Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[CH2:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH2:34][CH3:35]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: CCCN1CCNCC1
Agent: OC1CCNC1
Product: CCCN1CCN(c2cc(-c3ccc(Sc4ccccc4OC)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 1-propylpiperazine. A yellow solid 114 was obtained (0.033 g, 69%). 1H-NMR (CDCl3, 400 MHz) δ 1.03 (t, J=7.3 Hz, 3H), 1.83–1.92 (m, 2H), 2.65–3.10 (br, 8H), 2.98–3.04 (m, 2H), 3.83 (s, 3H), 6.89 (s, 1H), 6.99–7.06 (m, 3H), 7.09 (d, J=8.1 Hz, 1H), 7.43–7.52 (m, 3H), 7.85 (s, 1H), 8.26 (d, J=5.9 Hz, 1H); MS (APCI) m/z 488 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([CH2:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11][CH2:10]1.[Br:19]Br.O>CO>[Br:19][CH2:15][C:14](=[O:16])[CH2:13][C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:17])([F:18])[F:1])[CH2:10][CH2:11][CH2:12]1
Reactant: BrBr
Reactant: CC(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Solvent: CO
Solvent: O
Product: O=C(CBr)CC1(c2ccccc2C(F)(F)F)CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
To an ice-cooled solution of 1-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propan-2-one (2.56 g, 10 mmol) in MeOH (15 ml) was added Br2 (0.5 ml, 10 mmol) slowly via a syringe. The reaction mixture was stirred for 15 min at 0° C., then 30 min at room temperature. To the reaction mixture was added H2O (15 ml) and the mixture stirred for 15 min at room temperature. The reaction was monitored by TLC, and TLC showed no starting material left 15 min after addition of H2O. The resulting solution was extracted twice with 25% n-hexane in EtOAc. The combined organic extracts were washed twice with saturated aqueous NaHCO3 solution, dried over sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel with 2% ether-hexane to yield 1.97 g of product.
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[CH2:19][OH:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[CH2:19][O:20][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@@H]1c1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 80.2 %

Procedure:
To a stirred solution of N-Boc-2-(S)-hydroxymethyl-5-(R)-phenylpyrrolidine (1.10 g, 3.97 mmol), triphenylphosphine (1.25 g, 4.76 mmol) and methyl 4-hydroxybenzoate (724 mg, 4.76 mmol) was added diisopropyl azodicarboxylate (955 ml, 4.76 mmol) at rt, and the resulting mixture was stirred at 60° C. for 45 min. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent to give methyl 4-[N-Boc-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.31 g, 80%) as a colorless oil. 1H-NMR (CDCl3) δ1.19 and 1.47 (brs, total 9 H), 2.09-2.15 (m, 3 H), 2.33-2.37 (m, 1 H ), 3.94 (s, 3 H), 4.30 (brs, 1 H), 4.41 (brs, 2 H), 4.77 (brs, 1 H), 7.03 (d, J=8.8 Hz, 2 H), 7.24-7.36 (m, 5 H), 8.03-8.06 (m, 2 H); MS (ESI) m/z, 412 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
To a stirred solution of 4-bromo-4′-hydroxybiphenyl (5.05 g, 20.2 mmol) in DMF (100 ml) were added K2CO3 (4.20 g, 30.4 mmol) and 1 -bromoheptane (4.14 ml, 26.4 mmol), and then the mixture was heated at 80° C. After being stirred at 80° C. for 20 h, the mixture was cooled to room temperature. The mixture was diluted with Et2O (250 ml) and then the solution was washed with sat. brine (150 ml×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized from CH2Cl2-petroleum ether to give 4-bromo-4′-heptyloxybiphenyl (6.21 g, 88%) as a white solid; FAB-MS: m/z 347[MH+].
Reaction SMILES: [C:1]([N:4]1[CH2:9][C@H:8]2[CH2:10][C@@H:5]1[C:6](=[O:11])[O:7]2)(=[O:3])[CH3:2].[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)(CC)(C)C>[N:12]1([C:6]([C@H:5]2[CH2:10][C@@H:8]([OH:7])[CH2:9][N:4]2[C:1](=[O:3])[CH3:2])=[O:11])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCNC1
Reactant: CC(=O)N1C[C@H]2C[C@@H]1C(=O)O2
Solvent: CCC(C)(C)O
Product: CC(=O)N1C[C@H](O)C[C@@H]1C(=O)N1CCCNCC1
Reaction time: 17 h
Yield: 71.9 %

