Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:31]=[C:32]=[O:33])[CH2:27][CH2:28][CH2:29][CH3:30].C(Cl)Cl.CO>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:32]([NH:31][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:33])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CCCCCN=C=O
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: CCCCCNC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
A solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 4 mL of acetonitrile was stirred at 20° C. 156 μL (4 molar equivalents) of pentyl isocyanate in 3 mL acetonitrile were added. The mixture was magnetically stirred at 20° C. during 18 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95:5 ratio) to provide 37 mg (yield: 28%) of the desired product (formula below) as an orange powder
Reaction SMILES: [C:1]([CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[I:24]I>[B-](F)(F)(F)F.[Ag+].CO>[C:1]([CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([I:24])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: II
Reactant: COC(=O)C1C(c2ccc([Si](C)(C)C)cc2)C[C@@H]2CC[C@H]1N2C
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CO
Product: COC(=O)C1C(c2ccc(I)cc2)C[C@@H]2CC[C@H]1N2C

Procedure:
This compound was synthesized by the reaction of 2-Carbomethoxy-3-(4′-trimethylsilylphenyl)tropane with I2 in the presence of AgBF4 in MeOH as a solvent at 0 C. -rt (74%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>>[OH:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Reactant: CC(C)(CO)CBr
Agent: Cl
Product: CC(C)(CO)CN1CCC(c2cc3ccccc3c(=O)[nH]2)CC1
Yield: 15.2 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (510 mg) and 3-bromo-2,2-dimethyl-1-propanol (474 mg), 3-[1-(3-hydroxy-2,2-dim ethylpropyl)piperidin-4-yl]-2H-isoquinolin-1-one (92 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH3:12])[CH:11]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH3:16][N:17]([CH3:21])[C:18](=[O:19])[O:13][C:8]1[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])[CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: COC(COc1cc(C)cc(O)c1)OC
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COC(COc1cc(C)cc(OC(=O)N(C)C)c1)OC
Temperature: 80 °C

Procedure:
3-(2,2-Dimethoxyethoxy)-5-methylphenol (0.05 mole), N,N-dimethylcarbamoyl chloride (0.08 mole), triethylamine (0.05 mole) and xylene (50 ml) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is stirred and heated at 80° C. for a period of about 12 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then washed with water and dried over anhydrous magnesium sulfate. The dried solution is then filtered and stripped of solvent and unreacted starting materials to yield the desired product O-[3-(2,2-dimethoxyethoxy)-5-methylphenyl] N,N-dimethylcarbamate as the residue.
Reaction SMILES: [C:1]([C:3]1[CH:51]=[CH:50][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:23]3[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH3:34])=[C:28]4[C:24]=3[CH:25]=[CH:26][N:27]4C(OC(C)(C)C)=O)([O:15][CH:16]([F:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(OC(F)C(OCC)=O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N.Cl[Sn](Cl)(Cl)Cl>ClCCl>[C:1]([C:3]1[CH:51]=[CH:50][C:6]2[NH:7][C:8]([C:10]([C:23]3[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH3:34])=[C:28]4[C:24]=3[CH:25]=[CH:26][NH:27]4)([O:15][CH:16]([F:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]([F:14])([F:12])[F:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(F)OC(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CCOC(=O)C(F)OC(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(F)OC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(2-ethoxy-1-fluoro-2-oxoethoxy)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(2-ethoxy-1-fluoro-2-oxoethoxy)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 35-E) (94 mg, 0.128 mmol) in dichloromethane (2.0 ml) at 0° C. was added SnCl4 (1.0 M in DCM, 1.279 mL, 1.279 mmol); this mixture was stirred at 0° C. for 30 min followed by warming to room temperature and stirring for 1.0 hr additional. The reaction mixture was partitioned between EtOAc/saturated sodium bicarbonate solution upon which an emulsion formed. Both layers were filtered over a plug of Celite® and then returned to the separatory funnel as two distinct layers. The organic layer was washed with brine solution, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified with FCC eluting with ethyl acetate/heptane (0-100%) to provide the title compound. MS (ESI+) m/z 505.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6]S[CH2:4][CH2:3]1.O.O[O:33][S:34]([O-:36])=O.[K+]>C(#N)C.CO>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][S:34](=[O:36])(=[O:33])[CH2:4][CH2:3]1
Reactant: O=S([O-])OO
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCSCC4)c3n2)cc(OC)c1OC
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCS(=O)(=O)CC4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A suspension of (4-methyl-tetrahydro-thiopyran-4-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (9 mg, 0.02 mmol) in acetonitrile (0.4 ml), MeOH (0.4 ml), and water (0.2 ml) was treated with Oxone (26 mg, 0.04 mmol) and stirred overnight at room temperature. The reaction mixture was partitioned between EtOAc/water. The organic layers were collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography using 30% EtOAc in hexanes as eluant to provide 6 mg (62%) of (4-methyl-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as an off white solid. M+H=460.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:16])[CH:3](OC(=O)C)[O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.C(O)(=O)C>CCCCCC>[Cl:1][C:2]([Cl:16])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OC(Oc1cccc(C)c1)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1cccc(OC=C(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
71 g of 3-(2,2,2-trichloro-1-acetoxy-ethoxy)-toluene and 150 ml of acetic acid are stirred in a reaction vessel at 35°-45° C. 37 g of zink dust are added subsequently in the course of 2 to 3 minutes and the resultant reaction mixture is stirred for 1 hour at room temperature. The suspension is then mixed with hexane, filtered and washed. Acetic acid is removed by shaking out the organic phase with 2 N NaOH. After evaporation, 43 g 3-(2,2-dichlorovinyloxy)-toluene are obtained as a colourless oil, which can be used for processing without purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:33])[C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([Br:32])[CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.CCOC(C)=O>ClCCl>[Br:32][C:24]1[CH:23]=[C:22]([C:21]([CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[O:33])[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)cc(C(F)(F)F)c2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Br)cc(C(F)(F)F)c1)C1CCNCC1
Yield: 135.2 %

