Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([OH:33])[CH2:21][C:22]#[C:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[O:31][CH3:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Si](OC[C@@H]1CO1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.ClC1C=CC(C#C)=C(OC)C=1.C([Li])CCC.B(F)(F)F.CCOCC>>[C:14]([Si:1]([O:18][CH2:19][C@@H:20]1[CH2:21][CH2:22][C@H:23]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[O:31][CH3:32])[O:33]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: COc1cc(Cl)ccc1C#CC[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C#Cc1ccc(Cl)cc1OC
Agent: CC(C)(C)[Si](OC[C@@H]1CO1)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: COc1cc(Cl)ccc1[C@H]1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1

Procedure:
tert-Butyl{[(2S,5R)-5-(4-chloro-2-methoxyphenyl)tetrahydrofuran-2-yl]methoxy}diphenylsilane was prepared from (2S)-1-{[tert-butyl(diphenyl)silyl]oxy}-5-(4-chloro-2-methoxyphenyl)pent-4-yn-2-ol using the general method of T. X. M. Nguyen et al., Letters in Organic Chemistry 2009, 6, 630-636. This alkyne was prepared via reaction of tert-butyl[(2S)-oxiran-2-ylmethoxy]diphenylsilane with 4-chloro-1-ethynyl-2-methoxybenzene, using n-butyllithium and boron trifluoride diethyl etherate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH:46][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=3)[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: COc1ccc(C2CCOCC2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccc(C)nc3)nc12

Procedure:
From 6-methylnicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 368 (M+H+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:21][O:22][C:18]=2[CH:17]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([N:23]3[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[N:8]=[N:7]4)[CH2:25][CH2:24]3)=[N:21][O:22][C:18]=2[CH:17]=1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: Fc1ccc2c(N3CCNCC3)noc2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2c(N3CCN(CCCCn4nnc5ccccc54)CC3)noc2c1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 6-fluoro-3-(piperazine-1-yl)benzisoxazole (6.1 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.3 g compound (I-36) with a yield of 70.0%. ESI-MS [M+H]+: m/z 395.2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]1[CH:20]([Si](C)(C)C)[CH:19]=[CH:18][N:17]([Si](C)(C)C)[CH:16]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([C:19]1[CH:18]=[N:17][CH:16]=[C:15]([C@@H:11]2[CH2:12][CH2:13][CH2:14][N:10]2[CH3:9])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Reactant: O=Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1c1cncc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
To a stirred solution of benzaldehyde (0.07 mL, 0.75 mmol) in freshly distilled THF was added dropwise 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine i (0.21 g, 0.68 mmol). A degassed solution of TBAF in THF (1 M) stored over molecular sieves was slowly added to the mixture. The reaction mixture was stirred under Ar at RT for one day. It was then poured into a saturated aqueous solution of NaHCO3. The product was extracted with diethyl ether (2 times). The combined organic layers were washed with brine and dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was purified by RPLC (silica gel, 10% MeOH/EtOAc) to give 31% (0.0525 g) of (S)-3-benzyl-5-(1-methylpyrrolidin-2-yl)-pyridine iv as a clear oil. IR (thin film, neat, NaCl): 3236, 2954, 2778, 1666, 1613, 1449, 1037 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.40-8.34 (m, 2 H), 7.88 (dd, 1 H, J=1.6 and 13.2 Hz), 7.37-7.24 (m, 4 H), 5.84 (s, 1 H), 3.13-3.02 (m, 2 H), 2.25-1.69 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ 148.43, 147.42, 143.90, 140.11, 138.19, 133.30, 133.25, 128.82, 127.95, 126.81, 74.24, 74.03, 69.15, 57.04, 40.47, 35.10, 22.51. HRMS Calcd for C17H20N2: 252.1626 [M+H]+. Found: 252.1635 [M+H]+. [α]25D−26 (CH2Cl2, c=1.51).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2/[CH:21]=[CH:22]/[CH:23]([OH:32])[CH2:24][CH:25]([OH:31])[CH2:26][C:27]([O:29]C)=O)=[CH:4][C:3]=1[CH3:33].[OH-].[Na+].ClC(OCC)=O.CCN(CC)CC>CO.C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2/[CH:21]=[CH:22]/[C@@H:23]2[O:32][C:27](=[O:29])[CH2:26][C@@H:25]([OH:31])[CH2:24]2)=[CH:4][C:3]=1[CH3:33]
Reactant: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)c(C)c2)CC(N2CCCC2)CC1(C)C
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O)CC(=O)O3)C(C)(C)CC(N3CCCC3)C2)ccc1F

