Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[CH2:6][NH:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C(OC)(C)(C)C.O>[Cl:12][CH:13]([Cl:17])[C:14]([N:5]1[CH2:6][C:7](=[O:9])[NH:8][CH:4]1[CH:1]([CH3:3])[CH3:2])=[O:15]
Reactant: CC(C)C1NCC(=O)N1
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C1NC(=O)CN1C(=O)C(Cl)Cl
Reaction time: 10 h
Yield: 49 %

Procedure:
45 g (0.35 mole) of 2-isopropyl-4-oxo-imidazolidine (Example 3) were dissolved in 250 ml of methyl tert.-butyl ether, 17.2 g (0.43 mole) of sodium hydroxide in 20 ml of water were added, and 57 g (0.39 mole) of dichloroacetyl chloride were then added dropwise at from 10° to 15° C. The mixture was stirred for 10 hours and the solid precipitate was filtered off with suction, washed with water and dried under reduced pressure to give 41 g (49% of theory) of 1-dichloroacetyl-2-isopropyl-4-oxo-imidazolidine of melting point 172°-173° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].[OH-].[Na+].Cl.[CH3:12][S:13]([N:16]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[C:17]1=[O:24])(=[O:15])=[O:14]>O.CC(C)=O>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:21]([N:18]1[CH2:19][CH2:20][N:16]([S:13]([CH3:12])(=[O:15])=[O:14])[C:17]1=[O:24])=[O:22])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H](O)[C@@H](NC(=O)N1CCN(S(C)(=O)=O)C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
D-Threonine (5.0 g) was suspended in water (50 ml) and treated with 2M aqueous sodium hydroxide solution to pH 10, forming a clear solution. The pH was then re-adjusted to 7.5 with concentrated hydrochloric acid and the still clear solution cooled to 15°. 3-Methanesulphonyl-2-oxoimidazolidine-1-carbonyl chloride (9.5 g) was then added portionwise over 2 minutes, with simultaneous addition of 2M aqueous sodium hydroxide to maintain the pH at 6.0-7.5. Following this, acetone (30 ml) was added to give a clear solution which was then stirred at room temperature for 1 hour whilst still maintaining the pH at 6.0-7.5. After evaporation of the acetone in vacuo the aqueous residue was extracted well with ethyl acetate and the organic extracts were discarded. The pH of the aqueous phase was then adjusted to 1.5 with concentrated hydrochloric acid and the mixture was extracted using 3×50 ml portions of ethyl acetate:tetrahydrofuran (1:1). The organic extracts were dried and the solvent was evaporated to give the title compound as a white solid, (7.3 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[ClH:13].[N:14]1([C:19](=N)[NH2:20])C=CC=N1>CC#N>[ClH:13].[N:1]1([C:19](=[NH:14])[NH2:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(N)n1cccn1
Reactant: C1CCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N=C(N)N1CCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of pyrrolidine (5.8 mL, 70.30 mmol) in CH3CN (30 mL). Triethylamine (9.8 mL, 70.17 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (10.2 g, 69.59 mmol) was added to the reaction. The reaction mixture was stirred overnight at 60° C. The product was collected by filtration to yield 7.5 g (71%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]C([O-])(C)C.[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:18])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of 3-oxo-piperazine-1-carboxylic acid benzyl ester (2.00 g, 8.54 mmol) in DMF (30 mL) was added KOtBu (1.54 g, 13.7 mmol) under Ar. The resulting solution was stirred at room temperature for 15 min and cooled to 0° C. MeI (0.85 mL, 14 mmol) was then added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. DMF was removed in vacuo and the residue was chromatographed on silica (5-50% EtOAc:hexane) to obtain the title compound (1.40 g, 66%). 1H-NMR (CDCl3; 400 MHz): δ 7.32 (m, 5H), 5.13 (s, 2H), 4.13 (s, 2H), 3.70 (m, 2H), 3.34 (m, 2H), 2.97 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH:16]([CH3:18])[CH3:17].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:20]([NH:19][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:42])([F:41])[F:43]
Reactant: Cc1sc(C(=O)O)cc1-c1c(C(C)C)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C(C)C)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
