Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.C(=O)=O.CC(C)=O.C[O:17][C:18]([C:20]1([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]1)=O.C(#N)C>C1COCC1>[O:17]=[C:18]([C:20]1([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]1)[CH2:2][C:3]#[N:5]
Reactant: COC(=O)C1(C(F)(F)F)CC1
Reactant: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CC#N
Product: N#CCC(=O)C1(C(F)(F)F)CC1
Temperature: 22 °C
Yield: 97 %

Procedure:
Add 2 M LDA solution in THF (19.15 mL, 38.3 mmol) to a dry ice-acetone cooled solution of 1-trifluoromethyl-cyclopropane-1-carboxylic acid methyl ester (2.93 g, 17.4 mmol) and acetonitrile (1.43 g mL, 34.8 mmol) in THF (30 mL). Stir reaction mixture at −70° C. for 1.5 hours and then allow to warm to 22° C. for 2 hours. Concentrate, add hexanes, and filter to give a yellow solid. Wash with hexanes and treat with diethyl ether (250 mL) then 2 N HCl (150 mL). Extract aq. layer with diethyl ether (4×100 mL). Dry the combined organic phases over sodium sulfate. Removal of solvent provides 3-Oxo-3-(1-trifluoromethyl-cyclopropyl)-propionitrile (2.99 g, 97% yield). MS (ES−): m/z=176.1 [M+H].
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>C(OCC)C>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
To a −78° C. solution of n-butyl lithium (10.4 mL, 2.5M in hexane, 26 mmol) in diethyl ether (20 mL) was added 2-bromothiazole (3.28 g, 1.8 mL, 20 mmol) slowly via syringe. The reaction mixture was stirred for 15 minutes, followed by the slow addition of 1,4-dioxaspiro[4.5]decan-8-one (4.22 g, 27 mmol) in diethyl ether (55 mL). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with two portions of ethyl acetate. The combined organic layers were concentrated. The residue was chromatographed on silica gel eluting with 0%-40% ethyl acetate-hexane to obtain the title compound (4.53 g, 94%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.69 (d, J=3.2, 1H), 7.55 (d, J=3.2, 1H), 3.88 (s, 4H), 2.11 (td, J=4.2, 12.8, 2H), 1.93-1.80 (m, 2H), 1.80-1.53 (m, 4H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.C1COCC1.Cl>[Zn].CO>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([NH2:11])[C:10]=3[CH:2]=[N:3]2)[CH:16]=1
Reactant: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1cccnc1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc2c1cnn2Cc1cccnc1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a vial containing 3-iodo-4-nitro-1-(pyridin-3-ylmethyl)-1H-indazole (0.145 g, 0.381 mmol) was added THF (2.4 mL) and MeOH (1.2 mL). To this solution was added Zn dust (0.249 g, 3.81 mmol) followed by HCl (2.54 mL, 7.63 mmol, 3.0 M aqueous). The mixture was stirred for 1.0 hours. The mixture was filtered through GF/F paper and the collected solids were washed with CHCl3 (30 mL). A saturated aqueous KOAc solution was added to the filtrate until the pH was neutral and then a saturated aqueous Rochelle's Salt solution was added. The mixture was stirred vigorously, the layers were separated and the aqueous phase was extracted with CHCl3. The combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (1 to 10% MeOH/CH2Cl2) to afford the product as a thick oil (0.041 g, 47%).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:4]=2[CH2:3]1.[N:21]1([CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][O:31][C:30]2=[O:34])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:24]3[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][O:31][C:30]4=[O:34])[CH2:22][CH2:23]3)[CH2:3][C:4]=2[CH:16]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: FC(F)(F)c1ccc2c(c1)CC(Cl)c1ccccc1S2
Solvent: ClC(Cl)Cl
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(C(F)(F)F)ccc3Sc3ccccc32)CC1