Procedure:
In a manner similar to Scheme I, 34 (0.19 g) was treated with 2N NaOH in methanol at 0°-5° C. for 18 h, followed by ethyl chloroformate (0.254 mmol) and Et3N in CH2Cl2 at 0°-5° C. Workup and purification of the residue by SiO2 using 1% Et3N in EtOAc as eluent yielded the product. mp 120°-3° C. Anal. C26H34FNO3. 0.5 H2O: Theory C: 71.53; H: 8.08; N: 3.21; Found C.: 71.60; H: 8.17; N: 3.03.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:33])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[NH:15][C:14]([CH:16]3[CH2:18][CH2:17]3)=[N:13][C:12]=2[C:19]2[C:20]([Cl:32])=[C:21]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:8]=[CH:7][N:6]=1.C([O-])(O)=O.[Na+].Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1.O.O>[Cl:32][C:20]1[C:21]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][C:19]=1[C:12]1[N:13]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[NH:15][C:11]=1[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][CH2:3][C@@H:2]([NH:1][C:40](=[O:41])[O:42][CH3:43])[CH3:33])[N:10]=1
Reactant: COC(=O)Cl
Reactant: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)[nH]c2-c2ccnc(NC[C@H](C)N)n2)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)[nH]c2-c2ccnc(NC[C@H](C)NC(=O)OC)n2)c1Cl
Reaction time: 0.08 h

Procedure:
To a mixture of (S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide in THF-water (1:1, 2 mL) at 0° C. was added solid NaHCO3 (137 mg, 1.6 mmol) and the resulting mixture was stirred for 5 minutes. Methyl chloroformate (14 μL, 0.18 mmol) was added and the reaction mixture was stirred at 0° C. for 15 minutes. The reaction was diluted with water and extracted with EtOAc (2×). The combined organic portions were washed with water, brine, dried (Na2SO4), and concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC. Product fractions were combined and lyophilized to give (S)-methyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (19.9 mg) as the TFA salt (4A-3): LCMS (m/z) 548.0 (MH+), tR=0.61 minute, 1H NMR (400 MHz, CD3OD) δ 1.04 (t, J=7.4 Hz, 3H) 1.14 (d, J=6.6 Hz, 3H) 1.27 (t, J=4.5 Hz, 2H) 1.34-1.44 (m, 2H) 1.80-1.95 (m, 2H) 3.14-3.21 (m, 2H) 3.67 (br s, 3H) 3.97 (br s, 1H) 6.40 (br s, 1H) 7.45 (d, 7.0 Hz, 1H) 7.54 (m, 1H) 7.84 (d, J=7.4 Hz, 1H) 8.13 (d, J=5.1 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22]CC2C=CC=CC=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([OH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccccc2)ccc(C(C)=O)c1OCCCC(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc(C(C)=O)c1OCCCC(=O)OCC
Yield: 70.5 %