To a solution of 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylic acid (137 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [Prepared in Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.572 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide (211 mg, 0.334 mmol, 64.2% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]2[C:60](=[O:69])[NH:61][C:62]3[C:67]([CH:68]=2)=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:55][CH2:54]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:53]3[CH2:54][CH2:55][CH:56]([C:59]4[C:60](=[O:69])[NH:61][C:62]5[C:67]([CH:68]=4)=[CH:66][CH:65]=[CH:64][CH:63]=5)[CH2:57][CH2:58]3)[CH2:15][C:4]=2[CH:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCc2c(cc(Br)c3[nH]ncc23)C[C@H]1CC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
(S)-2-(4-Bromo-8-oxo-6,7,8,10-tetrahydro-3H-oxepino[3,4-e]indazol-7-yl)acetic acid (90 mg, 0.265 mmol) was dissolved in N,N-dimethylformamide (2.5 mL). N,N-Diisopropylethylamine (150 μl, 0.861 mmol) was added to the mixture followed by TBTU (94.5 mg, 0.294 mmol). 3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (90.3 mg, 0.341 mmol) was added to the reaction mixture. Reaction stirred at room temperature for 3 hours. Reaction was quenched with water. Material was extracted twice with ethyl acetate. Organic phase was filtered. Filtrate was concentrated by roto-vap. Residue was purified by prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 19% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.98 (s, 1H) 12.21 (s, 1H) 8.86 (s, 1H) 8.13 (d, J=3.36 Hz, 1H) 8.05 (t, J=6.87 Hz, 1H) 7.81-7.93 (m, 2H) 7.70 (d, J=8.24 Hz, 1H) 7.57 (t, J=7.63 Hz, 1H) 6.38 (d, J=14.65 Hz, 1H) 6.00 (d, J=14.95 Hz, 1H) 4.98 (d, J=13.12 Hz, 1H) 4.48-4.56 (m, 2H) 3.67-3.74 (m, 1H) 3.54-3.67 (m, 1H) 3.30-3.53 (m, 3H) 3.04-3.16 (m, 1H) 2.95-3.04 (m, 1H) 2.36 (t, J=11.14 Hz, 1H) 2.28 (t, J=9.46 Hz, 1H) 1.91-2.04 (m, 1H) 1.77-1.90 (m, 1H). High resolution M/E (M+H)+=549.1132.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:22])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])#[CH:2].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH3:22][C:13]1[S:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([C:9]([N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[C:1]#[C:2][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])[N:12]=1
Reactant: Brc1ccccc1
Reactant: C#CC1CCCCN1C(=O)c1nc(C)sc1-c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCCCC2C#Cc2ccccc2)c(-c2ccccc2)s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of (2-ethynylpiperidin-1-yl)(2-methyl-5-phenyl-1,3-thiazol-4-yl)methanone (25 mg, 0.081 mmol), bromobenzene (23 mg, 0.15 mmol), CuI (4.6 mg, 0.024 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DMF (0.5 mL) was purged subsurface with nitrogen. Palladium tetrakis (9.3 mg, 0.0081 mmol) was added and the reaction was heated at 90° C. overnight. The reaction was stirred over excess Quadrapure TU overnight, then filtered and dried. The residue was subjected to purification via reverse phase HPLC to provide the title compound which gave a high resolution mass spectrum (ES+) m/z of 387.1527, calculated for M+H+ [C24H22N2OS: 387.1526].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([N+:20]([O-:22])=[O:21])=[CH:11][C:12]=2[S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.5 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00323 mol) in acetic anhydride is cooled with an ice bath, treated with nitric acid (0.15 mL, 0.00329 mol), warmed to room temperature, stirred for 20 hours and poured into water. The mixture is decanted and the insolubles are dissolved in ethyl acetate. The ethyl acetate solution is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an amber residue. Flash chromatography of the residue using silica gel and a 1:1 ethyl acetate/hexanes solution gives the title product as a tan solid (0.43 g, mp 174°-180° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCCCCCCCCCCC>[Cu]I.CC1C=CC=CC=1C>[CH2:1]([O:8][C:12]1[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1cc(C)cc(I)c1
Reactant: CCCCCCCO
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCCCCCCC
Solvent: Cc1ccccc1C
Product: CCCCCCCOc1cc(C)cc(C)c1
Temperature: 120 °C

Procedure:
