Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]1[O:32][CH:33]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[N:35]=1>CN(C=O)C>[C:18]([O:17][C:16]([NH:15][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:30][C:31]1[O:32][CH:33]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[N:35]=1)=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1coc(CCl)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1coc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.3 %

Procedure:
To a stirred solution of (S)-tert-butyl ((3-hydroxyphenyl)(phenyl)methyl)-carbamate (I8, 1 g, 3.34 mmol) in DMF (9.4 mL) at 0° C. under nitrogen was added K2CO3 (0.693 g, 5.01 mmol) followed by methyl 2-(chloromethyl)oxazole-4-carboxylate (0.586 g, 3.34 mmol). After 10 minutes at 0° C., the reaction was allowed to warm to room temperature and the stirring was maintained for 21 h. The reaction mixture was then partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL) and the combined organic phases were dried over MgSO4, filtered then concentrated in vacuo to give the title compound (1.66 g) as an off-white solid. The residue was taken on to the next step without further purification. LCMS (Method 1): [MH+]=439 at 4.22 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: COc1ccc(C(F)(F)F)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Product: COc1ccc(C(F)(F)F)cc1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 4-[2-methoxy-5-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (Preparation 319, 512 mg, 1.43 mmol) was hydrogenated for 16 hours over palladium (10 wt. % on activated carbon, 10 mg, 0.009 mmol) at a pressure of 40 psi. The reaction mixture was filtered through Celite™ and concentrated in vacuo to afford the title compound as a white solid, 503 mg.
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:12]=2)[CH2:7]1)[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:1][CH:2]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:12]=2)[CH2:7]1)[CH2:3][OH:4]
Reactant: CCCCCCCCc1ccc2c(c1)CC(C(N)C(=O)O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCc1ccc2c(c1)CC(C(N)CO)C2

Procedure:
The carboxylic acid 10 is reduced with lithium aluminum hydride to provide compound (9).
Reaction SMILES: C[Mg]Br.[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:10]=[C:9]2[C@@H:25]1[CH2:27][C@H:26]1[C:28](N(OC)C)=[O:29])#[N:5].[CH2:34]1COCC1>C(OCC)C>[C:28]([C@@H:26]1[CH2:27][C@H:25]1[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]#[N:5])[CH:7]=2)[N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:10]=1)(=[O:29])[CH3:34]
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)[C@@H]1C[C@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of methylmagnesium bromide (3.0 M in diethyl ether, 0.826 ml, 2.48 mmol, 1.05 equiv) was added to a suspension of [trans-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]cycloprop-1-yl]-N-methoxy-N-methylcarboxamide (1 g, 2.36 mmol) in anhydrous diethyl ether (25 ml). The resulting mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted anhydrous THF (15 ml) and stirred for an additional 3 h at 0° C. The cold mixture was quenched with aqueous 1 M hydrochloric acid (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude reaction mixture was purified by silica gel column chromatography using a step gradient [2:1, 1:1 (hexanes/ethyl acetate)] to afford 0.518 g (58% yield) of trans-3-(2-acetyl-cyclopropyl)-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile as a white solid: LC-MS (column=Phenomenex Luna C18 S10, 3×50 mm, start % B=0, final % B=100, gradient time=2 min, flow rate=5 ml/min) m/e 379 (M+H)+, tR 2.45 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:38])([F:37])[C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][C:28]4[N:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=O)[CH:29]=4)=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:13][CH:14]=1.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl.CN(C=O)C.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[F:38][C:8]([F:37])([F:7])[C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][C:28]4[CH:29]=[C:30]([C:34]([N:43]5[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]5)=[O:36])[N:31]=[CH:32][N:33]=4)=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)c2cc(Oc3ccc4c(c3)CCN4C(=O)Nc3cccc(C(F)(F)F)c3)ncn2)CC1
Reaction time: 1 h

