Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.6 %

Procedure:
To 5-Acetyl-2-oxindole (2 g) in 15 mL of trifluoroacetic acid in an ice bath was slowly added 1.8 g of triethylsilane; the reaction was then stirred at room temperature for 5 hours. One mL of triethylsilane was added and the stirring continued overnight. The reaction mixture was poured into ice water and the resulting precipitate collected by vacuum filtration, washed copiously with water and dried under vacuum to give 1.3 g (71% yield) of the title compound as a yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[O:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22](O)=[O:23].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[O:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]([N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:23]
Reactant: O=C(O)[C@H]1CCCO1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (5.63 g, 23.3 mmol), (R)-tetrahydrofuran-2-carboxylic acid (2.24 mL, 23.3 mmol), DIPEA (10.2 mL, 58.3 mmol), and HOBt (3.15 g, 23.3 mmol) in dry dichloromethane (100 mL) at 25° C. was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (4.45 g, 23.3 mmol) in one portion. The mixture was stirred at 25° C. for 16 h then 1N HCl (50 mL) was added. The organic phase was separated, washed with saturated sodium bicarbonate solution, dried with Na2SO4, filtered and concentrated to afford intermediate (S)-benzyl 1-((R)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate as a yellow oil which was carried forward directly.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:27]([NH:29][CH2:30][CH2:31][S:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:28])[CH2:6][S:7]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].C(N[C@H](C(NCCSC(=O)C)=O)CS)(=O)C.C(Cl)Cl.CO>C(Cl)(Cl)Cl>[C:1]([NH:4][C@H:5]([C:27]([NH:29][CH2:30][CH2:31][S:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:28])[CH2:6][SH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)c1ccccc1
Agent: CC(=O)N[C@@H](CS)C(=O)NCCSC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N[C@@H](CS)C(=O)NCCSC(=O)c1ccccc1
Yield: 63 %

Procedure:
This compound is obtained by the S-detritylation of 12 (4.44 mmol). The protocol used is the same as that described in example 1 for the synthesis of I-152. After the various treatments, a gum is collected, which gum is purified by flash chromatography on a silica gel column (eluent: AcOEt/petroleum ether 50%). I-198 is isolated in the form of a white solid with a yield of 63%. Rf CH2Cl2/MeOH, 9.5/0.5): 0.38. M.p.=128-130° C. [α]D20=−24.7° (c 1.01, CHCl3).
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:8]=1)[CH3:5])([OH:3])=[O:2].S(Cl)(Cl)=O.[C:24]1(C)C=CC=CC=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[N:9]1[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([O:3][CH3:24])=[O:2])[CH3:5])=[N:8]1
Reactant: Cc1ccccc1
Reactant: CC(Oc1ncn(-c2ccc(Cl)cc2Cl)n1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)Oc1ncn(-c2ccc(Cl)cc2Cl)n1

Procedure:
Three g of the compound of Example 23 was added to 75 ml of toluene and 5 ml of thionyl chloride, and the solution was heated under reflux for 2 hours. It was then cooled and evaporated under vacuum. Fifty ml of toluene was added to the residue, and that solvent was also removed under vacuum. To the residue was then added 50 ml of methanol, and the solution was heated under reflux for 2 hours, cooled and evaporated under vacuum. The residue was recrystallized from toluene to obtain 0.68 g of the desired product, m.p. 74°-75°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:25]=1[CH2:26]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:26][C:25]3[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:24]=3[CH3:23])=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(C)c1CO
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1ccc(C2CN(CCC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.5 %

Procedure:
To a solution of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.45 g; 1.5 mmol) in THF (10 mL) was added 2,6-dimethylbenzyl alcohol (0.22 g; 1.6 mmol), followed by DIAD (0.43 mL; 2.2 mmol) and triphenylphosphine (0.58 g; 2.2 mmol). The resulting mixture was stirred at RT for 3 days. Subsequently, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 2:1) to afford 3-{2-[4-(2,6-dimethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (0.38 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH2:11].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][C:20](=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)c1ccc(C)cc1N
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(C)ccc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
To a 0° C. solution of 2-amino-4-methyl-benzoic acid methyl ester (1.5 g, 9.0 mmol) and triethylamine (1.4 g, 13.5 mmol) in methylene chloride (30.0 mL) is added butyryl chloride (1.2 g, 10.8 mmol) dropwise. The mixture is stirred at 0° C. for 30 min and is quenched with saturated sodium bicarbonate (10 mL). The organic phase is washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as syrup (2.2 g, 100%). LC-ES/MS m/e 236.3 (M+1).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([OH:3])=O.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.ClC1C=CC=CC=1Cl>C(OCC)(=O)C>[CH3:16][C:15]1([CH3:19])[N:14]2[C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[CH:4]=[C:1]2[O:3][CH2:18]1
Reactant: CC(C)(N)CO
Reactant: O=C(O)Cc1ccccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1Cl
Product: CC1(C)COc2cc3ccccc3c(=O)n21

