Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([O:18]CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:16]=[O:18])[CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14]
Reactant: CCOCC
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Temperature: 25 °C
Yield: 94 %

Procedure:
A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethyl chroman, (0.5 g, 1.865 mmol) in anhydrous dichloromethane (5 mL) was treated with a 1M solution (1.86 mL, 1.86 mmol) of titanium tetrachloride in dichloromethane followed by α,α-dichloro methyl ether (0.214 g, 1.865 mmol). The reaction mixture was allowed to warm to ambient temperature for 4 h. The reaction mixture was diluted with diethyl ether, washed with brine (×1) and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane to afford the title compound as a yellow solid (0.52 g, 94%).
Reaction SMILES: [CH2:1]([CH:4]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]2[C:6]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:7][C:8]3[C:13]2=[CH:12][CH:11]=[C:10]([O:19]COC)[CH:9]=3)[CH2:5]1)[CH:2]=[CH2:3].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([CH:4]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]2[C:6]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:7][C:8]3[C:13]2=[CH:12][CH:11]=[C:10]([OH:19])[CH:9]=3)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1CC2(CCCC)Cc3cc(OCOC)ccc3C2=C(C)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC1CC2(CCCC)Cc3cc(O)ccc3C2=C(C)C1=O
Temperature: 50 °C

Procedure:
A solution of (2SR,9aSR)-2-allyl-9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (5 mg, 0.015 mmol) in THF (0.5 mL) was treated with 6N HCl (0.5 mL) and the resulting solution was heated at 50° C. overnight. The mixture was diluted with EtOAc (30 mL), washed with 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to a yellow oil. The crude product was purified by PLC on a 0.025×20×20 cm silica gel GF plate using 2:1 hexanes-EtOAc as developing solvent. The UV visible band at Rf 0.43-0.57 afforded (2SR,9aSR)-2-allyl-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a gum.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>C(#N)C>[Cl:15][CH2:16][CH2:17][NH:18][C:19]([NH:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:14])[CH:12]=1)=[O:20]
Reactant: O=C=NCCCl
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCCCl)cn1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine (419 mg, 2.18 mmol) and 2-chloroethyl isocyanate (230 mg, 2.18 mmol) in acetonitrile (5 mL) were heated at 65° C. for 16 hours. The reaction was cooled to room temperature and concentrated on the rotovap. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient), dried and triturated with ethyl acetate/hexanes (1/9) to afford (1-(2-chloroethyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)1H-pyrazol-4-yl)urea (258 mg, 40%) as a yellow solid. MS M+H calculated 298.10. Found 298.1
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH2:9])=[C:5]([NH2:10])[N:4]([CH3:11])[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:16]=1[C:17](O)=O>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[NH:9][C:17]([C:16]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:23][C:15]=3[O:14][CH3:13])=[N:10][C:5]=2[N:4]([CH3:11])[C:3]1=[O:12]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1cc(OCc2ccccc2)ccc1C(=O)O
Product: COc1cc(OCc2ccccc2)ccc1-c1nc2c([nH]1)c(=O)n(C)c(=O)n2C

Procedure:
Prepared analogously to Example 14 from 1,3-dimethyl-4,5-diamino-1H,3H-pyrimidin-2,6-dione and 2-methoxy-4-benzyloxybenzoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21]C)=[O:20])([O-:3])=[O:2].O.[OH-].[Li+]>O1CCCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([OH:21])=[O:20])([O-:3])=[O:2]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinate 1.1g (1 g, 2.93 mmol, 1.00 equiv) in tetrahydrofuran/water (1:1) (20 mL), lithium hydroxide hydrate (1.26 g, 30.00 mmol, 10.23 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2×20 mL of ethyl acetate and the aqueous layers combined. The solution was adjusted to pH 5 with hydrochloric acid. The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 0.8 g (83%) of 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinic acid as a yellow solid.
Reaction SMILES: [C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:27](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:27][N:19]1[C@H:20]2[C@@:15]([CH3:24])([C:14]3[CH:25]=[CH:26][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[CH:12][C:13]=3[CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]1=[O:23]
Reactant: CC(C)(C)O
Reactant: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc5ccccc45)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (22 mg, 0.065 mmol), 0.20 mL of t-butanol, and potassium t-butoxide (22 mg, 0.19 mmol). Methyl iodide (0.012 mL, 0.19 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 16 mg (70%) of the title compound as a yellow solid, upon trituration from diethyl ether/hexanes. mp 172°-173°. FDMS: m/e=353.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.Br[CH2:9][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)Cl.C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[C:10](=[O:16])[CH2:9][S:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[CH3:15]
Reactant: Cc1nnc(S)s1
Reactant: CCOC(=O)C(=O)CBr
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C(=O)CSc1nnc(C)s1
Yield: 91.3 %

