Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:32][CH2:31][CH2:30][CH2:29][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:33])([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:5]1[CH2:32][CH2:31][CH2:30][CH2:29][C:8]2[C:9]([C:37]3[CH2:38][CH2:39][O:34][CH2:35][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1-c1cccnc1)-c1c(C3=CCOCC3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 125 °C

Procedure:
A mixture of 75 mg of 25b, 37 mg of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane, 41 mg of K2CO3 and 17 mg of tetrakis(triphenylphosphine)palladium(0) in 3 ml of degassed DMF was heated under N2 atmosphere at 125° C. for 2 hr. The reaction was cooled and diluted with 15 ml of water. The product was extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated. The remainder was chromatographed over silcagel (using a gradient of heptane/acetone as eluent). The product isolated was triturated with diethyl ether, providing 57 mg of white crystalline 25c; Mp 208-210° C. LC-MS-ESI: [M+1] 512.13. NMR (CDCl3) δ 8.70, 8.58, 7.88, and 7.37 (4×m, 4, pyridine-H), 7.68 and 6.87 (2×s, 2, Ar—H), 1.60 (s, 9, tertC4H9), 3.87 (s, 3, OCH3), 5.75 (m, 1, CH), 4.30 (m, 2, CH2O), 4.70 (bm, 1, CH2), 3.55 (bm, 1, CH), 3.85 (bm, 4, 2×CH2) 3.00 and 3.20 (2×bm, 2, CH2), 2.63 (bm, 2, CH2), 2.35 (m, 2, CH2), 1.70-2.05 (bm, 4, 2×CH2).
Reaction SMILES: C(O[CH:4]=[C:5]([CH3:12])[C:6](=O)[C:7]([F:10])([F:9])[F:8])C.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][C:5]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:14][NH:15][CH:4]=1
Reactant: NN
Reactant: CCOC=C(C)C(=O)C(F)(F)F
Solvent: O
Solvent: CCO
Product: Cc1c[nH]nc1C(F)(F)F
Yield: 84.9 %

Procedure:
1.7 g (10.2 mmol) of 4-ethoxy-3-methyl-1,1,1-trifluoro-3-buten-2-on and 0.6 g (12.0 mmol) hydrazine hydrate were stirred in 50 ml of ethanol at room temperature for 2 hours. The ethanol was distilled off iunder reduced pressure, and the residue was separated with ethyl acetate and water. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.3 g of 4-methyl-3-trifluoromethylpyrazol (yield 86.7%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([Cl:8])Cl)#[N:2].[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10]>>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[P:6]([Cl:8])[O:5][CH2:4][CH2:3][C:1]#[N:2])([CH3:11])[CH3:10]
Reactant: N#CCCOP(Cl)Cl
Reactant: CC(C)NC(C)C
Product: CC(C)N(C(C)C)P(Cl)OCCC#N

Procedure:
Chemistry FIG. 11 illustrates the synthesis of diphosphitylating and triphosphitylating reagents (6 and 7). Phosphorus trichloride (21, 20 mmol) was reacted with 3-hydroxypropionitrile (22, 1 eq) to yield 2-cyanoethylphosphorodichloridite (23). The subsequent reaction of 23 with diisopropylamine (20 mmol, 1 eq) afforded 2-cyanoethyl diisopropylphosphoramidochloridite (24). Addition of water (1 eq) gave the intermediate 25 that was reacted with 24 (1 eq) or 23 (0.5 eq) to yield the diphosphitylating (26, 97%) and triphosphitylating (27, 94%) reagents, respectively. The chemical structures of 26 and 27 were determined by nuclear magnetic resonance spectra (1H NMR, 13C NMR, 31P NMR) and high-resolution time of flight electrospray mass spectrometry. Stability studies using spectroscopic methods showed that the compounds remained stable even after two weeks storage at −20° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([Sn:14]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])N(C)C)[CH2:11][CH2:12][CH3:13].[CH2:26]([N:33]=[N+:34]=[N-:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([Sn:14]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[N:35]=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Reactant: C#Cc1ccc(F)cc1
Reactant: [N-]=[N+]=NCc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2ccccc2)c1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4-Fluorophenyl acetylene (525 mg, 4.37 mmol) was added to 1,1,1-tributyl-N,N-dimethylstannanamine (1.46 g, 4.37 mmol), and the mixture was stirred in a sealed vial at 50° C. for 2 hours. The mixture was cooled to ambient temperature, and the vial was stirred unsealed for 10 minutes. Benzyl azide (850 μL, 6.80 mmol) was added, and the vial was resealed and heated to 130° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-35% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 544.4 (M+H)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].N1C=CN=C1.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[Si:18]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Yield: 55.1 %

