Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:14][C:15]#[N:16]>CN(C)C=O>[C:15]([CH2:14][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)#[N:16]
Reactant: N#CCBr
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC#N)c1
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
To a solution of ethyl 1H-pyrazole-4-carboxylate (0.98 g, 7.0 mmol) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.42 g, 10.5 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 20 min. Bromoacetonitrile (0.63 mL, 9.10 mmol) was added to the reaction mixture, the ice bath was removed and the mixture was stirred for 4.5 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (1.14 g, 90%) as a colorless oil.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH3:17].I[CH2:19][CH2:20][CH3:21].O>CS(C)=O>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10](=[O:14])[N:11]2[CH2:19][CH2:20][CH3:21])=[CH:6][C:5]=1[CH3:17]
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 115.2 %

Procedure:
A mixture of powdered potassium hydroxide (1.26 g, 22.38 mmol) in DMSO (40 mL) was stirred at 0° C. for 10 min. 7-bromo-4,4,6-trimethyl-3,4- dihydro-1H-quinoline-2-one (Example 1e) (3.0 g, 11.19 mmol) was added cautiously, followed immediately by the addition of 1-iodopropane (5.5 mL, 55.95 mmol). The reaction mixture was warmed up to room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane washed with water and brine, dried (MgSO4), filtered and evaporated to give 4.0 g of 7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one and used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 0.98 (t, J=7.5 Hz,1 H), 1.26 (s, 6 H), 1.65 (t, J=7.5 Hz, 1 H), 2.37 (s, 3 H), 2.46 (s, 2 H), 3.88 (t, J=7.8 Hz, 2 H), 7.13 (s, 1 H), 7.15 (s, 1 H).
Reaction SMILES: C1COCC1.[C:6]([C:9]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:12]2[C:13]([CH3:28])([CH3:27])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[C:23](=[O:24])[C:11]=2[CH:10]=1)=[CH:20][CH:19]=[C:18]([C:25]#[N:26])[CH:17]=4)(=[O:8])[CH3:7].Cl[C:38]([CH3:42])([CH3:41])[C:39]#[CH:40].C(N(CC)CC)C>[Cu]Cl.O>[C:6]([C:9]1[C:30]([N:31]2[CH2:32][CH2:33][N:34]([C:38]([CH3:42])([CH3:41])[C:39]#[CH:40])[CH2:35][CH2:36]2)=[CH:29][C:12]2[C:13]([CH3:28])([CH3:27])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[C:23](=[O:24])[C:11]=2[CH:10]=1)=[CH:20][CH:19]=[C:18]([C:25]#[N:26])[CH:17]=4)(=[O:8])[CH3:7]
Reactant: CC(=O)c1cc2c(cc1N1CCNCC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N1CCN(c2cc3c(cc2C(C)=O)C(=O)c2c([nH]c4cc(C#N)ccc24)C3(C)C)CC1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To the anhydrous THF solution (0.5 mL) of 9-acetyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound H8-5, 25 mg, 0.06 mmol), 3-chloro-3-methyl-but-1-yne (0.013 mL, 0.12 mmol), copper (I) chloride (0.6 mg, 0.006 mmol) and triethylamine (0.017 mL, 0.12 mmol) were added at room temperature. After stirring for 30 min, the mixture was added with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by amino silica gel column chromatography (dichloromethane/methanol) to obtain the title compound (white solid, 9.8 mg, 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[ClH:10].Br[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Br>ClC1C=CC=CC=1.C(OCC)C>[ClH:10].[ClH:10].[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: BrCCNCCBr
Agent: Cl
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: Fc1ccc(N2CCNCC2)cc1F
Temperature: 25 °C
Yield: 201.2 %