Procedure:
A solution of 5-methyl-1, 3,4-thiadiazole-2-thiol (264 mg, 2 mmol) and ethyl bromopyruvate (0.264 mL, 2.1 mmol) in methylene chloride (10 mL) and acetonitrile (10 mL) was stirred at 20° C. for 3 hours under nitrogen. The precipitates were filtered, washed with methylene chloride, and dried under vacuum. This gave the expected product, 3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (450 mg, yield 69%) as a solid. 1H-NMR (300 Hz, D3COD and d6-DMSO) δ (ppm): 4.22 (q, J=7.1 Hz, 2H), 3.78 (d, J=14.1 Hz, 1H), 3.71 (d, J=14.1 Hz, 1H), 2.74 (s, 3H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: CN(C1C=CC=CC=1)/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[O:8].[CH2:15]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18].P(Cl)(Cl)(Cl)=O>C1COCC1>[CH2:15]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:20]1[CH:25]=[CH:24][C:23](/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[O:8])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CN(/C=C/C=C/C=O)c1ccccc1
Reactant: CCCCN(CCCC)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(/C=C/C=C/C=O)cc1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 13 %

Procedure:
To a solution of the vinylogous amide 2 (1.135 g, 6.06 mmol) and dibutylaniline (1.43 g) in dry THF (6 ml) at −20° C. was added a solution of phosphorus oxychloride (1.08 g, 1.17 eq.) and dibutylaniline (1.03 g, 1.98 eq. for the sum) in THF (3.6 ml) dropwise at such a rate as to keep the mixture between −10° C. and −20° C. Following the addition, the mixture was stirred at room temperature for 2 hours and at 50° C. for 35 minutes. To the reaction mixture (a dark blue-green oil) was added petroleum ether (25 ml) and the mixture was triturated; the ether was separated and discarded. Methanol (4 ml) was then added and the mixture was neutralized with 2N NaOH. Silicagel was then added, the suspension was diluted with ethyl acetate and methanol and dried to a solid on the rotovap. The crude product was purified by MPLC using hexanes-ethyl acetate 5-30% gradient to give the desired aldehyde as an intense yellow oil (225 mg, 13%). MS (EI): 285 (M+, 45%); 242 (100%); 200 (85%); 128 (30%); 118 (40%). H-NMR (CDCl3): 0.95 (t, J=12 Hz, 6H); 1.35 (m, 4H); 1.45 (m, 4H); 3.8 (t, J=9 Hz, 4H); 6.4, (d, J=17 Hz, 1 H); 6.5-6.8 (m, 3H); 7.1 (d, J=15 Hz,1 H); 7.5 (d, J=17 Hz,1 H); 7.8 (d, J=11 Hzm 2H); 9.8 (s,1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:21]C(=O)C1C=CC=CC=1)=[N:9]2.S(=O)(=O)(O)O.[N+:35]([O-])([OH:37])=[O:36].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:35]([O-:37])=[O:36])=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH2:21])=[N:9]2
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-((4aS,5S,7aS)-7a-(2-Fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (5.15 g) was dissolved in TFA (75 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 20 mL) was added, followed by fuming nitric acid (2 mL) dropwise over 20 mins. After stirring at 0° C. for 90 mins, the reaction mixture was poured onto ice (200 g) and basified to pH 12 with 6N NaOH (aq.). After allowing the ice to melt, the mixture was extracted with EtOAc (3×500 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound (22.1 g, purity approx. 71%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.89 (d, J=3.8 Hz, 1H), 3.09 (br. s., 1H), 3.28-3.54 (m, 1H), 3.80-4.03 (m, 1H), 4.50-4.70 (m, 3H), 4.71-4.86 (m, 1H), 7.21-7.30 (m, 1H), 8.18-8.28 (m, 1H), 8.45 (dd, J=6.8, 2.8 Hz, 1H)
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[CH:8])(=[O:4])[CH:2]=[CH2:3].[CH2:9]([N:21]=[N+:22]=[N-:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:9]([N:21]1[CH:8]=[C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:23]=[N:22]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCN=[N+]=[N-]
Reactant: C#CCOC(=O)C=C
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)OCc1cn(CCCCCCCCCCCC)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Propargyl acrylate (13 g, 0.118 mmoles), dodecyl azide (22.3 g, 0.118 mmoles) and tetrakis(acetonitrile)copper (I) hexafluorophosphate (0.75 g, 2 mmoles) are dissolved in DMF (200 ml) and stirred at room temperature under nitrogen for 24 hours. The reaction mixture is poured into water wherefrom the product precipitated as a white crystalline solid (33.5 g; yield 95%; mp 50-52° C.). 1H NMR (CDCl3, δ ppm) 7.78 (broad, 1H), 6.42 (d, 1H), 6.16 (dd, 1H), 5.82 (d, 1H), 5.30 (s, 2H), 4.32 (t, 2H), 1.92 (t, 2H), 1.28 (m, 20H), 0.88 (t, 3H). 13C NMR (CDCl3, δ ppm) 165.7, 142.4, 131.1, 127.9, 123.5, 57.6, 57.5, 50.2, 31.7, 30.1, 29.4, 29.3, 29.2, 29.1, 28.8, 26.3, 22.4, 13.9.
Reaction SMILES: [OH:1]O.[CH2:3]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(=O)C>[CH2:3]([S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccccc1SCc1ccccc1
Reactant: OO
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccccc1S(=O)Cc1ccccc1
Reaction time: 5 h
Yield: 94.6 %