Procedure:
17 g of 10-chloro-10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin in 90 ml of chloroform and 26.2 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone are heated under reflux for 14 hours. The mixture is evaporated and the residue treated with ice-water, ether and 2-N aqueous sodium hydroxide. After equilibration, the organic phase is washed with water and acidified with ethanolic hydrochloric acid. The precipitate which separates is filtered off and dissolved in about 400 ml of water. The aqueous solution is extracted with ether. The aqueous solution is treated with ice, made alkaline with aqueous sodium hydroxide solution and extracted with about 350 ml of benzene. The benzene phase is dried over sodium sulphate, filtered and evaporated. There is obtained 3-[2-[4-(10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2 -oxazolidinone as an oil. By treatment with maleic acid there is obtained the corresponding maleate which is crystallised from ethanol/ether; melting point 168°-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].O[N:11]1C(=O)C2=CC=CC=C2C1=O>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][NH2:11]
Reactant: Nc1ccccc1CO
Reactant: O=C1c2ccccc2C(=O)N1O
Product: NOCc1ccccc1N

Procedure:
Prepared by a similar procedure as described for preparation 31 starting from 2-amino-benzylalcohol and N-hydroxyphthalimide. 13C-NMR (CDCl3) δ 146.4, 131.2, 129.7, 121.4, 118.1, 115.9, 76.6.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]2[C:7]=1[O:6][C@@H:5]([CH2:4][NH2:1])[CH2:14][CH2:13]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CCc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (R)-2-(azidomethyl)-8-(2,6-dichlorophenyl)-6-fluorochroman (0.26 g, 0.73 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.74 g, 2.2 mmol) and the reaction mixture stirred at room temperature for 2 days. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under vacuum. The solvent was removed under vacuum. Chromatography with 0–10% methanol in methylene chloride plus 1% NH4OH afforded {[(R)-8-(2,6-dichlorophenyl)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]methyl}amine as a colorless oil. The colorless oil was dissolved in ethyl acetate and made into its hydrochloride salt (0.18 g, 67%) as a white crystalline solid using excess ethereal hydrochloric acid, mp 190–192° C.; MS (ES) m/z 326.0 ([M+H]+); [α]D25=−4.39° (c 1% solution in MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.ClC(OCC)=O.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=[C:27]2[C:33]3[CH:34]=[C:35]([CH2:38][NH2:39])[CH:36]=[CH:37][C:32]=3[CH:31]=[CH:30][C:29]3[CH:40]=[CH:41][CH:42]=[CH:43][C:28]2=3)[CH2:23][CH2:22]1>C(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]3[CH:31]=[CH:30][C:29]4[CH:40]=[CH:41][CH:42]=[CH:43][C:28]=4[C:27](=[C:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)[C:33]=3[CH:34]=2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(CN)cc32)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCc1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1C=C2
Reaction time: 0.5 h