Procedure:
60 μl (0.7 mMol) oxalylchloride are added to a solution of 200 mg (0.45 mMol) 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidine-4-carboxylic acid in 4 ml CH2Cl2 and 1 drop of DMF. After 1 h at rt, the solution is concentrated in vacuo. The residue is re-dissolved in THF and 108 μl (0.97 mMol) 1-methylpiperazine are added dropwise. After 2 h stirring, the mixture is diluted with EtOAc and sat. Na2CO3, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; EtOAc→EtOAc/EtOH+2% Et3N 4:1) and crystallization from EtOAc gives the title compound: m.p.: 203-204° C.; TLC(EtOAc/EtOH/NH3conc. 90:10:1): Rf=0.21.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1F)[NH2:7])([O-:3])=[O:2].[CH3:12][O-:13].[Na+].Cl.O>CO>[CH3:12][O:13][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[O-]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 21 h
Yield: 97.3 %

Procedure:
To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis., USA) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0° C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum to yield 17.5g (97%) of product as a dark brown solid, which was used without further purification. 1H NMR (400MHz, DMSO-d6) δ 7.09 (d, J=9Hz, 1H), 7.01 (dd, J=2.8, 1.3Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:14]1([C:2]2[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([NH2:9])=[O:8])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 24 h
Yield: 19.9 %

Procedure:
A mixture of 5-chloro-2-nitrobenzamide (2.0 g, 10.0 mmol), morpholine (2.6 mL, 30 mmol), and K2CO3 (4.1 g, 30 mmol) in DMF (20 mL) was stirred at 110° C. for 24 h. The reaction mixture was poured into water (100 mL) and the resulting precipitate was collected by filtration and recrystallized from ethanol to yield the product as a yellow solid (0.5 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[OH-:25].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:25])[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1
Reactant: FC(F)(F)c1nn2c(Cl)cc(Cl)nc2c1Cc1cccc(Cl)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-dichloro-3-[(2,3-dichlorophenyl)methyl]-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (0.83 g, 2.0 mmol) in THF (10 mL) and water (2.5 mL) was added 1.6 mL of 6N sodium hydroxide solution. Reaction mixture was stirred at 45° C. overnight. Reaction mixture was concentrated down to s small volume, and diluted with 10 mL of icy water. The pH of reaction solution was adjusted to ˜7, and extracted with ethyl acetate (35 mL×2). Combined organic layers were dried over anhydrous sodium sulfate, and concentrated to dryness. The crude material was purified with column chromatography. Product was obtained and used without further purification in the next step. (0.273 g, 34%); LC/MS: MS (ES+) m/e 396 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:60]1([C@H:66]([NH2:68])[CH3:67])[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][C@@H:66]([CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)[CH3:67])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H](N)C1CCCCC1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)N[C@H](C)C2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then (1R)-1-cyclohexylethanamine (60.9 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water and dried to give the title compound (196 mg) as a yellow solid. LC-MS (ES) m/z=465 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: BrCc1cccnc1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12
Product: O=C(c1cn(Cc2cccnc2)c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-1,2-dihydrospiro[indole-3,4′-piperidine] (prepared according to example 8) with commercially available 3-bromomethyl-pyridine gave the title compound.
Reaction SMILES: O.NN.[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([N+:22]([O-])=O)=[CH:17][C:16]=2[CH3:25])[CH:11]=[CH:12][CH:13]=1)([CH3:7])[CH3:6]>C(O)CC.[Pd]>[CH3:7][C:5]([C:8]1[CH:9]=[C:10]([O:14][C:15]2[C:16]([CH3:25])=[CH:17][C:18]([NH2:22])=[C:19]([CH3:21])[CH:20]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])[CH3:6]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cccc(C(C)(C)C)c1
Agent: [Pd]
Agent: NN
Solvent: CCCO
Solvent: O
Product: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N
Temperature: 90 °C

Procedure:
Hydrazine hydrate (4.3 ml) is added dropwise to a mixture of 1-{[3-(1,1-dimethylethyl)phenyl]oxy}-2,5-dimethyl-4-nitrobenzene (8.65 g) and 5% palladium-on-charcoal (100 mg) in n-propanol (60 ml) heated to 90° C. The reaction mixture is maintained at 90° C. for 2 h and then filtered through Celite. Concentration gives the title compound.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:28][C:24]1[CH:23]=[C:22]([NH:21][C:15]2[N:14]=[C:13]([C:11]3[CH:10]=[N:9][N:8]([CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5][C:6]#[N:7])[CH:12]=3)[C:18]([O:19][CH3:20])=[CH:17][N:16]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cnc(Nc2cccc(N)c2)nc1-c1cnn(C(CC#N)C2CC2)c1

