Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:7][CH:6]=1.[F:23][C:24]([F:31])([F:30])[CH:25]([Mg]Br)[CH2:26]C>O1CCCC1>[F:23][C:24]([F:31])([F:30])[CH2:25][CH2:26][C:4]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:21]
Reactant: CCC([Mg]Br)C(F)(F)F
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Solvent: C1CCOC1
Product: O=C(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 0 °C
Yield: 80.5 %

Procedure:
N-Methoxy-N-methyl-6-(4-trifluoromethyl-phenyl)-nicotinamide (2.0 g, 6.45 mmol) is suspended in anhydrous tetrahydrofuran (25.0 mL), and cooled to 0° C. with stirring under nitrogen. 1,1,1-Trifluoro-butyl magnesium bromide (11.3 mL, 1.14M in tetrahydrofuran, 12.9 mmol) is slowly added to the reaction over 1 h. The reaction is allowed to warm slowly to room temperature and monitored by TLC. Upon complete consumption of starting material, the reaction is carefully acidified with 1N hydrochloric acid, extracted with diethyl ether, washed, dried, and concentrated. The 4,4,4-Trifluoro-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butan-1-one (1.80 g, 5.19 mmol) 80% yield, is used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)=[O:13])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>C(O)C>[CH3:30][C:29]([NH:33][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)=[O:13])=[CH:8][CH:7]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)N
Reactant: O=C(c1ccc(OCCCCl)cc1)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)NCCCOc1ccc(C(=O)c2cccc3[nH]ccc23)cc1
Temperature: 140 °C