Procedure:
102 ml of 30% hydrogen peroxide solution are added dropwise at a temperature of +10° C. to a solution of 219 g of 2-benzylthiophenylsulfonamide obtained in accordance with Example P1 in 500 ml of concentrated acetic acid. The reaction mixture is then stirred for 5 hours at a temperature of +25° C., the product slowly crystallising out. After separating off the crystals, washing with water and drying, 219 g (94.6%) of 2-benzylsulfinylphenylsulfonamide are obtained in the form of colour less crystals having a melting point of from +206° to ÷209° C.
Reaction SMILES: [Br-].[PH4+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O.O.C[CH2:19][O:20][C:21]([CH3:23])=[O:22]>C1COCC1>[CH3:19][O:20][C:21](=[O:22])[CH2:23][CH2:9][CH2:4][CH2:5][CH:6]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: CCOC(C)=O
Reactant: O=C(c1ccccn1)c1ccccn1
Agent: [Br-]
Agent: [PH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC=C(c1ccccn1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
NHMDS (2.26 mL, 2.26 mmol) as a solution in THF was added to methyl 6-triphenylphosphonium bromide hexanoate II (1.072 g, 2.38 mmol) in THF (8 mL) at 0° C. under Ar(g). After 15 min, di-pyridin-2-yl-methanone (220 mg, 1.2 mmol) in THF (4 mL) was added; the reaction mixture was stirred for 1 h, and was then allowed to warm to rt. After 20 h stirring, water (15 mL) and EtOAc (15 mL) were added, the phases were separated, and the aqueous phase was extracted with EtOAc (2×10 mL). The organic phases were combined, dried over MgSO4, filtered, and then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CH2Cl2/MeOH (100:0.5 to 100:2) as eluant to furnish III as a colourless oil (155 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:22]=[N+:23]=[O:24].O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:7]=1[N+:23]([O-:24])=[O:22]
Reactant: O=[N+]=O
Reactant: CCOC(=O)CC(C)(C)c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(C)(C)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
276 mg (1.45 mmol) of ethyl 3-(4-chlorophenyl)-3-methylbutanoate were dissolved in 10 ml of dichloromethane, and the mixture was cooled to 0° C. A little at a time, 278 mg (1.38 mmol) of nitronium tetrafluoroborate were then added, and the mixture was stirred at a temperature between 0° C. and 10° C. for 4 h. 10 ml of water and 10 ml of dichloromethane were then added, and the phases were separated. The organic phase was dried over magnesium sulphate and concentrated to dryness. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 223 mg of the title compound (68% of theory).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[OH:14].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[O:14][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1ccc(CO)cc1
Reactant: COC(=O)c1cc(S(N)(=O)=O)ccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(N)(=O)=O)ccc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4.8 mmol 2-hydroxy-5-sulfamoyl-benzoic acid methyl ester, 5.2 mmol 4-methoxybenzyl alcohol and 5.2 mmol triphenylphosphine in 8 ml THF was added 5.2 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 350.2 ([M−H]−, 100%)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]#[CH:9])[C:4](=[O:10])[CH2:3]1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[CH3:15][C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]#[CH:9])[C:4](=[O:10])[CH2:3]1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCN1C[C@@H](O)CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN1C[C@@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A mixture of 25 g of (S)-4-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 39.8 g of t-butyldimethylsilyl chloride and 38.5 ml of triethylamine in 200 ml of dichloromethane was stirred under argon overnight. The mixture was washed with 300 ml of water, dried and evaporated. The