Procedure:
A mixture of 3,4-difluoroaniline (3.6 g) and bis(2-bromoethyl)amine hydrochloride (5.0 g) in 50 mL of chlorobenzene is warmed to reflux under argon for 48 hours. The mixture is cooled to room temperature, diluted with 100 mL of diethyl ether, and extracted with three 150 mL portions of 1N HCl. The aqueous extracts are backwashed with three 50 mL portions of ether, which are discarded. The combined aqueous fractions are basified to pH 11 with 12N NaOH. The resulting mixture is extracted with three 50 mL portions of methylene chloride, and the combined organic extracts are dried over sodium sulfate. The solvent is removed under reduced pressure, and the resulting residue is taken up in 50 mL of diethyl ether and filtered through Celite. The resulting solution is treated with a 1 M ethereal HCl solution (56 mL), and the resulting precipitate is collected and dried under vacuum to give 5.1 g of the title compound, mp 100-104° C. (decomposes). ##STR7## Preparation of 2-[4-(3,4-difluoro-phenyl)-piperazin-1-ylmethyl]-quinoline
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[C:14]([C:26]([O:28]C)=[O:27])=[C:15]([C:18]2[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=2)[S:16][CH:17]=1)=[O:11].[OH-].[Li+]>O1CCCC1.CO.O.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[C:14]([C:26]([OH:28])=[O:27])=[C:15]([C:18]2[CH:23]=[N:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=2)[S:16][CH:17]=1)=[O:11]
Reactant: COC(=O)c1c(NC(=O)c2cc3ccccc3o2)csc1-c1cnc(OC)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc(-c2scc(NC(=O)c3cc4ccccc4o3)c2C(=O)O)cn1

Procedure:
The ester 161 and lithium hydroxide in tetrahydrofuran: methanol:water (3:2:1) is stirred at room temperature for 4 h. The mixture is diluted with DMF and purified by HPLC to provide 162.
Reaction SMILES: C([O:4][C@H:5]1[C@H:12]([O:13]C(=O)C)[C:9]2([CH2:11][CH2:10]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:18]=2)[C@@H:6]1[O:32]C(=O)C)(=O)C.C[O-].[Na+]>CO>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:7]2[C@H:6]([OH:32])[C@@H:5]([OH:4])[C@H:12]([OH:13])[C:9]3([CH2:11][CH2:10]3)[O:8]2)=[CH:18][C:19]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O)cc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(Cc2cc([C@@H]3OC4(CC4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of Acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester (60 mg, 0.1 mmole) in dry methanol (3 mL), sodium methoxide (3 mg) was added at room temperature and stirred for overnight. Reaction mixture evaporated to dryness. The crude product was purified by preparative HPLC to furnish 25 mg of (5S,6R,7R,8S)-5-[4-Chloro-3-(4-hydroxy-benzyl)-phenyl]-4-oxa-spiro[2.5]octane-6,7,8-triol.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[NH:8][CH:9]=[C:10]([F:12])[CH:11]=1)=[O:6])[CH:2]=[CH2:3].[Cl-].[NH4+:14].[OH-].[Na+].[OH-].[NH4+]>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.C(OC)(C)(C)C>[CH2:1]([O:4][C:5]([C:7]1[N:8]([NH2:14])[CH:9]=[C:10]([F:12])[CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(F)c[nH]1
Reactant: [NH4+]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: C=CCOC(=O)c1cc(F)cn1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
1-Amino-4-fluoro-1H-pyrrole-2-carboxylic acid allyl ester was prepared following the N-amination procedure described in Tetrahedron Lett., 47, 5341-43 (2006). 4-Fluoro-1H-pyrrole-2-carboxylic acid allyl ester (Example 14e, 2.49 g, 14.74 mmol) was mixed together with solid ammonium chloride (4.81 g, 90.75 mmol), 30% aqueous sodium hydroxide solution (42.4 mL), 29.56% aqueous ammonium hydroxide solution (13.71 mL) and trioctylmethylammonium chloride (“Aliquat® 336”, 0.166 g, 0.411 mmol) in methyl tert-butyl ether (50 mL). Under vigorous stirring, a 6.15% aqueous bleach solution (“Chlorox”, 146 mL) was slowly added via addition funnel upon which the color of the solution turned orange. After stirring for 2 h at 25° C., the layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (2×10 mL). The combined organic layers were washed with a saturated sodium thiosulfate solution (50 mL) and the organic layer was dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 20% ethyl acetate in hexanes) to afford the desired product, 1-amino-4-fluoro-1H-pyrrole-2-carboxylic acid allyl ester (2.02 g, 10.99 mmol, 62.1% yield). 1H NMR (400 MHz, CDCl3) δ: 4.73 (2H, d, J=5.5 Hz), 5.26-5.29 (1H, m), 5.34-5.40 (1H, m), 5.52 (2H, bs), 5.93-6.02 (1H, m), 6.49-6.53 (1H, m), 6.78-6.80 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:13]3=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.I[CH3:34].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:34])[C:13]3=[N:14][S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10][N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN2CCS(=O)(=O)N=C2C1c1ccc(-c2ccccc2)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2CCS(=O)(=O)N=C2C1(C)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 8 h

