieselguhr, the filter cake is washed three times with THF and the filtrate is freed from the solvent. The reaction product is reacted further without further purification. This gives 471 mg (89% of theory) of the desired product.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:22](=[O:31])[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]3=[O:30])=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.5 g (20.26 mmol) of tert-butyl(+/−)-2-cyclopentyl-2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-phenyl)acetate were initially charged in 95 ml of dichloromethane, 31.2 ml (405.2 mmol) of trifluoroacetic acid were added and the mixture was stirred at room temperature for 2 h. Water (250 ml) was then added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water, dried over magnesium sulfate and concentrated. This gave 6.98 g (95% of theory) of the target compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[C:10]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:12]([CH2:25][F:26])([CH2:23][F:24])[N:11]=1>CN(C)C=O>[F:26][CH2:25][C:12]1([CH2:23][F:24])[N:11]=[C:10]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(Cl)=NC(CF)(CF)O2
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1C1=NC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.2 %

Procedure:
In 1 ml of N,N-dimethylformamide was dissolved 62 mg of 2-pyrrolidinone and 35 mg of sodium hydride (60%) was added thereto under nitrogen stream. The mixture was stirred at room temperature for 20 minutes and 90 mg of 4-chloro-2,2-bisfluoromethyl-6-nitro-2H-1,3-benzoxazine dissolved in 2 ml of N,N-dimethylformamide was added thereto. The mixture was stirred at 45°-55° C. for 5 hours. After addition of saturated saline solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 50 mg of 2,2-bisfluoromethyl-6-nitro-4-(2-oxo-1-pyrrolidinyl)-2H-1,3-benzoxazine represented by the following formula having a melting point of 195°-198° C.
Reaction SMILES: [F:1][C@@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:3]([NH:6][S@@](C(C)(C)C)=O)[CH:4]=[CH2:5].CO.Cl.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>C(Cl)Cl>[F:1][C@@H:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@H:3]([NH:6][C:23](=[O:22])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:4]=[CH2:5]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=C[C@@H](N[S@](=O)C(C)(C)C)[C@@H](F)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C=C[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 105.4 %

Procedure:
To a 150 mL RBF containing (R)—N-((1S,2R)-1-fluoro-1-phenylbut-3-en-2-yl)-2-methylpropane-2-sulfinamide (107.00 mg, 397 μmol) was added methanol (5 mL) and the mixture was allowed to stir at 0° C. for 10 min. At this time, HCl (4N) (993 μl, 3972 μmol) was added and the reaction was allowed to stir for 30 min. Then TEA (1384 μl, 9930 μmol) was added to the mixture followed by DCM (2 ml) and BOC2O (173 mg, 794 μmol) in one portion. The reaction was allowed to stir overnight and then the bulk of the methanol was removed by evaporation. The residue was dissolved in EtOAc and washed with HCL (0.5 N, 2×40 ml). The combined aqueous layers were back extacted with EtOAc. The combined organics were washed with sodium bicarbonate (1×50 ml, sat) and brine and then dried with sodium sulfate. The dried solution was passed though a plug of silica gel to give tert-butyl (1S,2R)-1-fluoro-1-phenylbut-3-en-2-ylcarbamate (111.0 mg). Rf=0.45 in 20% EtOAc in hexanes, UV active and stain yellow to anisaldehyde. LC/MS give an ionization for eliminated product (mass=190).