Procedure:
A mixture of (1R,4R)-5-acetyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-one (310.3 g, 2.0 mol) and [1,4]diazepane (500.85 g, 5 mol) in t-amyl alcohol (3.0 L) was held at 90° C. for 17 h. The mixture was then concentrated to remove t-amyl alcohol (2.4 L). The resulting slurry was filtered and washed with EtOAc (1 L) to provide the title compound as a solid (367 g, 72%). MS (ESI): mass calcd. for C12H21N3O3, 255.2; m/z found, 256.2 [M+H]+. 1H NMR (CDCl3): 5.95 (br s, 1H), 4.93-4.68 (m, 1H), 4.48-4.32 (m, 1H), 3.90-3.65 (m, 5H), 3.54-3.41 (m, 1H), 3.12-2.74 (m, 4H), 2.32-2.22 (m, 1H), 2.16-1.68 (m, 6H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:23][C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:25].C(=O)([O-])O.[Na+]>C(#N)C>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]([CH2:23][N:12]2[CH2:13][CH2:14][N:9]([CH2:8][C:7]3[CH:6]=[C:5]([O:4][CH3:3])[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:10][CH2:11]2)=[O:25])=[CH:28][CH:29]=1
Reactant: COc1ccc(OC(=O)CCl)cc1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(OC(=O)CN2CCN(Cc3cc(OC)c(OC)c(OC)c3)CC2)cc1

Procedure:
A mixture of 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (prepared by the method disclosed in Belgian Pat. No. 560,330) (50 g), 4-methoxyphenyl chloroacetate (prepared by the method disclosed in U.S. Pat. No. 3,657,318) (33 g), sodium hydrogen carbonate (49 g) and acetonitrile (700 ml) is stirred at 60° C. for 3 hours. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to give crude 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(3,4,5-trimethoxybenzyl)piperazine (free base) (60 g) as an oily substance. This crude free base (60 g) is dissolved in a mixture of water (200 ml) and acetonitrile (50 ml) and thereto is added fumaric acid of about 2 moles (41 g) to 1 mole of the free base, and the mixture is heated. After the reaction mixture is allowed to cool at room temperature, the precipitated crystals are separated by filtration and recrystallized from a mixture of water and acetonitrile to give 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(3,4,5-trimethoxybenzyl)piperazine difumarate monohydrate (73.5 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[N:21][C:15]=3[NH:14][C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]2=3)=[O:10])=[CH:5][CH:4]=1.[CH3:32]I>CCCCCC.ClCCl>[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[N:21][C:15]=3[N:14]([CH3:32])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]2=3)=[O:10])=[CH:7][CH:8]=1
Reactant: CI
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CN1c2ccccc2N(C(=O)c2ccc(-c3ccccc3)cc2)Cc2cccnc21
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Sodium hydride (60% suspension, 0.10 g, 2.5 mmol) washed with hexane and dried under nitrogen, was suspended in dry N,N-dimethylformamide (15 mL). Following addition of 1,1′-biphenyl-4-yl-(5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone of Example 4 (0.76 g, 2.0 mmol), methyl iodide (0.5 mL, 2.4 mmol) was added. After stirring for 1 hour, the reaction was quenched with water and extracted with dichloromethane The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow solid. Purification of the residue by flash chromatography using a solvent gradient from 25% to 35% of ethyl acetate in hexane gave a white foam which was redissolved in dichloromethane, concentrated in vacuo to a foam, then crystallized by sonication from ethyl acetate/hexane to provide the title compound (0.48 g, 61.3%) as a white solid, m.p. 220-223° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>ClCCl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:19](=[O:20])[C:18]2[C:17]([F:16])=[CH:25][CH:24]=[CH:23][C:22]=2[F:26])=[N:6][CH:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Temperature: 25 °C