Procedure:
A mixture of 1 g. of 2-carboxymethylbenzoic acid, 0.5 g. of 2-amino-2-methylpropanol, and 5 ml. of o-dichlorobenzene was heated to 150°-160° C. for 4 hours. After cooling, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was dissolved in 30 ml. of ethyl acetate. Then, the solution was successively washed with diluted hydrochloric acid, a diluted sodium carbonate solution, and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. By recrystallizing the residue obtained from cyclohexane, 700 mg. of 3,3-dimethyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-b]isoquinoline was obtained.
Reaction SMILES: [CH:1]1([C:6]2[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([NH:17][CH2:18][CH2:19][CH:20]=[O:21])[CH2:15][CH3:16]>C1C=CC=CC=1>[CH2:14]([N:17]([CH2:18][CH2:19][CH:20]=[O:21])[C:12]([NH:11][C:9]1[S:10][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:7][N:8]=1)=[O:13])[CH2:15][CH3:16]
Reactant: CCCNCCC=O
Reactant: O=C=Nc1nnc(C2CCCC2)s1
Solvent: c1ccccc1
Product: CCCN(CCC=O)C(=O)Nc1nnc(C2CCCC2)s1

Procedure:
A mixture of 5-cyclopentyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-propylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-propyl-3-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:18]3[C@@H:17]4[CH2:19][C@@H:16]4[CH2:15][C:14]=3[C:13]([C:20](O)=[O:21])=[N:12]2)[CH:6]=1)(=[O:4])=[O:3].[NH2:23][C@@H:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:25][OH:26]>>[OH:26][CH2:25][C@@H:24]([NH:23][C:20]([C:13]1[C:14]2[CH2:15][C@H:16]3[CH2:19][C@H:17]3[C:18]=2[N:11]([C:7]2[CH:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:10]=[CH:9][N:8]=2)[N:12]=1)=[O:21])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: CS(=O)(=O)c1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cc(S(C)(=O)=O)ccn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aR,5aR)-2-(4-(methylsulfonyl)pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (S)-2-amino-3,3-dimethylbutan-1-ol. LCMS m/z=419.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.44-0.48 (m, 1H), 1.05 (s, 9H), 1.23-1.28 (m, 1H), 2.21 (t, J=5.8 Hz, 1H), 2.26-2.32 (m, 1H), 2.79-2.85 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.04 (dd, J=16.6 and 6.3 Hz, 1H), 3.16 (s, 3H), 3.67-3.74 (m, 1H), 3.94-4.04 (m, 2H), 6.96 (d, J=9.2 Hz, 1H), 7.69 (dd, J=5.0 and 1.5 Hz, 1H), 8.38 (s, 1H), 8.72 (d, J=5.0 Hz, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:20])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[C:9]1[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].O.[OH-].[Na+]>C(OCC)C>[CH3:7][C:8]1([CH3:20])[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]=[C:9]1[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCC1=CC(=O)CCC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=CCCCC1=CC(O)CCC1(C)C
Yield: 78.2 %

Procedure:
To a suspension of lithium aluminum hydride (250 mg) in diethyl ether (20 mL) was added dropwise a solution of 4,4-dimethyl-3-pent-4-enyl-cyclohex-2-enone (1.05 g) obtained in Step 2 in diethyl ether (5 mL) under ice-cooling and nitrogen atmosphere, followed by stirring the reaction mixture under ice-cooling for 30 minutes. Then, after successive dropwise addition of water (0.25 mL), 4N aqueous sodium hydroxide solution (0.25 mL) and water (0.75 mL), the reaction mixture was stirred at room temperature for 30 minutes. After the resulting insolubles were filtered off, the filtrate was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=15:1 to 10:1) to give 4,4-dimethyl-3-pent-4-enyl-cyclohex-2-enol (830 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]2[CH:17]=[CH:18][CH:19]=[C:9]2[CH2:8][CH2:7]1)=[O:5].O.O.Cl[Sn]Cl>C(O)C.O1CCCC1>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]3[CH:17]=[CH:18][CH:19]=[C:9]3[CH2:8][CH2:7]2)=[O:5])=[C:2]([Cl:1])[CH:23]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCc2cccn2-c2ccccc21
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
To a solution of 0.50 g of 6,7-dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 10 ml of ethyl alcohol and 2 ml of tetrahydrofuran is added 2.35 g of SnCl2.2H2O and the mixture stirred at 55° C. for 30 minutes. The solvents are evaporated in vacuo to a residue which is stirred with 20 ml of 1 N NaOH and 40 ml of ethyl acetate for 15 minutes and filtered through diatomaceous earth. The filter pad is washed with 2×10 ml of ethyl acetate and the combined extracts washed with brine, dried (Na2SO4) and evaporated in vacuo to give 0.47 g of solid residue which is triturated with ether-hexane to give 0.43 g of light yellow crystalline solid. Ms(CI): 338(M+H, Cl35); 340(M+H, Cl37).
Reaction SMILES: CO[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1.B(Br)(Br)[Br:19]>>[Br:19][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: COCCc1ccc2oc(S(N)(=O)=O)cc2c1
Reactant: BrB(Br)Br
Product: NS(=O)(=O)c1cc2cc(CCBr)ccc2o1