Procedure:
A suspension of tert-butyl 9-(2-fluorobiphenyl-4-yl)-3,4,6,7-tetrahydropyrazino[2,1-c][1,2,4]thiadiazine-8(9H)-carboxylate 2,2-dioxide (0.71 g), iodomethane (0.115 ml) and NaH (60%, 93 mg) in DMF (16 mL) was stirred at 0° C. to room temperature overnight. The reaction mixture was added with water and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane). The obtained material was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (150 mg) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](O)=[O:19]>>[CH3:27][O:26][C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[C:23]=1[O:24][CH3:25])[C:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([OH:12])[CH2:11][CH:2]1[CH3:1])=[O:19]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC1CC(O)c2ccccc2N1
Product: COc1cc(C(=O)N2c3ccccc3C(O)CC2C)cc(OC)c1OC
Yield: 33.4 %

Procedure:
Starting with 2-methyl-1,2,3,4-tetrahydro-4-quinolinol (3.00 g, 18.3 mmol) synthesized in the published manner and 3,4,5-trimethoxybenzoic acid (2.0 g, 10.9 mmol), the same procedure as shown in Reference Example 19 was repeated to give the titled compound (1.30 g, yield: 33%) as a white crystal. (cis:trans=1:1)
Reaction SMILES: [O:1]1CCC[CH2:2]1.C([Mg]Cl)CCC.CCCCCC.C([Li])CCC.Br[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:31][O:32][CH3:33])=[CH:26][N:25]=1.[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[CH3:33][O:32][CH2:31][CH:30]([C:27]1[CH:28]=[CH:29][C:24]([CH:2]=[O:1])=[N:25][CH:26]=1)[O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1
Reactant: C1CCOC1
Reactant: COCC(OC1CCCCO1)c1ccc(Br)nc1
Agent: CCCC[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COCC(OC1CCCCO1)c1ccc(C=O)nc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To tetrahydrofuran (250 mL) cooled to −20° C. were successively added a 2M butylmagnesium chloride tetrahydrofuran solution (11.2 mL) and a 1.6M n-butyllithium hexane solution (28.0 mL). The reaction mixture was stirred at −20° C. for 10 min, and a solution of 2-bromo-5-[2-methoxy-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyridine (17.66 g) in tetrahydrofuran (15 mL) was added at −20° C. to −10° C. over 20 min. The reaction mixture was stirred at −10° C. for 30 min and N,N-dimethylformamide (8.2 g) was added. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (9.48 g, yield 64%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 266 (MH+).
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.F[C:25]1[C:34]([O:35][CH3:36])=[C:33]2[C:28]([C:29](=[O:44])[C:30]([C:41]([OH:43])=[O:42])=[CH:31][N:32]2[C@@H:37]2[CH2:39][C@@H:38]2[F:40])=[CH:27][CH:26]=1>CS(C)=O>[NH2:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:25]3[C:34]([O:35][CH3:36])=[C:33]4[C:28]([C:29](=[O:44])[C:30]([C:41]([OH:43])=[O:42])=[CH:31][N:32]4[C@@H:37]4[CH2:39][C@@H:38]4[F:40])=[CH:27][CH:26]=3)[CH2:13]2)[CH2:10][CH2:11]1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(N2CC[C@@H](C3(N)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
After adding 3-(R)-[1-tert-butoxycarbonylaminocyclopropyl]pyrrolidine (165 mg, 731 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (2 ml), 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (180 mg, 609 μmol) was added thereto and it was heated under reflux for 13 hours under a nitrogen atmosphere. After concentrating the reaction solution under reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (5 ml) to the residue while cooling with ice, stirring was performed at room temperature for 30 minutes. 1 mol/l Hydrochloric acid (5 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (50 ml×4), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution and the insolubles were removed by filtration. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×4) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by preparative chromatography (development at the lower layer of a 7:3:1 mixture of chloroform methanol:water), recrystallized in isopropyl alcohol, and dried under a reduced pressure. 146 mg (60%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[OH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:24]2[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 66.4 %