Procedure:
To a stirred solution of 2-bromo-5-amino-pyrazine (24 mmol), triethyl amine (TEA) (5 mL) in dry dichloromethane (DCM) (50 mL) at 00° C. was added 2,6-difluoro-benzoyl chloride (3.0 mL, 24 mmol) dropwise. The mixture was allowed to warm to room temperature over 2 h before it was washed with water (2×100 mL) and dried. Removal of solvents gave N-(5-bromo-pyrazin-2-yl)-2,6-difluorobenzamide (b) as white solid.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[C:2]1=[O:14].Cl.[OH2:16]>>[O:13]=[C:4]1[CH2:5][CH2:6][C:7]2[C:12](=[C:11]([CH2:1][C:2]([OH:14])=[O:16])[CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: O
Reactant: O=C1CCc2cccc3c2N1C(=O)C3
Agent: Cl
Product: O=C(O)Cc1cccc2c1NC(=O)CC2

Procedure:
A solution of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2,4(1H)-dione (1.87 g, 0.01 mole) in water (10 ml) is treated with a drop of concentrated hydrochloric acid. The mixture is refluxed 24 hours (or until the starting dione can no longer be detected by thin layer chromatography). The solution is cooled, and concentrated at reduced pressure. The product is purified by flash chromatography to vield 1,2,3,4-tetrahydro-2-oxo-8-quinoline acetic acid.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([Mg]Br)[CH2:9][CH:10]([CH3:12])[CH3:11].[Mg].C(Br)CC(C)C>CCOCC.[Cu]I>[CH3:3][C:2]([CH3:5])([C:1](=[O:6])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)CC[Mg]Br
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(C)CCBr
Product: CC(C)CCC(=O)C(C)(C)C
Reaction time: 16 h

Procedure:
To a stirred mixture of pivaloyl chloride (6.02 g, 0.05 m) and copper (I) iodide (0.10 g, 0.6 mm) in dry ether (50 mls) at -60° C. under nitrogen was added dropwise isoamyl magnesium bromide [prepared from magnesium turnings (1.8 g, 0.075 m) and isoamyl bromide (7.55 g, 0.05 m) in dry ether (70 mls]. The cooling bath was removed and the reaction mixture stirred for 16 hours then poured cautiously into ice-cold dilute hydrochloric acid and extracted with ether. The combined ethereal extracts were washed with saturated aqueous sodium hydrogen carbonate solution, brine, dried (anhydrous MgSO4) and evaporated. The residue was chromatographed on silica using gradient elution (dichloromethane (0-30%) in petrol) to give the ketone as a pale yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[N:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccon2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(CN2CCNCC2)no1

Procedure:
A solution of 0.84 g (3.2 mmol) of the title compound from Step B above in 5 mL dichloromethane and 5 mL trifluoroacetic acid was stirred at ambient temperature for 1 h. All volatiles were removed in vacuo and the crude light brown residue was carried forward without purification. LC/MS: m/z (ES) 168.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])(C)(C)C.CCCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>C1COCC1>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[B:20]([OH:25])[OH:21]
Reactant: Cc1cccc(Br)c1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cccc(B(O)O)c1C
Temperature: -78 °C
Yield: 185.2 %