Procedure:
To a solution of 0.6 g (3.2 mmole) of 4-amino-5-chloro-2-methoxybenzoic acid in 15 ml of methylene chloride cooled to -15° C. was added 0.347 g (3.7 mmol) of ethyl chloroformate. The solution was stirred for 30 minutes and 1.0 g (3.2 mmole) of 1-methyl-4-(3-aminomethyl-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine in 10 ml of methylene chloride was added. The solution was allowed to stir at room temperature for 2 hours. The solution was washed with 1N sodium hydroxide solution, water, and brine, and then was dried (MgSO4). After filtration, the solvent was removed under reduced pressure to give 4-amino-5-chloro-2-methoxy-N-((5(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cyclohepten-3-yl)methyl)benzamide as an amorphous foam.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[Cl:21][C:22]1[CH:29]=[C:28](F)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>C(COC)OC>[Cl:21][C:22]1[CH:29]=[C:28]([CH:27]=[CH:26][C:23]=1[C:24]#[N:25])[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
Potassium tert-butoxide (5.57 g, 49.68 mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g, 24.84 mmol) in glyme (100 ml) and the mixture stirred for 30 min. before addition of 2 chloro-4-fluoro-benzonitrile (7.73 g, 49.68 mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate (250 ml) and water (200 ml). The organic layer was separated, dried over magnesium sulfate and the solvent evaporated. The residue was purified by flash chromatography eluting with ethyl acetate:isohexane (4:1) to give the subtitle compound as a colourless solid (3.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][O:31]C3CCCCO3)[CH2:13][N:12]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11](=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][OH:31])[CH2:13][N:12]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[C:11](=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CC(CCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(C(=O)N2CC(CCO)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 11.5 using 4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-2-one (3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH3:41])[CH:33]=2)=[O:31])=[CH:4][C:5]([F:28])=[C:6]([CH2:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26]C)=[O:25])[CH2:20][CH2:19]2)=[O:10])[CH:7]=1.C1COCC1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:3]([NH:29][C:30]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH3:41])[CH:33]=2)=[O:31])=[CH:4][C:5]([F:28])=[C:6]([CH2:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][O:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)=[O:10])[CH:7]=1
Reactant: COC(=O)C1CCC(OC[C@@H]2CCCN2C(=O)Cc2cc(Cl)c(NC(=O)c3cn(C)c4ccccc34)cc2F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2cc(F)c(CC(=O)N3CCC[C@H]3CO[C@H]3CC[C@H](C(=O)O)CC3)cc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To methyl 4-(1-((5-chloro-2-fluoro-4-(1-methyl-3-indolylcarbonylamino)phenyl)acetyl)-(2S)-pyrrolidinyl methoxy)-1-cyclohexanecarboxylate (556 mg, 0.953 mmol) were added THF (10 ml) and 0.25N NaOH (10 ml, 2.50 mmol). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was poured in 1N HCl (100 ml), followed by extraction with chloroform-methanol (5:1, 2×100 ml). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. To the residue were added chloroform and hexane. The crystals thus precipitated were collected by filtration under reduced pressure and dried under reduced pressure to give the title compound (400 mg, 74%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>O>[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]([CH3:10])[C:2]=1[NH:1][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C#N)cc(Cl)c1N
Solvent: O
Product: Cc1cc(C#N)cc(Cl)c1NS(C)(=O)=O
Temperature: 150 °C
Yield: 46.1 %

Procedure:
A mixture of 4-amino-3-chloro-5-methylbenzonitrile (155 mg, 930 μmol) and methanesulfonylchloride (2.13 g, 18.6 mmol, 1.44 mL) is heated under microwave conditions to 150° C. for 7 h. The mixture is cooled to rt, diluted with water and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC using heptane:EA 1:1 to give N-(2-chloro-4-cyano-6-methyl-phenyl)-methanesulfonamide (105 mg) as an orange solid; LC-MS**: tR=0.48 min; 1H NMR (CDCl3): δ2.59 (s, 3H), 3.18 (s, 3H), 6.27 (s, 1H), 7.55 (d, J=1.3 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10](OC)([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[CH2:16]([Si](C)(C)C)[CH:17]=C.[CH2:23](Cl)Cl>Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:23])([CH3:12])[CH2:11][CH:16]=[CH2:17])=[CH:6][CH:5]=1
Reactant: C=CC[Si](C)(C)C
Reactant: COC(=O)c1ccc(C(C)(C)OC)cc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: C=CCC(C)(C)c1ccc(C(=O)OC)cc1
Temperature: -78 °C
Yield: 38 %