Procedure:
14.1 g of 1-bis(4-fluorophenyl)methoxy-2-chloroethane, 10.1 g of 4-hydroxypiperidine, 12 g of sodium carbonate and 0.2 g of sodium iodide were added to 200 ml of methyl isobutyl ketone, and the mixture was heated under reflux for 4 hours. At the end of this time, it was filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography. Elution with a 10:1 by volume mixture of ethanol and methylene chloride afforded 11.5 g (yield 66%) of the title compound as a pale yellow oily substance. p Infrared Absorption Spectrum (CHCl3), νmax cm-1 : 2920, 1600, 1505.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:10]([CH3:32])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.BrC1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=1>ClCCl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:24][S:21]([C:19]1[CH:18]=[CH:17][C:16]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[C:15]([C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[CH2:9][CH:10]2[CH3:32])=[O:31])[CH:20]=1)(=[O:23])=[O:22]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1cc(S(C)(=O)=O)ccc1N1CCOCC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cc(S(C)(=O)=O)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of rac-4-(5-Methanesulfonyl-2-morpholin-4-yl-benzoyl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.54 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml) and the reaction mixture was stirred at room temperature for 30 min. After such time the reaction mixture was concentrated in vacuo, and the residue was dissolved in toluene (5 ml). To the solution were added 1-Bromo-4-trifluoromethyl-benzene (0.15 ml, 1.1 mmol), sodium-tert butylate (128 mg, 1.4 mmol), 2-(dicyclohexylphosphino)biphenyl (3.8.mg, 0.011 mmol), and tris(dibenzylidene-acetone)dipalladium-chloroform complex (5.5 mg, 0.005 mmol). The reaction mixture was then stirred for 16 hours at 80° C. After allowing to cool to room temperature the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2, 70 g, dichloromethane/methanol 0-5%) to give the title compound (83 mg, 30%). MS (m/e): 512.3 (M+H+)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:32])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:19]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH2:30][CH3:31].[C:33](O)(=[O:36])[CH2:34][OH:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C([O-])(O)=O.[Na+]>[CH2:28]([N:25]([CH2:26][CH3:27])[C:20]1[CH:19]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][C@H:3]([OH:32])[CH2:2][NH:1][C:34](=[O:35])[CH2:33][OH:36])=[C:7]([CH2:30][CH3:31])[CH:8]=3)[N:17]=2)[CH:23]=[C:22]([CH3:24])[N:21]=1)[CH3:29]
Reactant: O=C(O)CO
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of (R)-1-amino-3-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propan-2-ol (310 mg, 0.705 mmol), glycolic acid (59 mg, 0.776 mmol) and HOBt (114 mg, 0.846 mmol), EDC hydrochloride (149 mg, 0.776 mmol) is added. The mixture is stirred at rt for 1 h before it is diluted with sat. aq. NaHCO3 and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with DCM containing 12% of methanol to give N-(3-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-(R)-2-hydroxy-propyl)-2-hydroxy-acetamide (296 mg) as an off-white powder; LC-MS: tR=0.78 min; [M+1]+=498.19.
Reaction SMILES: [C:1]([CH:3]1[C:11](=O)[C:10]2[N:6]([CH:7]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=2)[CH2:5][CH2:4]1)#[N:2].O.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[C:3]2[CH2:4][CH2:5][N:6]3[C:10]([C:11]=2[NH:20][N:19]=1)=[CH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]3
Reactant: NN
Reactant: CCOC(=O)c1cc2n(c1)CCC(C#N)C2=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2n(c1)CCc1c(N)n[nH]c1-2
Yield: 78.1 %

Procedure:
To ethyl 7-cyano-8-oxo-5,6,7,8-tetrahydroindolizine-2-carboxylate (12 g, 52 mmol) in ethanol a solution of hydrazine monohydrate (6.5 g, 130 mmol) and acetic acid (9 g, 150 mmol) was added. The reaction was refluxed for 62 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and NH3. The organic phase was dried on Na2SO4. 10 g of a pale yellow solid were obtained (yield 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:19][CH2:20]Br.O>CN(C)C=O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:20][CH2:19]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl(4-nitrophenyl)acetate (5.0 g) in N,N-dimethylformamide (100 mL) was added sodium hydride (60% in mineral oil, 1.9 g) in an ice bath, and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added 1,2-dibromoethane (4.1 mL) in an ice bath, and the mixture was stirred at the same temperature for 30 min, and the at room temperature for 1 hr. The reaction mixture was colled to 0° C., water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.0 g).