Procedure:
A solution of ethyl 4-(6-acetyl-3-benzyloxy-2-propylphenoxy)butanoate (2.2 g) in ethanol (30 ml) was hydrogenated over 10% palladium on activated carbon (0.45 g) under atmospheric pressure at room temperature. After hydrogen absorption ceased, the catalyst was removed and the solution was evaporated. The residue was purified by silica gel column chromatography, eluting with benzene-ethyl acetate (1:4), to give the title compound (1.2 g, 70.5%) as yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.[NH2:38][C@@H:39]([CH3:58])[C:40]([N:42]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:43][CH:44]([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])=[O:41]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:51]([N:42]([CH2:43][CH:44]([O:45][CH2:46][CH3:47])[O:48][CH2:49][CH3:50])[C:40](=[O:41])[C@@H:39]([NH:38][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])[CH3:58])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)N)OCC
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of 2-(3-benzylureidooxy)acetic acid (Compound VI-6) (53.8 mg, 0.24 mmol) and hydroxybenzotriazol (40.5 mg, 0.3 mmol) in dichloromethane (1 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (57.5 mg, 0.3 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) and the mixture was stirred at room temperature for 0.5 hr. A solution of (S)-2-amino-N-benzyl-N-(2,2-diethoxyethyl)propanamide (Compound IV-19) (58.9 mg, 0.2 mmol) in dichloromethane (1 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 18 hr. The reaction mixture was washed with sat. NaHCO3 aq. (1 ml), water (1 ml) and brine (1 ml). The organic layer was filtered on Celite (1 g) and magnesium sulfate (150 mg). The filtrate was concentrated in vacuo and the residue was purified with PTLC (development solvent: chloroform:methanol=98:2) to obtain the titled compound (60 mg, 80%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: Cc1nc(-c2cc3cccc(O)c3o2)no1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Product: Cc1nc(-c2cc3cccc(OC[C@@H]4CO4)c3o2)no1
Yield: 90 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 3-(7-hydroxybenzo(b)furan-2-yl)-5-methyl-1,2,4-oxadiazole (1.5 g) and (S)-glycidyl nosylate (1.8 g), the title compound (1.7 g) was obtained as white crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([OH:18])=O)[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([NH:19][CH2:20][C:21]3[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=3[CH3:27])=[O:18])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: CCCn1ncc2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(C3CC3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-cyclopropyl-1-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (90 mg, 0.368 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (70 mg, 0.460 mmol), 1-hydroxy-7-azabenzotriazole (100 mg, 0.736 mmol), DMSO (10 mL), EDC (141 mg, 0.736 mmol), and N-methylmorpholine (0.162 mL, 1.472 mmol). The final product was collected as 0.118 g (84%). LCMS E-S (M+H)=380.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78 (t, 3H), 0.99-1.16 (m, 4H), 1.85 (d, J=7.33 Hz, 2H), 2.13 (s, 3H), 2.22 (s, 4H), 4.25-4.43 (m, 4H), 5.90 (s, 1H), 7.43 (s, 1H), 8.21 (s, 1H), 8.75 (s, 1H), 11.57 (s, 1H).
Reaction SMILES: C[O-].C([Sn+](CCCC)CCCC)CCC.Br[C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C([O:30][C:31]([CH3:33])=[CH2:32])(=O)C.[F-].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([CH2:32][C:31](=[O:30])[CH3:33])[CH:18]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: C=C(C)OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(CC(C)=O)c1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Tributyltin methoxide (80.3 mL, 279 mmol), methyl 3-bromobenzoate (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium(II)acetate (2.6 g, 11.6 mmol) and tri-ortho-tolylphosphine (7.1 g, 23.2 mmol) were stirred together in toluene (350 mL) at 100° C. under nitrogen for 18 hours. After cooling, the reaction was treated with potassium fluoride solution (4M, 560 ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200 mL) and filtered through Celite®, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by chromatography eluting with ethylacetate: pentane 10:90 to 20:80 to give the title compound (45.3 g) as an orange oil. 1H NMR (400 MHz, CDCl3) δ: 2.18 (3H, s), 3.75 (2H, s), 3.91 (3H, s), 7.43–7.37 (2H, m), 7.87 (1H, s), 7.95–7.93 (1H, d); LRMS ESI m/z 215 [M+Na]+, 191 [M−H]−.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[C:29][CH2:30][CH2:31][CH2:32]O>C(Cl)Cl>[Br:1][CH2:32][CH2:31][CH2:30][C:29]#[C:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: OCCCC#Cc1ccccn1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCC#Cc1ccccn1
Temperature: 5 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
Br2 (1.11 mL, 21.4 mmol) was added to a solution of triphenylphosphine (8.30 g, 30.7 mmol) in DCM (40 mL) at −5° C. A solution of 5-pyridin-2-yl-pent-4-yn-1-ol (3.00, 18.6 mmol) in DCM (10 mL) was added dropwise to the reaction mixture in order to maintain a temperature lower than 5° C. The reaction mixture was stirred for 5 hours at −10° C. and was quenched with a saturated solution of NaHCO3. The aqueous phase was extracted with DCM. The resulting organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5) to yield 2-(5-bromo-pent-1-ynyl)-pyridine (1.20 g, 5.35 mmol, 29%) with a purity of 50%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:44][C:43](=[O:45])[O:42][N:41]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)=[CH:21][CH:20]=2)[C:12]([CH3:18])=[N:13][C:14]=1[CH2:15][CH2:16][CH3:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:44][C:43](=[O:45])[O:42][N:41]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[C:12]([CH3:18])=[N:13][C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Reaction time: 15 h
Yield: 87.8 %