A screw cap test tube was charged with n-heptanol (283 μL, 2.00 mmol), 3,5-dimethyliodobenzene (144 μL, 1.00 mmol), CuI (19.0 mg, 0.100 mmol), ligand (0.200 mmol), Cs2CO3 (977 mg, 3.00 mmol) and o-xylene (1 mL). The test tube was sealed with a screw cap. The reaction mixture was stirred magnetically and heated at 120° C. for 19 hours. The reaction mixture was allowed to reach room temperature. Dodecane (227 μL, 1.00 mmol; internal standard) was added and a GC sample was filtered through Celite and eluted with CH2Cl2. The yield of the desired product was determined using GC analysis; the results are tabulated below.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:6][C:15](=[O:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC/C=C/CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC=CCOC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.8 %

Procedure:
Trans-2-penten-1-ol (49.6 ml; 487.6 mmol) and (4-chloro-phenyl)-acetic acid (83.2 g; 487.6 mmol) were dissolved in 1200 ml of dichloromethane. After addition of EDC (140.2 g, 731 mmol) and DMAP (11.9 g, 97.5 mmol), the reaction mixture was stirred for 18 hours at room temperature. After evaporation under reduced pressure, the residue was dissolved with diethyl ether, washed with water, brine and dried over anhydrous sodium sulfate. Evaporation gave 136 g of an yellow oil, which was further purified by flash-chromatography (silica gel; hexane/ethyl acetate 9:1). Yield: 68 g (59%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[O:17][CH:16]([CH2:19][NH2:20])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH2:34]([O:33][C:31](=[O:32])[NH:20][CH2:19][CH:16]1[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:1]([CH3:3])[CH3:2])[C:18]=2[O:17]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)c1ccccc1-c1cccc2c1OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccccc1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2

Procedure:
Treatment of (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylamine (1.69 g, 5.56 mmol) with diisopropylethylamine (1.08 g, 8.34 mmol) and benzyl chloroformate (1.04 g, 6.12 mmol) generally according to the procedure described for Intermediate 12 gave 1.92 (89%) of (±)-benzyl[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a yellow oil. Rf=0.66 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C26H27NO3: C, 77.78; H, 6.78; N, 3.49. Found: C, 77.5; H, 6.7; N, 3.33. Chiral HPLC separation of (±)-[7-(2-isopropylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=8.131 min, Chiralcel OD, hexane:isopropanol 9:1); Fraction 2 (Rt=11.048 min, Chiralcel OD, hexane:isopropanol 9:1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:22])[CH:6]=[C:7]([CH2:20][CH3:21])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH3:2].[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:20]([C:7]1[CH:6]=[C:5]([O:22][CH2:26][CH:25]=[C:24]([Cl:28])[Cl:23])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH3:21]
Reactant: CCc1cc(O)cc(CC)c1OCCCCOCC=C(Cl)Cl
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=C(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
A reaction vessel was charged with 0.35 g of 3,5-diethyl-4-(4-(3,3-dichloro-2-propenyloxy)butyloxy)phenol, 0.16 g of 1,1,3-trichloro-1-propene, 0.15 g of potassium carbonate and 10 ml of N,N-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 50 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to silica gel chromatography, which afforded 0.33 g of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3,3-dichloro-2-propenyloxy)butyloxy)benzene (yield, 72%), nD24.4 1.5311.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13]2.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([C:14]1[NH:15][C:16]2[C:12]([C:13]=1[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][C:10]([F:9])=[CH:18][CH:17]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