Procedure:
A mixture of 7.75 g of the product of Step E, 6.83 g of potassium carbonate, 25.8 ml of tertbutylamine and 150 ml of ethanol was heated at 140° C. for 48 hours in an autoclave. After filtering, the filtrate was brought to dryness under reduced pressure and the 11.7 g of residue were chromatographed of silica (eluant: ethyl acetate-triethylamine (95-5)) to obtain 6.32 g of the desired product.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.CCN(CC)CC.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CC#N>[CH3:25][O:24][C:22](=[O:23])[CH2:21][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=2)=[N:4]1
Reactant: Oc1cccc(-c2nn[nH]n2)c1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)Cn1nnc(-c2cccc(O)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2H-tetrazol-5-yl)phenol (250.8 mg, 1.547 mmol) in MeCN (10 mL) at rt was added Et3N (0.237 mL, 1.701 mmol) followed by methyl bromoacetate (260 mg, 1.701 mmol). The reaction was stirred at rt for 16 h. Volatiles were removed. Chromatography over silica eluting with 30-60% EtOAc/hexanes afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.75 (d, 1H, J=7.5 Hz), 7.69 (s, 1H), 7.39 (t, 1H, J=8.0 Hz), 7.01 (dd, 1H, J=8.0, 2.3 Hz), 5.53 (bs, 1H), 5.50 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([CH3:7])=[C:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:14][C:15]1([CH3:27])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[O:16]1>CN(C=O)C.C(OCC)C>[CH3:7][C:3](=[C:4]([CH3:6])[CH3:5])[CH2:2][N:25]1[CH:26]=[C:22]([B:17]2[O:16][C:15]([CH3:27])([CH3:14])[C:19]([CH3:21])([CH3:20])[O:18]2)[CH:23]=[N:24]1
Reactant: CC(C)=C(C)CBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)=C(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
1-Bromo-2,3-dimethylbut-2-ene (3.78 g, 23.19 mmol), and cesium carbonate (15.11 g, 46.4 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.0 g, 15.46 mmol) in DMF (52 mL), and the mixture was stirred at 90° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with diethyl ether, washed with water (3×50 mL) and brine. The organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-40% EtOAc/hexane) to afford 1-(2,3-dimethylbut-2-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 7.62 (s, 1H), 4.74 (s, 2H), 1.83 (s, 3H), 1.74 (s, 3H), 1.59 (s, 3H), 1.31 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[C:28]([OH:32])([C:30]#[CH:31])[CH3:29].C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:31]#[C:30][C:28]([C:23]4[N:22]=[CH:27][CH:26]=[CH:25][N:24]=4)([OH:32])[CH3:29])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
A mixture of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (420 mg, 1.08 mmol), 2-(pyrimidin-2-yl)but-3-yn-2-ol (1 g, 6.75 mmol, 6.25 equiv), bis(triphenylphosphine)palladium(II) dichloride (800 mg, 1.14 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred under nitrogen for 1 hr at 90° C. The resulting mixture was concentrated under vacuum and the residue was purified by preparative HPLC to yield 18 mg (4%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as a light brown solid: 1H NMR (400 MHz, D2O) delta 8.75 (d, J=5.2 Hz, 2H), 7.52 (d, J=5.6 Hz, 1H), 7.46 (t, J=5 Hz, 1H), 7.30 (s, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 6.24 (d, J=5.2 Hz, 1H), 3.90 (s, 2H), 3.61 (s, 2H), 1.80 (s, 3H); LC-MS: m/z=+418 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:25][CH2:26][CH:27]1[O:29][CH2:28]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[CH2:28][CH:27]([CH2:26][Cl:25])[O:29][C:7]3([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: ClCC1CO1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN1C(=O)CN2CC(CCl)OC2(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
A mixture of 10 g. (35 mmole) of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H -1,4-benzodiazepin-2-one, 10 g. of aluminum chloride, and 200 ml. of dried benzene was treated with 30 ml. of 1-chloro-2,3-epoxypropane in 100 ml. of benzene. The reaction mixture was stirred overnight. Work-up as in Method A, Example 5, above gave 32 g. of a crude oil. The oil was dissolved in benzene, filtered over Florisil, evaporated to dryness and crystallized from ether-petroleum ether to give the above-titled product as colorless needles, m.p. 140°-142°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH:26](I)([CH3:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:26]([CH3:28])[CH3:27]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Reactant: CC(C)I
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OC(C)C)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and isopropyl iodide, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)C>[Si:13]([O:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C1OCCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxydihydrofuran-2(3H)-one (5 g, 49 mmol) in anhydrous DMF (50 mL) was added imidazole (6.7 g, 98 mmol) and TBDMS chloride (8.1 g, 54 mmol). The reaction was allowed to stir under an N2 atmosphere at room temperature overnight. The reaction was diluted with diethyl ether and washed with 1 N aqueous HCl×2 then brine×1. The organic phase was dried over Na2SO4 and the solvent removed in vacuo to yield 3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (11 g, 49 mmol) as a clear oil. [M+H] calc'd for C10H20O3Si, 217; found, 217.
Reaction SMILES: ClCCl.Cl.[F:5][C:6]([F:17])([F:16])[C:7]([N:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]1)=[O:8].[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]=O)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][NH:15][CH:12]3[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C:6]([F:5])([F:16])[F:17])[CH2:10][CH2:11]3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(N1CCC(NCc2ccc3c(c2)OCCO3)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 20 mL of a dichloromethane suspension containing 1.0 g of 1-(trifluoroacetyl)piperidine-4-amine hydrochloride, 0.71 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 0.25 mL of acetic acid were added, the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 1.37 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 minutes. The solvent was removed under reduced pressure, then water and ethyl acetate were added thereto, and the reaction mixture was adjusted to pH 1.5 with 1 mol/L hydrochloric acid. The aqueous layer was separated and washed with ethyl acetate, then ethyl acetate was added thereto, and the resultant solution was adjusted to pH 7.8 with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.4 g of a colorless oily substance, N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-(trifluoroacetyl)piperidine-4-amine.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:8]2[CH:13]=[N:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH:9]=2)[C:6]=1[CH3:7].[Cl:20][C:21]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]#[C:28][C:2]2[N:3]=[C:4]([CH3:19])[N:5]([C:8]3[CH:13]=[N:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH:9]=3)[C:6]=2[CH3:7])[CH:24]=[CH:23][N:22]=1
Reactant: COCCn1ncc(-n2c(C)nc(I)c2C)cc1=O
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Product: COCCn1ncc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, light brown crystalline solid, MS: m/e=384.2, 386.2 (M+H+), was prepared in accordance with the general method of example 35 from 5-(4-Iodo-2,5-dimethyl-imidazol-1-yl)-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 2-chloro-4-trimethylsilanylethynyl-pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.OO.S([O-])([O-])=[O:25].[Na+].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:25])([C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S([O-])[O-]
Reactant: Brc1ccc(P(c2ccccc2)c2ccc(Br)cc2)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 12 h