Procedure:
This material is prepared by treatment of 5-(2-methoxyethyl)-2-sulfamoylbenzo[b]furan with boron tribromide.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:9]1[CH:13]=[CH:12][C:11]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[C:10]1=2>>[C:1]1([C:20]2([OH:21])[C:10]3[S:9][CH:13]=[CH:12][C:11]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2ccsc21
Reactant: Cl[Mg]c1ccccc1
Product: OC1(c2ccccc2)c2ccccc2-c2ccsc21

Procedure:
from phenylmagnesium chloride and indeno[2,1-b]thiophen-8-one (prepared as described in Rawson and Wyberg, Rec. Trav. Chim. 90, 1971:46-55)
Reaction SMILES: [F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@:16]2([F:25])[C@H:4]([C@H:5]3[C@:13]([CH3:27])([CH2:14][C@@H:15]2[OH:26])[C@@H:8]([C:9](=[O:12])[CH:10]=[O:11])[C@H:7]([CH3:28])[CH2:6]3)[CH2:3]1.ClCC[OH:32]>>[F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@:16]2([F:25])[C@H:4]([C@H:5]3[C@:13]([CH3:27])([CH2:14][C@@H:15]2[OH:26])[C@@H:8]([C:9](=[O:12])[C:10]([OH:32])=[O:11])[C@H:7]([CH3:28])[CH2:6]3)[CH2:3]1
Reactant: OCCCl
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@H]1C(=O)C=O
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@H]1C(=O)C(=O)O

Procedure:
3.3 g. of 6α,9α-difluoro-11βhydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-al is reacted under the conditions described in Example 46, but with 2-chloroethanol. The crude product is chromatographed on silica gel. With 25-27% acetone-hexane, after recrystallization from acetone/hexane, 1.11 g. of the 2-chloroethyl ester of 6α,9α-difluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-oic acid is obtained; m.p. 172.0° C. [α]D25 =+123° (chloroform). UV: ε238 = 17,200 (methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([F:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]([F:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-4-fluoro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B6) (5.81 g, 20 mmol) and pyrrolidine (8.27 mL, 100 mmol) in DMSO (40 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (6.42 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]2[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]([O:20]C)=[O:19])[CH:13]=[N:12]2)[CH2:6][CH2:5]1>CO.C1COCC1>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]2[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[CH:13]=[N:12]2)[CH2:6][CH2:5]1
Reactant: COC(=O)/C=C/c1cnn(CC2CCN(C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(Cn2cc(/C=C/C(=O)O)cn2)CC1

Procedure:
An aqueous 3N sodium hydroxide solution (2 mL) was added to a solution of (E)-methyl 3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)acrylate (220 mg) in MeOH (5 mL) and THF (3 mL) was added aq NaOH (3N, 2 mL) to saponify the methyl ester. Workup was performed as described in Example 12 to generate 209 mg of pure product (0.84 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([OH:23])=[C:18]([Cl:24])[CH:17]=1)(=[O:14])=[O:13].[H-].[Na+].Cl[C:28]1[S:29][C:30]2[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:31]=2[N:32]=1>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:28]2[S:29][C:30]3[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[C:18]([Cl:24])[CH:17]=1)(=[O:13])=[O:14]
Reactant: O=S(=O)(Nc1cc(Cl)c(O)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)sc2c1
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a solution of 2-chloro-N-(3,5-dichloro-4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide (421, 1.52 g, 3.41 mmol) in 10 mL of DMF, was added NaH (Aldrich, 288 mg, 60%, 7.2 mmol). The mixture was stirred for 10 min, then 2-chloro-6-nitrobenzothiazole (411, 765 mg, 3.56 mmol) was added. The reaction mixture was stirred until no 421 remained by TLC. The mixture was diluted with EtOAc and 2N HCl, extracted 3× with EtOAc (100 mL). The organic layers were washed twice with a brine solution (100 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (15%-20% EtOAc/hexanes) to give 1.5 g (74%) of product.
Reaction SMILES: C(OC([N:8]1[C:11]2([CH2:14][N:13]([C:15](=[O:26])[NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:15]([N:13]1[CH2:12][C:11]2([N:8]([S:34]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[CH2:9][CH2:10]2)[CH2:14]1)=[O:26]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCc1ccc(Cl)cc1Cl)C2
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(CCN2S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
In analogy to the experimental procedure of example 6b) 6-(2,4-Dichloro-benzylcarbamoyl)-1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of tert-butyl 1-(2,4-dichlorobenzylcarbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate was converted using 4-chlorobenzene-1-sulfonyl chloride into the title compound which was obtained as an off-white solid (41 mg, 23%). MS m/e: 474 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1)=[O:2].N1C=CC=CC=1.[O-:35][Mn](=O)(=O)=O.[K+]>O>[CH2:13]([N:8]([C:9](=[O:12])[CH2:10][CH3:11])[C:6]1[S:7][C:3]([C:1]([OH:35])=[O:2])=[CH:4][CH:5]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)CC)c1ccc(C=O)s1
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCN(C(=O)CC)c1ccc(C(=O)O)s1