Procedure:
Add trifluoroacetic acid in dichloromethane (20%, 5 mL) to the solution of tert-butyl-4-(3-bromo-5-(trifluoromethyl)benzoyl)piperidine-1-carboxylate (387 mg, 0.88 mmol) in dichloromethane (5 mL) at 0° C., stir the mixture. TLC (PE:EtOAc=5:1) shows the reaction is complete. Concentrate under reduced pressure to dryness to afford the crude product (400 mg, 100%) which is used directly in next step. MS: (M+1): 336.0.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+].[N:27]#[C:28]Br>O1CCOCC1.O>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]2[O:13][C:28]([NH2:27])=[N:15][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(-c2ccccc2Nc2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.7 %

Procedure:
To a room temperature solution of 2-[(3-trifluoromethylphenyl)amino]benzoic acid hydrazide (532.7 mg, 1.81 mmoles) in 5 ml of dioxane is added sodium bicarbonate (155.0 mg, 1.84 mmoles) in 5 ml of water. After stirring at room temperature for five minutes, cyanogen bromide (192.0 mg, 1.81 mmoles) is added, and stirring is continued for 2.5 hours. The tan precipitate is removed by filtration and washed with 10 ml of 50% aqueous dioxane. Drying in vacuo provides 398.0 mg (69%) of 5-[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]-1,3,4-oxadiazol-2-amine, mp 185°-187° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>C1COCC1>[C:17]([CH2:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1)([OH:19])=[O:18]
Reactant: Cc1ccncc1C(=O)O
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)Cc1ccncc1C(=O)O
Temperature: 25 °C