Procedure:
10.05 g (24 mmol) of bis(4-bromophenyl)phenylphosphine were dissolved in 200 ml of ethyl acetate in a 500 ml four-necked flask with internal thermometer, mechanical stirrer, reflux condenser and dropping funnel and cooled to an internal temperature of 5° C. A solution of 2.25 ml (26.4 mmol) of H2O2 (35%) in 17.5 ml of water was added dropwise over the course of 30 min., and the mixture was stirred at room temperature for a further 12 h. 25 ml of saturated sodium sulfite solution were subsequently added, the organic phase was separated off, washed twice with saturated sodium sulfite solution and dried over sodium sulfate. The solvent was removed under reduced pressure. The purification was carried out firstly by column chromatography on silica using a solvent mixture of initially hexane:ethyl acetate 2:1 to hexane:ethyl acetate 1:1. Further purification was carried out by recrystallisation from heptane/toluene, giving 6.5 g of product in a purity of 99.7% (according to HPLC). 1H-NMR (500 MHz, CDCl3): [ppm] 7.46-7.66 (m). 31P-NMR (CDCl3): [ppm] 28.40.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:21]([N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH:27]=[C:26]([NH:28][C:2]2[N:20]=[C:5]3[C:6]([C:10]4[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:25]=[N:24]1)[CH3:22]
Reactant: CCn1cc(N)cn1
Reactant: FC(F)(F)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: CCn1cc(Nc2nc3c(-c4ccc(C(F)(F)F)cc4)cccn3n2)cn1

Procedure:
(1-Ethyl-1H-pyrazol-4-yl)-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1.5-a]pyridine (0.100 g, 0.31 mmol) and 1-ethyl-1H-pyrazol-4-ylamine (0.046 g, 0.41 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (52 mg, 44%). MP=162-164° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.77 (d, J=6.36 Hz, 1H), 8.38 (d, J=7.76 Hz, 2H), 7.85-7.97 (m, 3H), 7.81 (s, 1H), 7.47 (s, 1H), 7.11 (t, J=6.80 Hz, 1H), 4.10 (q, J=7.12 Hz, 2H), 1.36 (t, J=6.92 Hz, 3H). MS=373 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.I[CH2:10][CH2:11][OH:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:10][CH2:11][OH:12])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: OCCI
Product: O=c1ccc(Br)cn1CCO

Procedure:
5-Bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one was prepared from 5-bromopyridin-2(1H)-one and 2-iodoethanol following a procedure analogous to that described in Example 20 Step 1.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C@@H:13]([NH2:14])[C:11](=[O:12])[S:10][CH2:9]1.Cl.[CH:16](=O)[CH:17]([CH3:19])[CH3:18].[BH3-]C#N.[Na+]>CO>[CH2:16]([NH:14][CH:13]1[CH2:8][CH2:9][S:10][C:11]1=[O:12])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C=O
Reactant: N[C@@H]1CCSC1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)CNC1CCSC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.6 mmol of triethylamine are added at 0° C., under an inert atmosphere, to a solution of 4.23 mmol of D-homocysteine thiolactone hydrochloride and 8.46 mmol of isobutyraldehyde in 20 ml of methanol. After stirring for 4 hours at ambient temperature, the reaction mixture is cooled to 0° C. and 8.8 mmol of NaCNBH3 are slowly added in the course of 40 minutes. After stirring for 30 minutes at 0° C., the reaction mixture is hydrolysed and then extracted with ether. The combined organic phases are then washed with a saturated NaCl solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 99/1) allows the expected product to be isolated in the form of syrup.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29]I>CCOC(C)=O.CCCCCC>[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:14])[F:1])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccc(OC(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)C(CCCCCl)c1ccc(OC(F)F)cc1
Yield: 15.6 %

Procedure:
Step AZ (1): 2-(4-(Difluoromethoxy)phenyl)acetic acid (5.0 g, 24.8 mmol) was deprotonated with NaHMDS (2.0 M in THF, 24.7 mL, 49.5 mmol) and reacted with 1-chloro-4-iodobutane (3.03 g, 24.7 mmol) using a procedure analogous to Step AC (1) to afford after purification by silica gel column chromatography (0-70% EtOAc/hexane), 6-chloro-2-(4-(difluoromethoxy)phenyl)hexanoic acid (1.13 g, 3.86 mmol, 15.61% yield) as a pale-yellow oil. LC-MS (M−H)− 291.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.30 (d, J=8.9 Hz, 2 H), 7.08 (d, J=8.5 Hz, 2 H), 6.29-6.66 (m, 1 H), 3.54 (t, J=7.6 Hz, 1 H), 3.49 (t, J=6.6 Hz, 2 H), 2.04-2.13 (m, 1 H), 1.72-1.82 (m, 3 H), 1.32-1.51 (m, 2 H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]12([C:37](O)=[O:38])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:27]34[CH2:36][CH:31]5[CH2:30][CH:29]([CH2:35][CH:33]([CH2:32]5)[CH2:34]3)[CH2:28]4)=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C12CC3CC(CC(C3)C1)C2