A solution of 40 ml (313 mmol) of ethyl chloroglyoxylate and of 36 ml (313 mmol) of titanium tetrachloride in 1 l of dichloromethane is stirred for 15 min at room temperature. A solution of 50 g (241 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in dichloromethane is added and the mixture is stirred for 2 h at room temperature. The mixture is poured into water and the organic phase is separated by settling, washed with dilute sodium hydroxide solution and dried over sodium sulphate. 31.5 g (102 mmol) of product are obtained, which product is used as is in the following stage.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>C(Cl)Cl>[C:11]([O:10][C:8]([C@@H:3]([CH2:2][NH:1][S:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N+:24]([O-:26])=[O:25])(=[O:34])=[O:35])[C:4]([O:6][CH3:7])=[O:5])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@H](CN)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a mixture of (S)-methyl 3-amino-2-(tert-butoxycarbonyl)propanoate ii (1.6 g, 7.3 mmoL) in DCM (50 mL) was added DIPEA (1.64 mL, 9.4 mmoL) and 2-nitrobenzene sulfonyl chloride (1.62 g, 7.3 mmoL). The mixture was stirred at rt for 2 h. It was then concentrated, dissolved in ethyl acetate, which was then washed with sat. sodium bicarbonate, brine and dried over magnesium sulfate. It was then filtered, concentrated to yield 2.9 g (98%) of (S)-methyl 2-(tert-butoxycarbonyl)-3-(2-nitrophenylsulfonamido)propanoate iii as a yellow foam. 1H NMR (CD3OD, 300 MHz) δ 1.41 (s, 9H), 3.36–3.51 (m, 2H), 3.71 (s, 3H), 4.22 (m, 1H), 7.80–7.90 (m, 3H), 8.07–8.10 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1>O1CCOCC1>[CH2:20]([O:19][C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:2]2[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=2)[CH2:12][CH2:13]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C1CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 60 °C
Yield: 49.3 %

Procedure:
(2-Chloropyrimidin-5-yl)boronic acid (2 g, 13 mmol) and ethyl piperidine-4-carboxylate (1.94 mL, 13 mmol) were dissolved in 1,4-dioxane (20 mL) and heated to 60° C. under microwave irradiation for 1 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to dryness, to afford the title compound (1.79 g, 51%) as a yellow gum. Method C HPLC-MS: MH+ m/z 280, RT 0.94 minutes (89%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O>[Si:25]([O:24][CH2:23][CH2:22][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[O:9][CH2:10][C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH:3]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: Oc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a stirred solution of 4,5-dihydro-2-(3-hydroxyphenyl)-4(R)-phenyloxazole (3.3 g, 13.8 mmol) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in mineral oil, 0.62 g, 16 mmol) portionwise over 5 min. at ambient temperature. The mixture was stirred for 1 hour, and then a solution of 2-bromo-1-(tert-butyldimethylsilyloxy)ethane (4.94 g, 21 mmol) in N,N-dimethylformamide (5 ml) was added dropwise over 5 min. and the reaction mixture stayed overnight. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml), the aqueous layer was separated, extracted with ethyl acetate (2×50 ml) and the combined organic phase washed with 1N HCl (100 ml), aqueous 4% NaHCO3 solution (100 ml) and brine (100 ml), dried (MgSO4) and evaporated. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate/n-hexane (=1:6) to afford 1-(tert-butyldimethylsilyloxy)-2-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)phenoxy]ethane (4.7 g, 86%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=S)[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:31]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: COc1cccc(N=C=S)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add 3-methoxy phenyl isothiocyanate (69 uL, 0.512 mmol) and stir for 1.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 50 min. Upon cooling to room temp, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and suspend the solid in 1 N NaOH. Collect the solid wash with water and Et2O. Suspend the solid in boiling toluene/EtOAc. Cool the suspension to 4° C. and filter. Wash the solid with Et2O. Again suspend the solid in 1 N NaOH and stir for 1 hr. Collect the solid and wash with water and Et2O. Dry to afford the title compound: 1H NMR (400 MHz, DMSO-d6) ppm 3.78 (s, 3 H) 6.61 (dd, J=8.15, 1.83 Hz, 1 H) 7.14-7.19 (m, 1 H) 7.28 (t, J=8.15 Hz, 1 H) 7.34 (t, J=2.15 Hz, 1 H) 7.64 (dd, J=9.35, 6.69 Hz, 1 H) 7.70 (s, 1 H) 7.84 (br. s., 2 H) 7.72 (d, J=1.89 Hz, 1 H) 8.11 (br. s., 1 H) 10.67 (br. s., 1 H) 13.29 (br. s., 1 H); MS m/z=452.1 (M+1).