Procedure:
To a solution of 8.26 g of hydroquinone and 6.3 g of imidazole in 80 mL of pyridine was added 20.6 g of t-butyldiphenylchlorosilane in 20 mL of pyridine. After 1.5 h the mixture was partitioned between water and ethyl acetate. The organic layer was washed twice with phosphate buffer (pH 2) and once each with phosphate buffer (pH 8) and brine before being filtered through N/N/S and concentrated in vacuo. Preparative liquid chromatography [silica; hexane/ethyl acetate (85:15)] afforded 14.4 g of 4-(t-butyldiphenylsilyloxy)phenol. The structure was confirmed by its NMR spectrum.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:11]([C:15]2[CH2:16][N:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CCCCCCOc1nsnc1C1=CC=CN(C)C1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 7.5 mmol) and 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine (658 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.81 g (80%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:13]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:5][CH:4]=2)=[O:15])=[CH:19][CH:18]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cc1ccc2ccc(C(=O)O)c(O)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2ccc(C(=O)NCc3ccc(Cl)cc3)c(O)c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of 8-hydroxy-2-methylquinoline-7-carboxylic acid (0.305 g) of Preparation 5 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried to yield 0.337 g of the title product as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.I[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.CN1CCOCC1.Cl>O1CCOCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(Nc3ccc(C(=O)O)cc3)ccc21

Procedure:
1.02 g (5 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine, 1.24 g (5 mmol) of 4-iodobenzoic acid, 820 μl (7.5 mmol) of N-methylmorpholine, 360 mg (2.5 mmol) of Cu2O and 15 ml of dioxane were introduced successively into a round-bottomed flask. The entire contents were heated at reflux for 24 hours, the reaction medium poured into 15 ml of 5N hydrochloric acid, the precipitate filtered and the latter washed with water.
Reaction SMILES: N#N.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][C:11]=2[C:15]([OH:17])=O)=[CH:6][CH:5]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][C:11]=2[C:15]([Cl:26])=[O:17])=[CH:6][CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ncoc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid (51 mg, 0.25 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.86 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 5-(4-fluoro-phenyl)-oxazole-4-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:19](Cl)Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: ClCCl
Reactant: O=C(O)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Yield: 80 %