Procedure:
To a rapidly stirred suspension of 4-methylnicotinic acid HCl (952 mg, 5.48 mmol) in THF (25 ml) at −78° was added n-butyl lithium (17.0 mmol) over 20 min, maintaining the temperature below −50°. The reaction was maintained at −78° for 1.5 h, the temperature raised to −30° and after 40 min CO2 gas bubbled through the solution for 10 min maintaining the temperature between −30 to −20°. The reaction was then allowed to warm to ambient temperature, poured into water (30 ml) and to this was added 1M HCl (30 ml). The solution was washed with DCM (2×20 ml) and the aqueous layer concentrated in vacuo at a temperature below 50° to give crude 4-(carboxymethyl)nicotinic acid as a brown oil. m/z (ES+, 70V) 182 (MH+). The brown oil was dissolved in trifluoroacetic anhydride (15 ml) and after 10 min heated at 100° in a sealed tube for 4 days. The solvent was removed under vacuum and the resulting crude 3-(trifluoromethyl)-1H-pyrano[3,4-C]pyridin-1-one, m/z (ES+, 70V) 216 (MH+) dissolved in concentrated NH4OH (10 ml) and heated at 100° for 1 h, additional concentrated NH4OH (10 ml) added after 20 and 40 minutes. The reaction was allowed to cool to ambient temperature, and the pale brown aqueous solution separated. The organic layer was separated and concentrated in vacuo to yield a brown/orange oily solid purified by column chromatography (SiO2:EtOAc) to give the title compound (957 mg, 82%) as a pale yellow solid. δH (DMSO-d6) 9.24 (1H, s), 8.71 (1H, d, J 5.4 Hz), 7.65 (1H, d J 5.4 Hz), 7.11 91H, s), 3.19 (1H, br s). m/z (ES+, 70V), 215 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](Cl)=[O:36].Cl>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:35]([C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:25]=3)=[O:36])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3ccccc3c2)cc1
Reaction time: 20 h
Yield: 64.4 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-1,2-benzenediamine (200 mg, 0.826 mmol) and pyridine (0.25 mL) in chloroform (5 mL) was treated with 2-naphthoyl chloride (158 mg, 0.826 mmol). After 20 h, the mixture was poured into a mixture of ethyl acetate and 1 N aqueous hydrochloric acid. The organic layer was washed with water, saturated sodium chloride solution, and dried (potassium carbonate), filtered, and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate yielded 211 mg (65%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([C:19]4[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=4[O:17][CH2:16]3)[C:8]2=[O:26])=[CH:4][CH:3]=1.C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.[C:75]([N:82]1[CH2:86][CH2:85][C@@H:84]([NH2:87])[CH2:83]1)([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:25][C:21]1[C:22]([F:24])=[CH:23][C:18]2[O:17][CH2:16][C:9]3([C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:87][C@@H:84]5[CH2:85][CH2:86][N:82]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:83]5)=[CH:28][CH:27]=4)[C:8]3=[O:26])[C:19]=2[CH:20]=1
Reactant: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc(F)c(F)cc12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(CN3C(=O)C4(COc5cc(F)c(F)cc54)c4ccccc43)cc2)C1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of 1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.44 g, 1.0 mmol) in anhydrous toluene (10 mL) was added (±)-(1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine) (0.093 g, 0.15 mmol) and (R)-(+)-1-Boc-3-aminopyrrolidine (0.26 g, 1.4 mmol), followed by tris(dibenzylideneacetone)dipalladium (0) (0.458 g, 0.1 mmol) and sodium tert-butoxide (0.19 g, 2.0 mmol). The reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue dissolved in ethyl acetate (100 mL). The mixture was washed with water (2×75 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 20% to 40% gradient of ethyl acetate in hexanes to afford tert-butyl (3R)-3-({4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]phenyl}amino)pyrrolidine-1-carboxylate (0.403 g, 74%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 7.25-7.11 (m, 4H), 7.05-7.00 (m, 1H), 6.89 (d, J=7.7 Hz, 1H), 6.78 (dd, J=10.3, 6.3 Hz, 1H), 6.59 (s, 1H), 6.56 (s, 1H), 6.49 (dd, J=7.9, 7.9 Hz, 1H), 5.02-4.93 (m, 2H), 4.74-4.69 (m, 2H), 4.01 (br s, 1H), 3.76-3.68 (m, 2H), 3.46 (m, 2H), 3.20 (m, 1H), 2.21-2.12 (m, 1H), 1.87 (br s, 1H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:21])[C:18]=1[O:19][CH3:20])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH2:8]1)=[O:6].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:21])[C:18]=1[O:19][CH3:20])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:30])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CS(=O)c3ccccc32)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (500 mg) was dissolved in chloroform (10 mL), and 70% metachloroperbenzoic acid (320 mg) was added to the solution, and the mixture was stirred at 0° C. for 10 minutes. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (336 mg) as a colorless crystal.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][NH:7][C:8](=[O:42])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([S:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[C:26]([CH3:41])[CH:25]=2)[CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[CH3:30][C:28]1[CH:29]=[C:24]([S:23][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:43])=[O:3])=[O:42])=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][C:19]([F:20])([F:22])[F:21])[CH:25]=[C:26]([CH3:41])[C:27]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(SC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
Racemic 3-{4-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid ethyl ester (0.150 g, 0.240 mmol) is dissolved in tetrahydrofuran (1.0 mL) and sodium hydroxide (1.0 mL, 5N) is added. The reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized with hydrochloric acid (1.0 mL, 5N) and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated. The title compound is used without further purification. MS (ES): 596.3 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH:10]([CH2:14][CH3:15])[C:11](O)=O.C>O>[Cl:9][CH:10]([C:11]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1)[CH2:14][CH3:15]
Reactant: Nc1cccnc1N
Reactant: CCC(Cl)C(=O)O
Solvent: O
Product: CCC(Cl)c1nc2cccnc2[nH]1
Temperature: 80 °C