Procedure:
A mixture of 3-cyclopropyl-3-(4-{5-methoxy-2-[(3-nitrophenyl)amino]pyrimidin-4-yl}-1H-pyrazol-1-yl)propanenitrile (from example 321, 0.010 g, 0.000025 mol) in 2 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under balloon pressure of hydrogen, for 2 h. After filtering off the catalyst, the filtrate was evaporated to dryness to provide the desired product as a racemic mixture (8 mg, 86.39%). LCMS (M+H) 376.1.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[F:25][CH2:26][CH:27]1[CH2:29][O:28]1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][N:23]([CH2:29][CH:27]([OH:28])[CH2:26][F:25])[CH:24]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: O=C(NCC1(O)CCCCCC1)c1cc(-c2c[nH]cn2)ccc1Cl
Reactant: FCC1CO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC1(O)CCCCCC1)c1cc(-c2cn(CC(O)CF)cn2)ccc1Cl
Yield: 87.6 %

Procedure:
A solution of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(1H-imidazol-4-yl)-benzamide(5 mg, 0.014 mmol) and 2-fluoromethyl-oxirane (0.06 mL, 0.086 mmol) in N,N-dimethylformamide (0.2 mL) was heated at 65° C. in a sealed tube for 20 h. The mixture was diluted with ethyl acetate and washed with water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (5.2 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)([O-:3])=[O:2].Cl>ClCCl.CCOCC>[N+:1]([C:4]1[CH:9]=[C:8]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:6][C:5]=1[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
Tert-butyl 4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate was dissolved in dichloromethane (3 mL) and treated with 1N HCl in ether (4 mL). The reaction was stirred overnight then concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]([O:24][CH3:25])[CH2:21][CH2:20][CH:19]2[C:26](O)=[O:27])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:40]([O:43][NH2:44])[CH:41]=[CH2:42].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>C(OCC)(=O)C.C(Cl)Cl>[CH2:40]([O:43][NH:44][C:26]([CH:19]1[CH2:20][CH2:21][CH:22]([O:24][CH3:25])[CH2:23][N:18]1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:16])=[O:17])=[O:27])[CH:41]=[CH2:42]
Reactant: COC1CCC(C(=O)O)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Reactant: C=CCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCONC(=O)C1CCC(OC)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.9 %

Procedure:
A solution of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid (0.077 g, 0.19 mmol), HOBT (0.044 g, 0.29 mmol), O-allylhydroxylamine hydrochloride (0.043 g, 0.29 mmol), di-isopropylethylamine (0.066 mL, 0.38 mmol) and CH2Cl2 (2 mL) was treated with EDCl (0.056 g, 0.29 mmol). After stirring for 24 h at room temperature, the mixture was diluted with ethyl acetate, washed with 1M HCl, saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo, affording 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid allyloxy-amide (0.090 g, 100%) as a colorless syrup:
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([O:17]C)=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3oc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=c1c2ccc(O)cc2oc2c([N+](=O)[O-])ccc(Cl)c12

Procedure:
A mixture of 20.0 g of 1-chloro-6-methoxy-4-nitro-9H-xanthen-9-one and 27.04 g of anhydrous powdered aluminum chloride was heated under reflux in 400 ml of 1,2-dichloroethane under an argon atmosphere for three hours. The liquid portion of the reaction mixture was decanted and evaporated to a dark residue. Both residues were combined and treated with 200 ml of concentrated hydrochloric acid for one hour. The solid was collected and washed with water and 2-propanol. The grey solid was dried in vacuo at room temperature to afford the title compound, mp 179°-182° C.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([O:4][C:5](=[O:29])[NH:6][CH:7]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19][CH2:18]1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:3].[OH-].[Na+]>C1COCC1.CO>[CH3:3][C:2]([CH3:30])([O:4][C:5](=[O:29])[NH:6][CH:7]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH3:1]
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(NC(=O)OC(C)(C)C)[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(trans-4-(2,2,11,11-tetramethyl-4,9-dioxo-3,10-dioxa-5,8-diazadodecan-6-yl)cyclohexyl)acetate (0.58 g, 1.35 mmol) in THF (5 mL) and MeOH (5 mL) was added 3N NaOH (2.25 mL, 6.75 mmol). The resulting mixture was stirred at RT for 3 h. After removal of volatiles by evaporation, the residue was acidified by 0.5N HCl solution to pH ˜4.5 and extracted with EtOAc, dried over Na2SO4. Filtration and evaporation to dryness gave the acid in a quantitative yield. LC/MS: 423.1 (MNa)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].Br.[K+].[Br-]>C(Cl)(Cl)Cl>[O:4]=[C:3]1[CH:2]([NH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:7][CH2:6][O:5]1
Reactant: NC1CCOC1=O
Agent: Br
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COC(=O)CNC1CCOC1=O
Yield: 31 %