Procedure:
To a solution of 5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-6-propylpyrimidin-4(3H)-one (0.40 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.42 g), and the mixture was stirred for 15 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.35 g, 88%).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([CH3:13])([CH3:12])[S:4]1)[OH:2].[CH3:14][N:15]=[C:16]=[O:17]>>[CH3:14][NH:15][C:16]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([CH3:12])([CH3:13])[S:4]1)=[O:17]
Reactant: CCCCC1=NC(=NO)SC1(C)C
Reactant: CN=C=O
Product: CCCCC1=NC(=NOC(=O)NC)SC1(C)C

Procedure:
2-oxo-4-butyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-butyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 128°-130° C. The 2-oxo-4-butyl-5,5-dimethyl-3-thiazoline-oxime starting material melts at 117°-119° C.
Reaction SMILES: CO[C:3](OC)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH:4]=[O:5].[CH3:15]O>>[CH3:15][O:5][CH2:4][CH2:3][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: CO
Reactant: COC(C=O)(OC)c1ccc(O)cc1
Product: COCCc1ccc(O)cc1
Yield: 47 %

Procedure:
The procedure of Example 2 was repeated with a solution of 2.00 g (10.2) mmol) 4-hydroxyphenylglyoxal dimethyl acetal in 10 g methanol containing 0.37 g (10.2 mmol) hydrogen chloride and a 0.20 g dry 10% Pd/C catalyst being reacted with hydrogen gas pressurized at 50 psig at 25° C. A 47% yield of 4-(2'-methoxyethyl)phenol was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](N2C3C=CC=CC=3N=C2C(F)F)[CH:6]=[C:5]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[CH:30]([F:32])[F:31])[N:4]=1.[OH:33][CH2:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[F:31][CH:30]([F:32])[C:22]1[N:21]([C:5]2[N:4]=[C:3]([S:2][CH3:1])[N:8]=[C:7]([O:33][CH2:34][C@H:35]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]3)[CH:6]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Reactant: CSc1nc(-n2c(C(F)F)nc3ccccc32)cc(-n2c(C(F)F)nc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CSc1nc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
To a solution of 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-1H-benzimidazole] (2 g) in N,N-dimethylacetamide (10 mL) were added tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (965 mg) and cesium carbonate (2.1 g), followed by stirring at 60° C. for 5 hours. After the completion of the reaction, to the reaction solution was added ice water and the precipitated solid was collected by filtration. After drying, the resultant was dissolved in dichloromethane and purified by silica gel column chromatography (hexane:ethyl acetate=90:10-65:35) to obtain tert-butyl (3S)-3-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfanyl)pyrimidin-4-yl}oxy)methyl]pyrrolidine-1-carboxylate (2.01 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][OH:17])=[S:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[S:13][C:12]([NH:14][CH2:15][CH2:16][OH:17])=[N:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(NC(=S)NCCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2sc(NCCO)nc2c1
Yield: 82 %

Procedure:
A mixture of 28 parts of N-(2-chloro-5-nitrophenyl)N'-(2-hydroxyethyl)thiourea, 14.5 parts of potassium carbonate and 225 parts of N,N-dimethylformamide is stirred and refluxed for one hour. After cooling, 300 parts of water are added. The precipitated product is filtered off, washed with water and dried, yielding 20.5 parts (82%) of 2-[(5-nitro-2-benzothiazolyl)amino]ethanol; mp. 183.4° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCCC(O)c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N(CCCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a stirred solution of tert-butyl (S)-1-(4-bromophenyl)ethyl(4-hydroxy-4-phenylbutyl)carbamate (3.24 g, 7.1 mmol) in CH2Cl2 (20 mL) at rt was added 15% Dess-Martin periodinane solution in CH2Cl2 (23 mL, 10.8 mmol). The mixture was stirred overnight at rt. Satd aq NaHCO3 (50 mL) was added and the mixture was stirred for 10 min. Solid Na2S2O3 (5 g) was added and stirring was continued for 1 h. The mixture was extracted with CH2Cl2 (2×100 mL) and the combined organic layer was washed with brine (35 mL) and dried over Na2SO4. Removal of the solvent left an amber oil (3.19 g) which was purified by chromatography on a 40-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (S)-tert-butyl 1-(4-bromophenyl)ethyl(4-oxo-4-phenylbutyl)carbamate (2.32 g, 72%) as a yellow oil. LC-MS Method 1 tR=2.40 min, m/z=470, 468, 348, 346.