Procedure:
827 mg of 4-(1-methoxy-1-methyl-ethyl)-benzoic acid methyl ester (3.97 mmol) (prepared as described in example S102) and 1.26 ml allyltrimethylsilane (7.94 mmol) were dissolved in 10 ml DCM and the solution was cooled to −78° C. Then 4.77 ml of a 1 M solution of TiCl4 in DCM were added dropwise. After 30 h the reaction was quenched at −78° C. by addition of methanol. Then water was added and the mixture was extracted 3 times with DCM. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and concentrated. The remaining residue was purified by chromatography (silica gel; cyclohexane/EtOAc 95:5) to give 331 mg (38%) of 4-(1,1-dimethyl-but-3-enyl)-benzoic acid methyl ester as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.33 (s, 6H), 2.38 (d, J=7 Hz, 2H), 3.90 (s, 3H), 4.91-5.00 (m, 3H), 5.51 (m, 1H), 7.41 (d, J=9 Hz, 1H), 7.97 (d, J=9 Hz, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(OC(C)(C)C)=O)=[C:18]([F:30])[CH:17]=2)[CH2:11]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:30])[CH:17]=2)[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (0.15 mL) was added to a solution of 5-(S)-aminomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one (0.325 g, 1.0 mmol) and pyridine (0.25 mL) in DCM (4.0 mL). The mixture was stirred at r.t. for 4 h, and solvent was removed under vacuum. The resulted 5-(S)-acetamidomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazoli-dine-2-one was washed with water (2×3 mL), diethyl ether (3 mL), and dried under vacuum. 50% TFA in DCM (3 mL) was added, and the mixture was kept at r.t. for 1 h. Solvents were removed under vacuum, and the residue distributed between ethyl acetate (40 mL) and saturated aq. sodium bicarbonate (20 mL). Organic layer was washed with aq. sodium bicarbonate, water, brine, dried (MgSO4). Solvent was removed under vacuum to afford the product as a white solid. Yield 0.25 g (95%). MS (m/z): [M+H]+=268.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13]C[C:11](=O)[CH:10](CC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I.O.[O:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:9][CH:10]([CH3:11])[C:26](=[O:22])[C:25]([CH3:19])([CH2:24][CH3:23])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CCC1CN(Cc2ccccc2)CCC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1(C)CN(Cc2ccccc2)CC(C)C1=O
Reaction time: 1 h

Procedure:
1-Benzyl-3-ethyl-piperidin-4-one (33 g, 152.0 mmole) was added to the stirred suspension of sodium hydride (9.5 g, 200.0 mmole) in tetrahydrofuran (300 ml) at 32° C. and stirring was continued for 1 hr. Methyl iodide (30 ml, 490.0 mmole) in dry tetrahydrofuran (100 ml) was added it at 0-5° C. The resulting mixture stirred at room temperature for 4 hr, water (100 ml) and ethyl acetate (800 ml) were added respectively. Organic layer was separated, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1-benzyl-3,5-dimethyl-3-ethylpiperidin-4-one. Yield 22.0 g (59%), C16H23NO, m/z 246 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:21])[C@H:10]([NH:13]C(OC(C)(C)C)=O)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.Cl.[OH-].[Na+]>O>[NH2:13][C@H:10]([CH2:11][OH:12])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N[C@H](CO)C(=O)NCc1ccccc1
Yield: 73.52 %