Procedure:
This compound (9) was synthesized from (±)-α-amino-γ-butyrolactone×HBr using a method analogous to the synthesis described in Example 4. FC (silica gel, CHCl3). Yield: 31%. IR (KBr): 3333 (N--H), 1770, 1740 (C=O), 1216, 1165 (C--O). 1H-NMR (CDCl3): 2.05-2.18 (m, 1H); 2.47-2.57 (m, 1H); 3.57 (d, J=17.6, 1H); 3.63 (d, J=17.6, 1H); 3.64 (dd, J=8.1, 9.8, 1H); 3.75 (s, 3H); 4.21 (dt, J=6.3, 9.8, 1H); 4.42 (dt, J=2.3, 8.8, 1H).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[CH:9][CH:8]=1>>[S:1]([O:14][CH2:13][C:12]([O:11][C:10]1[CH:17]=[CH:18][C:7]([Cl:6])=[CH:8][CH:9]=1)([CH3:15])[CH3:16])(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(CO)Oc1ccc(Cl)cc1
Product: CC(C)(COS(N)(=O)=O)Oc1ccc(Cl)cc1
Yield: 58 %

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 2-(4-chlorophenoxy)-2-methylpropanol to give white solid, mp 76°-79° C., in 58% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Cl-].[I-:17]>C(O)(=O)C.C(OCC)(=O)C>[I:17][C:8]1[CH:7]=[CH:6][C:5]([NH2:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: [I-]
Reactant: CC(C)c1ccccc1N
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(I)ccc1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-isopropyl-phenylamine (262 mg, 1.94 mmol) and sodium acetate (159 mg, 1.94 mmol) in 5 mL acetic acid, was added iodide monochloride (409 mg, 2.58 mmol) at room temperature. The mixture was stirred at room temperature for 20 minutes, then diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give 4-iodo-2-isopropyl-phenylamine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]([OH:11])[C:3]=1[CH3:12].[H-].[Na+].C([Li])CCC.O1[C:22]([CH3:39])([CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:21]1.Cl>O1CCCC1>[CH3:12][C:3]1[C:4]([OH:11])=[C:5]([CH3:10])[C:6]2[CH2:9][CH2:36][C@:34]([CH2:33][CH2:32][CH2:31][C@@H:30]([CH2:29][CH2:28][CH2:27][C@@H:26]([CH2:25][CH2:24][CH2:23][CH:22]([CH3:39])[CH3:21])[CH3:38])[CH3:37])([CH3:35])[O:8][C:7]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C)c(O)c(C)c(C)c1O
Reactant: CC(C)CCCC(C)CCCC(C)CCCC1(C)CO1
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 1 h
Yield: 78.1 %

Procedure:
10 g (66.7 mmol) of tetramethylhydroquinone are dissolved in 100 ml of dry tetrahydrofuran, 4 g (139 mmol) of sodium hydride (80% in mineral oil) are added thereto at room temperature, 45 ml of butyllithium (1.6 molar in hexane) are subsequently added dropwise and the mixture is stirred for 1 hour. 10 g (44.3 mmol) of 1,2-epoxy -2,6,10,14-tetramethylpentadecane are now added dropwise; the mixture is left to react for 12 hours while stirring. 100 ml of 1N methanolic hydrochloric acid are added and the mixture is stirred at 50° C. for 2 hours. The mixture is subsequently concentrated at 50° C. and the residue is chromatographed on silica gel with toluene, whereby there are obtained 14.9 g (75%) of α-tocopherol.