Procedure:
57.8 g of N-(5-formyl-thien-2-yl)-N-hexadecyl-propionic acid amide are dissolved in 300 cc. of pyridine. A solution of 14.6 g of KMnO4 in 198 cc. of pyridine and 85 cc. of water is added with stirring and cooling such that the temperature of the reaction does not rise above -3° C. Stirring is continued until all of KMnO4 has been reacted. Thereafter, the solvent is distilled off, the residue is triturated with dillued acid and the mixture is extracted with chloroform. The chloroform layer is separated, washed with water and dried over Na2SO4. The solvent is evaporated and the resulting crude product is purified chromatographically on a column of silicic acid gel using chloroform as eluant.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=[NH:29])(C1C=CC=CC=1)C1C=CC=CC=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>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Cl:8][C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([NH2:29])=[CH:7][N:6]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Cl)ncc1Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ncc1N
Temperature: 110 °C
Reaction time: 15 h

Procedure:
308 mg of 5-bromo-2-chloro-4-methylpyridine was dissolved in 6 mL of toluene, added with 680 mg cesium carbonate, 0.3 mL of benzophenoneimine, 42 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl and 46 mg of tris(dibenzylideneacetone)bis palladium, and stirred under nitrogen atmosphere at 110° C. for 15 hours. The reaction solution was allowed to cool to room temperature, then added with saturated brine, extracted with ethylacetate, dried over magnesium sulfate, and then the solvent was evaporated. The residue was added with 10 mL of tetrahydrofuran and 10 mL of 5N hydrochloric acid, and stirred at room temperature for 1 hour. The reaction solution was added with aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), to afford 56 mg of the title compound.
Reaction SMILES: Br[CH:2]([C:16](=[O:18])[CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:4].[C-:19]#[N:20].[Na+].Cl>CS(C)=O.O>[CH3:17]/[C:16](/[OH:18])=[C:2](/[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:4])\[C:19]#[N:20]
Reactant: [C-]#N
Reactant: CC(=O)C(Br)C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 2-bromo-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (10 g) [obtained from above step-b] and sodium cyanide (1.69 g) in DMSO (30 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and acidified with 50% HCl solution. Precipitated solid was filtered and washed with water. The solid was dried to give Teriflunomide (7.12 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[O:16][C@H:17]1[CH2:26][CH2:25][C@@H:24]2[C@@H:19]([CH2:20][C@@H:21]([C:34]([OH:36])=[O:35])[N:22](C(OC(C)(C)C)=O)[CH2:23]2)[CH2:18]1)([OH:3])=[O:2].C(OCC)(=O)C.[ClH:43]>C(OCC)C>[ClH:43].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]=1[O:16][C@H:17]1[CH2:26][CH2:25][C@@H:24]2[C@@H:19]([CH2:20][C@@H:21]([C:34]([OH:36])=[O:35])[NH:22][CH2:23]2)[CH2:18]1)([OH:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](Oc3cc(-c4ccccc4)ccc3C(=O)O)C[C@@H]2C[C@H]1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(O)c1ccc(-c2ccccc2)cc1O[C@H]1CC[C@H]2CN[C@H](C(=O)O)C[C@H]2C1

Procedure:
The material from step B (350 mg, 0.71 mmol) was treated with ethyl acetate saturated with hydrogen chloride (7 mL) for 4 hours at room temperature. The mixture was concentrated in vacuo to afford, after trituration with ethyl acetate and diethyl ether, the desired aminoacid (250 mg, 82%).