Procedure:
To a 500 mL four-neck round bottom flask, 34.0 g (R)-N-benzyl-2-(tert-butoxycarbonylamino)-3-hydroxypropionamide and 350 mL dichloromethane were added, and the mixture was stirred to obtain a clear solution. At 20-25° C., 40.0 g concentrated hydrochloric acid (having a mass concentration of 36.0%) was added, and the reaction was continued. TLC tracking was performed, till the raw materials were completely converted. After the reaction was completed, the temperature was decreased to 20° C. The mixture was suction-filtered, to obtain a white needle-like crystal. The obtained white crystalline solid was dissolved in 50 g water. At 20-25° C., 30% sodium hydroxide solution was added to adjust the pH value of the system to 8-9. After the addition, the solution was stirred continuously, and a white flaky crystal was precipitated. The mixture was suction-filtered, and the filter was washed and dried, to obtain a target product of 16.5 g (0.085 mol). The molar yield was 73.52%.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:20]([Mg]Cl)[CH2:21][CH3:22].[NH4+].[Cl-]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH2:20][CH2:21][CH3:22])[N:11]=2)=[CH:14][CH:15]=1
Reactant: CCC[Mg]Cl
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)cc2)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1nc(Oc2ccc(Cl)cc2)ccc1C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of product from Step 2 (73.0 g, 0.245 mol) and Fe(acac)3 (4.3 g, 12.2 mmol) in THF (1.2 L) cooled at −30° C. was added a solution of n-propylmagnesium chloride (2 M in Et2O, 245 mL, 0.49 mol) over 45 min, while maintaining the reaction temperature below −30° C. The dark-colored reaction mixture was stirred for an additional 15 min and poured into a saturated aqueous solution of NH4Cl (1.5 L). The organic layer was separated and washed with brine (1×250 mL). After removal of the solvent, the crude product was purified by chromatography on silica gel eluting with 100% hexane and then with 15:1 hexane:ethyl acetate to furnish the title product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:13]2[CH2:14][O:15]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: BrCC1CO1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)ccc1OCC1CO1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
A mixture of 5-bromo-2-hydroxybenzaldehyde (10 g, 50 mmol), epibromohydrin (13.6 g, 100 mmol) and K2CO3 (10.3 g, 75 mmol) in DMF (50 ml) was heated at 60° C. for 2 h. The mixture was cooled to ambient temperature and water and EtOAc was added. The phases were separated and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (isooctane/EtOAc) to give the title compound (12.3 g). MS m/z (rel. intensity, 70 eV) 256 (M+, 41), 201 (77), 200 (bp), 199 (84), 63 (60).
Reaction SMILES: C([O:5][C:6](=[O:94])[CH2:7][N:8]([CH2:86][C:87]([O:89]C(C)(C)C)=[O:88])[CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:18][C:17]=2[O:31][CH3:32])[CH:13]=[C:12]([CH2:33][N:34]([CH2:77][CH2:78][C:79]2[CH:84]=[CH:83][C:82]([NH2:85])=[CH:81][CH:80]=2)[CH2:35][C:36]2[N:41]=[C:40]([CH2:42][N:43]([CH2:52][C:53]([O:55]C(C)(C)C)=[O:54])[CH2:44][C:45]([O:47]C(C)(C)C)=[O:46])[CH:39]=[C:38]([C:60]3[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]([O:70]C(C)(C)C)=[O:69])=[CH:62][C:61]=3[O:75][CH3:76])[CH:37]=2)[N:11]=1)(C)(C)C>FC(F)(F)C(O)=O>[NH2:85][C:82]1[CH:81]=[CH:80][C:79]([CH2:78][CH2:77][N:34]([CH2:35][C:36]2[N:41]=[C:40]([CH2:42][N:43]([CH2:44][C:45]([OH:47])=[O:46])[CH2:52][C:53]([OH:55])=[O:54])[CH:39]=[C:38]([C:60]3[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]([OH:70])=[O:69])=[CH:62][C:61]=3[O:75][CH3:76])[CH:37]=2)[CH2:33][C:12]2[N:11]=[C:10]([CH2:9][N:8]([CH2:7][C:6]([OH:94])=[O:5])[CH2:86][C:87]([OH:89])=[O:88])[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][C:17]=3[O:31][CH3:32])[CH:13]=2)=[CH:84][CH:83]=1
Reactant: COc1cc(OCC(=O)OC(C)(C)C)ccc1-c1cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)nc(CN(CCc2ccc(N)cc2)Cc2cc(-c3ccc(OCC(=O)OC(C)(C)C)cc3OC)cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OCC(=O)O)ccc1-c1cc(CN(CC(=O)O)CC(=O)O)nc(CN(CCc2ccc(N)cc2)Cc2cc(-c3ccc(OCC(=O)O)cc3OC)cc(CN(CC(=O)O)CC(=O)O)n2)c1

Procedure:
A solution of compound 4 (40.0 mg, 0.031 mmol) in trifluoroacetic acid (0.40 ml) was stirred at room temperature for 2 hours. After evaporation without heating, the mixture was triturated with diethyl ether (10 ml) and filtered. Filtration left a pure product. The yield was 53 mg. 1H NMR (d6-DMSO, 400 MHz): δ 7.87 (2H, m), 7.75 (2H, s), 7.38 (2H, m), 7.17 (2H, m), 6.99 (2H, m), 6.68 (2H, d), 6.61 (2H, m), 4.74 (4H, s), 4.54 (4H, s), 4.09 (4H, m), 3.80 (6H, s), 3.56 (8H, s), 3.09 (4H, m).
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(-c3nnc(C(F)(F)F)o3)cc12
Agent: BrB(Br)Br
Product: Oc1cccc2oc(-c3nnc(C(F)(F)F)o3)cc12
Yield: 94.7 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(4-methoxybenzo(b)furan-2-yl)-5-trifluoromethyl-1,3,4-oxadiazole (4.0 g) and boron tribromide (15 ml), the title compound (3.6 g) was obtained as yellow crystals.