Procedure:
To 2,6-dichloro-4-nitrobenzoic acid (12.8 g, U.S. Pat. No. 3,423,475) was added anhydrous CH2Cl2 (60 mL) and thionyl chloride (40 mL) then the resulting mixture was refluxed for 19 h. The mixture was allowed to cool to room temperature and evaporated. Additional CH2Cl2 (10 mL) was added and the solution was evaporated. MeOH (100 mL) was added to the residue and the mixture was refluxed for 17 h. The mixture was allowed to cool to room temperature and placed in an ice-bath. The precipitated solid was collected by filtration to give methyl 2,6-dichloro-4-nitrobenzoate (10.8 g, 80%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:18][CH2:17]1)([O:8][Si](CC)(CC)CC)[C:4]([F:7])([F:6])[F:5].[Li]CCCC.[F:39][C:40]([F:51])([F:50])[CH2:41]OS(C(F)(F)F)(=O)=O>C1COCC1.CCCCCC>[F:39][C:40]([F:51])([F:50])[CH2:41][N:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([C:3]([OH:8])([C:2]([F:1])([F:33])[F:32])[C:4]([F:7])([F:5])[F:6])[CH2:21][CH2:20]1)[S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N(CC(F)(F)F)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.45 g (0.87 mmol) of trans N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide in 5 mL of dry THF was cooled to −78° C. and treated dropwise with 0.7 mL (1.13 mmol) of a 1.6M solution of nBuLi in hexane. The solution was warmed to −40° C., treated with 1.0 g (4.33 mmol) of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester and then allowed to reach RT. The mixture was stirred for 30 min at RT and then refluxed for 2 hrs. The solvent was evaporated, the residue redissolved in 2 mL of THF and treated with an excess of TBAF. Distribution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases and chromatography on silica gel with heptane/EtOAc 2:1 gave 0.17 g (40%) of trans N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide as a light yellow oil, MS: 486 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)(C)C>[NH2+:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[C:22]([C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O-:14])=[O:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Reactant: C1COCCN1
Solvent: CC(C)O
Product: C1COCC[NH2+]1
Product: CC(C)(C)c1cc(Nc2cccc(C(=O)[O-])c2)cc(C(C)(C)C)c1O

Procedure:
A mixture of 1.70 g (0.005 mole) of 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid (prepared in Example 13) and 50 ml of hot isopropyl alcohol was filtered to remove a small amount of insoluble material. The resulting solution was deoxygenated with a stream of nitrogen gas. Under a nitrogen atmosphere, a solution of 0.44 g (0.005 mole) of morpholine in 1.5 ml of isopropyl alcohol was added with rapid stirring. Evaporation provided a solid which was recrystallized from a mixture of isopropyl alcohol and isopropyl ether to give solid morpholinium-3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoate, m.p. 147°-150° C. Analysis: Calculated for C21H27NO3C4H9NO: % C, 70.1; % H, 8.5; % N, 6.5; Found: % C, 69.8; % H, 8.5; % N, 6.4.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[C:25]1(=O)[CH2:28]C[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH:25]([CH3:28])[CH3:26])[CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCNCC2)n1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCN(C(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
A solution of (S)-4-Isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one (20 mg, 0.060 mmol) in THF (2 mL) was added cyclobutanone (10 mg, 0.17 mmol) and sodium triacetoxyborohydride (20 mg, 0.09 mmol). The reaction was stirred at room temperature for 18 hours. The solvent is then removed under vacuum. The crude material was then purified using reverse phase C18 ODB column water-acetonitrile 0.1% TFA modifier to give (S)-4-Isopropyl-3-{2-[(S)-1-(1-isopropyl-piperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-oxazolidin-2-one (20 mg) in 62% yield.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:37]([OH:39])[CH3:38]>CN(C)C=O>[N:25]1([CH2:24][CH2:23][O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]3[N:14]=[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:4]5[CH:3]=[N:2][N:1]([CH2:38][CH2:37][OH:39])[CH:5]=5)[N:11]4[N:12]=3)=[CH:21][CH:20]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Reactant: CC(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.40 g, 1.03 mmol) in dimethylformamide (10 ml) was added potassium carbonate (2 g) followed by 1-chloroethanol (140 μl, 2.06 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo to provide a yellow solid. No further purification was required. Yield: 0.45 g, 89%; LCMS method: 2, RT: 2.10 min, MI: 434 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([I:13])=[N:10][C:9]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+].Cl>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([I:13])=[N:10][C:9]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1nc(I)oc1-c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc(I)oc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a stirred solution of methyl 5-(2-chlorophenyl)-2-iodo-1,3-oxazole-4-carboxylate (20.0 g, 55.2 mmol) in EtOH (300 mL) was added a solution of NaOH (3.3 g, 82.8 mmol) in water (100 mL). The reaction mixture was allowed to stir at rt overnight and was then acidified by the addition of 1M HCl. The solution was concentrated to a small volume and then extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give 5-(2-chlorophenyl)-2-iodo-1,3-oxazole-4-carboxylic acid (12.0 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[CH2:16]([O:18][CH:19]([O:27][CH2:28][CH3:29])[CH2:20][N:21]1[CH:25]=[C:24](I)[N:23]=[CH:22]1)[CH3:17].CC(OC)(C)C>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:24]3[N:23]=[CH:22][N:21]([CH2:20][CH:19]([O:27][CH2:28][CH3:29])[O:18][CH2:16][CH3:17])[CH:25]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CCOC(Cn1cnc(I)c1)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(Cn1cnc(-c2cc3nccc(Cl)c3s2)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (9.26 g, 54.6 mmol) in THF (88 mL) at −15° C. was added n-BuLi (21.84 mL, 54.6 mmol). After 30 min, a solution of ZnCl2 0.5M in THF (109 mL, 54.6 mmol) was added at −15° C. and the reaction mixture was warmed to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.841 g, 0.73 mmol) and iodide 260 (11.29 g, 36.4 mmol) in THF (33 mL) was added and the mixture was heated to reflux for 3 h then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; AcOEt/Hex:0/100 to 100/0 over 20 CV) to produce a material that upon trituration with. MTBE afforded the title compound 261 (1.2 g, 3.41 mmol, 9% yield) as light-brown solid. MS (m/z): 437.45 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[Li+].[BH4-].CO>CCOCC>[Cl:1][C:2]1[CH:12]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:13][CH2:14][C:15]([F:16])([F:17])[F:18]
Reactant: CCOC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: OCc1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 40 °C
Yield: 98.6 %