Procedure:
5.0 g of 2,3-diaminopyridine in 200 g of polyphosphoric acid are heated at 120° C. for 0.5 h. The solution is cooled to 80° C. and 5.7 ml of 2-chlorobutyric acid are added. Thereafter, the reaction mixture is heated to 130° C. for 22 h. After cooling, the polyphosphoric acid is hydrolysed with 136 ml of water. After reheating to 90° C., charcoal is added under vigorous stirring. Subsequently, the suspension is filtered through a celite pad while still hot (70° C.). The filter cake is rinsed with 100 ml of water and the pH 4 using 9 M aqueous sodium hydroxide solution. The mixture is extracted three times each with 200 ml of ethyl acetate, the combined organic phases are dried using sodium sulfate, concentrated and purified by chromatography on silica gel (eluent: toluene/ethyl acetate 1:1) to give 5.19 g of the title compound as a colorless, amorphous solid. M.p. 137° C. MS: 196.0/198.0 (MH+, 100%/32%). TLC: Rf=0.50 (dichloromethane/methanol 10:1).
Reaction SMILES: C([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:17](=[O:26])[C:18]([CH3:25])([CH3:24])[CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:12]1)(OCC1C=CC=CC=1)=O>O1CCOCC1.[Pd]>[CH:27]1([N:16]([C:17](=[O:26])[C:18]([CH3:25])([CH3:24])[CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:13]2[CH2:14][CH2:15][NH:11][CH2:12]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(=O)OCC(C)(C)C(=O)N(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(=O)OCC(C)(C)C(=O)N(C1CCCCC1)[C@H]1CCNC1
Reaction time: 12 h
Yield: 94.1 %

Procedure:
To a solution of (3S)-1-Cbz-3-[cyclohexyl (acetyloxypivaloyl)amino]pyrrolidine (1.00 g, 2.25 mmol), prepared in Step B, in dioxane (10 mL) was added portionwise Pd/C (200 mg), and the mixture was stirred for 12 h under hydrogen. The reaction solution was filtered though Celite and the filtratae concentrated to give the title compound (657 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=O)[N:11]([C:15]3[C:16]([CH3:35])=[C:17]([CH3:34])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[C@H:20]([C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)[C:19]=4[C:32]=3[CH3:33])[C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1>CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:15]3[C:16]([CH3:35])=[C:17]([CH3:34])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[C@H:20]([C:25]5[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=5)[C:19]=4[C:32]=3[CH3:33])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([C@@H]2c3c(C)c(N4C(=O)CC(c5ccc(F)cc5)CC4=O)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCCCCC
Product: Cc1ccc([C@@H]2c3c(C)c(N4CCC(c5ccc(F)cc5)CC4)c(C)c(C)c3OC2(C)C)cc1
Yield: 76 %

Procedure:
Using (3R)-4-(4-fluorophenyl)-1-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)piperidine-2,6-dione obtained in Example 24, the title compound was synthesized in the same manner as in Example 28. Yield 76%. mp. 141–144° C. (hexane).
Reaction SMILES: O[Li].O.[CH2:4]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:13]([O:15]CCC(C)C)=[O:14])[CH2:5][CH:6]([CH3:8])[CH3:7].Cl>O.CO.C1COCC1>[CH2:4]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:13]([OH:15])=[O:14])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CCOC(=O)c1cc(OCCC(C)C)cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.2 %

Procedure:
4.05 g (96.6 mmol) LiOH.H2O were dissolved in a mixture of 100 mL H2O, 30 mL methanol and 40 mL THF. 5.2 g (16 mmol) 9 were added and it was stirred at r.t. for 20 h, during this time turning into a yellow, homogeneous solution. Most of the THF and methanol were taken off by rotovapping, the remaining solution was acidified with 2 N HCl and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried with MgSO4 and put under vacuum, yielding 3.9 g (96%) of a yellow solid, which was pure by NMR. For characterization, a sample was recrystallized from ethyl acetate. mp 142° C.; 1H NMR (CDCl3) δ 8.53 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 7.98 (t, J1=2.4 Hz, J2=2.4 Hz, 1H), 7.94 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 4.14 (t, J=6.4 Hz, 2H, PhOCH2CH2CH(CH3)2), 1.99-1.80 (m, 1H), 1.80-1.70 (m, 2H), 1.01 (d, J=6.3 Hz, 6H, CH(CH3)2); 13C NMR (acetone-d6) 165.52, 160.75, 150.12, 133.90, 122.35, 116.67, 113.68, 68.41, 38.33, 25.68, 22.74; ESI-MS m/z 252 [M−1]+.