Procedure:
To a solution of 3-bromo-o-xylene (500 mg, 2.7 mmol) in THF (15 mL) at −78° C. under N2 was slowly added 1.7 M tert-butyl lithium in pentane (1.77 mL, 3.0 mmol). This was stirred at −78° C. for 30 m. To the reaction mixture was added B(OiPr)3 (2.05 g, 11 mmol), and the reaction mixture was raised to 20° C. and stirred for 2 h. 3 N HCl (10 mL) was added to the reaction mixture and the acidic solution was stirred for 90 m. The reaction mixture was extracted using EtOAc (4×50 mL), and the organic solution was extracted using a 1 N solution of NaOH (100 mL). The aqueous solution was washed with Et2O (2×50 mL), acidified to pH 1 using concentrated HCl, and then extracted using EtOAc (4×50 mL). The organic solution was then washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford 2,3-dimethylphenylboronic acid compound (750 mg, 45%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[C:26]([CH2:32]Br)=[N:27][C:28]([Cl:31])=[CH:29][CH:30]=1>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:32][C:26]3[C:25]([Br:24])=[CH:30][CH:29]=[C:28]([Cl:31])[N:27]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccc(Br)c(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (4.94 g, 15.77 mmol) in THF (75 mL) was added NaH (60% dispersion in mineral oil) (0.526 g, 13.14 mmol). After stirring the reaction at room temperature for 10 minutes, 3-bromo-2-(bromomethyl)-6-chloropyridine (3.0 g, 10.51 mmol) was added as a solution in THF (20 mL). The reaction was stirred at room temperature for 16 hours and then quenched with saturated NH4Cl (40 mL). The mixture was diluted with EtOAc (100 mL) and hexanes (50 mL). The organic layer was washed with water (2×100 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 50% EtOAc/hexanes afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=518.8 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.90 (s, 1H), 7.81-7.83 (m, 3H), 7.18 (d, J=8.5 Hz, 1H), 5.87 (d, J=8.5 Hz, 1H), 5.02 (d, J=17.2 Hz, 1H), 4.42 (m, 1H), 4.32 (d, J=17.1 Hz, 1H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cc(F)cc(C#N)c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-5-fluorobenzonitrile (2.5 g, 12.5 mmol), (trimethylsilyl)acetylene (2.86 ml, 20 mmol), bis(acetate)bis(triphenylphoshpino) Palladium(II) (936 mg, 1.25 mmol) and triethylamine (35 ml) in toluene (35 ml) was 15 degassed by bubbling nitrogen through the solution and then stirred at 95° C. for 30 minutes. Filtration and concentration to yield a crude product. It was diluted with EtOAc (150 ml). The organic phase was washed with saturated NaHCO3 solution (50 ml), brine (50 ml) and the organic layer was dried over sodium sulfate. Filtration and concentration to yield a product A293.1 (2.4 g, 88%). HPLC: 95%, retention time: 4.05 minute (condition A). LC/MS (M+H)+=218.2.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([O:34]CC)=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>CO.O.O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([OH:34])=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCCC(C(=O)O)C3)ccc2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
NaOH (0.75 mL, 2M, 1.5 mmol) was added to a solution of ethyl 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}piperidine-3-carboxylate (158 mg, 0.36 mmol) in 10 mL of MeOH—H2O (1:1) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (40 mL). The solvent was concentrated to 40 mL. The resulting solution was neutralized with HCl solution and the product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 108 mg (72%); MS (ESI) (M+H)+=464.0.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.ICC>O1CCCC1>[CH2:1]([S:15][C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Fc1ccc(S)cc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCI
Product: CCSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
Triethylamine (5.44 mL, 39 mmol) was added to a solution of 4-fluorobenzenethiol (5 g, 39 mmol) and iodoethane (3.78 mL, 46.8 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at ambient temperature for 2 hours and then filtered. The filtrate was concentrated, triturated with hexane, and dried under vacuum to afford the title compound (4.8 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]1.[F:34][C:35]1[CH:36]=[C:37]([C@H:42]([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:43][C:44](O)=[O:45])[CH:38]=[C:39]([F:41])[CH:40]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:53][C:50]1[CH:49]=[CH:48][C:47]([C@@H:42]([C:37]2[CH:38]=[C:39]([F:41])[CH:40]=[C:35]([F:34])[CH:36]=2)[CH2:43][C:44]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=2[CH2:8][CH2:9][C@H:10]2[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:11]2)=[O:45])=[CH:52][CH:51]=1
Reactant: O=C(O)C[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)C[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2R,5R)-2-(2-(3-amino-5-fluoropyridin-4-yl)ethyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-4-carboxylate (75 mg, 0.16 mmol) and (3S)-3-(3,5-difluorophenyl)-3-(4-fluorophenyl)propanoic acid (44 mg, 0.16 mmol) in pyridine (1.0 mL) was cooled to −10° C. in an ice-acetone bath. To the stirred solution was added POCl3 (0.016 mL, 0.17 mmol) and the mixture was stirred for 30 min. The reaction was quenched by the addition of aqueous NaHCO3 solution and the resulting mixture was extracted with two portions of EtOAc. The combined EtOAc layers were dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-70% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a gum. LC MS: RT=1.41 min, M+H=743 (2 min gradient)