Procedure:
To a solution of ethyl 5-chloro-6-(2,2,2-trifluoroethoxyl)nicotinate (7.51 g, 26.5 mmol) in Et2O (200 mL) was added LiBH4 (0.865 g, 39.7 mmol), followed by drop wise addition of methanol (1.611 ml, 39.7 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×200 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (6.31 g). LCMS m/z 242.1 (M+H)+, Rt 0.77 min.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:16][CH2:17][CH2:18][OH:19]>C(Cl)Cl>[OH:19][CH2:18][CH2:17][CH2:16][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Sc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
In 100 ml of methylene chloride were dissolved 11.1 g (100 mmol) of 4-mercaptopyridine and 13.9 ml (100 mmol) of triethylamine, and 9.04 ml (100 mmol) of 3-bromo-1-propanol was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with a 1N aqueous solution of sodium hydroxide and water and dried. Then the solvent was distilled off. -The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 14.2 g of the desired compound (yield: 83.9%, yellow oil).
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[CH2:21]([O:28][C@@H:29]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:32][C:30]1([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]=[O:68])[CH:62]=1)[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C@@H:29]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[S:32][C:30]1([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[OH:68])[CH:62]=1)[OH:31])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Reactant: Brc1ccc(OC2CCOCC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(OC2CCOCC2)cc1)c1cccc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
2.6 M n-butylithium hexane solution (0.8 mL) was added to a mixture of 1-bromo-4-(4-tetrahydropyranyloxy)benzene (0.545 g, 2.12 mmol) and tetrahydrofuran (6 mL) at −78° C. After stirred for 1.5 hours, a tetrahydrofuran (8 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-(3-formylphenyl)-5-thio-D-glucopyranose (0.70 g, 1.06 mmol) was added and further stirred for three hours, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 2,3,4,6-tetra-O-benzyl-1-C-[3-[(4-(4-tetrahydropyranyloxy)phenyl)(hydroxy)methyl]phenyl]-5-thio-D-glucopyranose (0.67 g, 76%).