Procedure:
The title compound, light yellow solid (94 mg, 77%), MS (ISP) m/z=489.4 [(M+H)+], mp 200° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and adamantane-1-carboxylic acid.
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].Br[CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[C:13]([OH:18])=[C:12]([CH2:19][CH3:20])[CH:11]=1>C(OCC)C>[CH2:19]([C:12]1[CH:11]=[C:10]([CH2:9][CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[CH:15]=[C:14]([CH2:16][CH3:17])[C:13]=1[OH:18])[CH3:20]
Reactant: C[Si](C)(C)CCl
Reactant: CCc1cc(CBr)cc(CC)c1O
Agent: [Mg]
Solvent: CCOCC
Product: CCc1cc(CC[Si](C)(C)C)cc(CC)c1O

Procedure:
Mix magnesium turnings (240 mg, 10 mmol) and anhydrous ethyl ether under an inert atmosphere. Add a solution of chloromethyltrimethylsilane (1.9 g, 10 mmol) in anhydrous ethyl ether. Stir until the magnesium metal dissolves. Add a solution of 4-bromomethyl-2,6-diethylphenol (2.43 g, 10 mmol) in anhydrous ethyl ether and reflux the mixture until the reaction is complete. Pour onto a mixture of ice/hydrochloric acid and separate the layers. Wash the ethereal layer with water, dry (MgSO4) and evaporate to give the title compound which is purified by silica gel chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[CH:9]1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([O:15][C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)=[O:14])[N:10]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)O)c3)c(F)c2)C(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-carboxyimidazol-1-y l)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (181 mg, 0.5 mM), 4-nitrophenol (139 mg, 1 mM), dicyclohexylcarbodiimide (144 mg, 0.7 mM) and 4-dimethylaminopyridine (61 mg, 0.5 mM) were dissolved in N,N-dimethylformamide (2 ml). The mixture was stirred at ambient temperature for 17 hours, diluted with dichloromethane (20 ml), washed with 1M aqueous sodium dihydrogen phosphate (10 ml), water (2×10 ml), and dried over magnesium sulfate. After filtration and evaporation to a suitable volume, the solution was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give title product (210 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@@H:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][O:22]C2CCCCO2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].Cl>CO>[Br:1][C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@@H:20]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][OH:22])[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8]
Reactant: Cc1c(Br)c(=O)n(C[C@H](COC2CCCCO2)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Agent: Cl
Solvent: CO
Product: Cc1c(Br)c(=O)n(C[C@H](CO)c2ccccc2)c(=O)n1Cc1c(F)cccc1F

Procedure:
To the THP protected alcohol (0.945 g, 4 mmol) in THF was added 4d.1 (1.311 g, 1.0 eq), followed by addition of Ph3P (1.311 g, 1.25 eq) and di-tert butyl azodicarboxylate (1.15 g, 1.25 eq). The mixture was stirred at room temperature overnight. The mixture was then concentrated and purified by flash column chromatography to give 5-bromo-1-[2,6-difluorobenzyl]-3-{3-(2-tetrahydro-2H-pyranyloxy)-2(R)-phenylpropyl}-6-methylpyrimidine-2,4(1H,3H)-dione [MS (CI) m/z 464.9 & 466.9 (MH+−THP); tR=2.782 (method 4)]. 5-Bromo-1-[2,6-difluorobenzyl]-3-{3-(2-tetrahydro-2H-pyranyloxy)-2(R)-phenylpropyl}-6-methylpyrimidine-2,4(1H,3H)-dione (110 mg) was treated with 1N HCl (10 mL)/MeOH (10 mL) at room temperature for 1 hour. The reaction mixture was concentrated and purified by prep TLC plate to yield 5-bromo-1-[2,6-difluorobenzyl]-3-{3-hydroxy-2(R)-phenylpropyl}-6-methylpyrimidine-2,4(1H,3H)-dione. MS (CI), m/z 464.9 & 466.9 (MH+); tR=2.613 (method 4). Suzuki coupling with 2-fluoro-3-methoxyphenylboronic acid by the procedure of Step 8B gave compound 8b.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:25])=[CH:22][CH:21]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(OC(F)(F)F)cc3)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-(trifluoromethoxy)benzoyl chloride (36 μL, 0.229 mmol) and mixing for 24 h, 50.1 mg (>100%) of the title compound were recovered.