residual oil was purified by chromatography, (silica gel) giving 42.7 g of (S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-(2-propynyl)-2-pyrrolidinone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(Nc2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottom flask is charged with 3-nitrophenylboronic acid (4.2 g, 25 mmol), dry molecular sieves (5 g), copper acetate (1.95 g, 12.5 mmol) and dry dichloromethane (150 mL). Triethylamine (8.7 mL, 62.5 mmol) is added followed by the addition of 4-fluoro-3-nitroaniline (2.27 g, 12.5 mmol). The resulting mixture is stirred at ambient temperature for three days. The mixture is filtered through celite and washed with EtOAc. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane=1:3) to give the desired product: 1H NMR (400 MHz, DMSO) δ 9.12 (s, 1 H), 7.82 (m, 1 H), 7.79-7.37 (m, 1 H), 7.73-7.70 (m, 1 H), 7.56-7.49 (m, 4 H); LC-MS: 278.3 (MH+).
Reaction SMILES: [O:1]1[C:24]2=[C:25]3[C@:20]([CH3:27])([CH2:21][CH2:22][C:23]2=[O:26])[C@@H:19]2[C@H:4]([C@H:5]4[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:8]([CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:7][CH2:6]4)[C@@H:3]2[O:29][C@:2]123.[BH4-].[Na+].Cl>O1CCCC1.O>[O:1]1[C:24]2=[C:25]3[C@:20]([CH3:27])([CH2:21][CH2:22][C@@H:23]2[OH:26])[C@@H:19]2[C@H:4]([C@H:5]4[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:8]([CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:7][CH2:6]4)[C@@H:3]2[O:29][C@:2]123
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 0.402 g (1 mmole) of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3-one in 30 ml of tetrahydrofuran was added 38 mg (1 mmole) of sodium borohydride at a temperature of 0° C. and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with water and neutralized by adding cold 1N-hydrochloric acid in small portions. From this mixture, the tetrahydrofuran was distilled off under reduced pressure at a temperature not exceeding 20° C. and the residue was diluted with water and extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane =1:10, v/v) to recover 0.250 g of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy- 20-methylpregn-4-en-3β-ol (yield: 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([Sn](C)(C)C)=[CH:27][N:26]=1)[CH2:22][CH3:23].[Cl-].[Li+]>O1CCOCC1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:21][CH2:22][CH3:23])=[N:26][CH:27]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Reactant: CCCOc1ccc([Sn](C)(C)C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCCOc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (VP4) (2.0 g, 2.9 mmol) was mixed with 2-n-propyloxy-5-trimethylstannylpyridine (4.6 g, 50%, 7.7 mmol), Pd(PPh3)4 (0.35 g, 0.3 mmol) and lithium chloride (50 mg) in dioxane and refluxed under nitrogen (7 hours). After chromatography and recrystallization in heptane/ethyl acetate 95:5, 2-(2,6-difluorophenyl)-4-[4-(2-n-propyloxypyridin-5-yl)phenyl]oxazoline was obtained, 1.21 g, colorless crystals;
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCCC1=O.[Br:22][C:23]1[N:28]=[C:27]([C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=1.CN1CCCC1=O>O>[Br:22][C:23]1[N:28]=[C:27]([C:29]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:30])[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1cccc(Br)n1
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1ccccc1Nc1ccccc1)c1cccc(Br)n1
Yield: 49 %

Procedure:
Dissolving 4.4 g (24 mmol) of N-phenyl-1,2-phenylenediamine into 30 milliliter of N-methylpyrrolidone, 10 milliliter of 6-bromo picolinoyl chloride/N-methylpyrrolidone was dropped under cooling with ice. The resultant solution was further stirred at room temperature for 4 hours. After completion of the reaction, the reacted solution was poured into 400 milliliter of water and the resultant solution was further stirred. The resultant solids were separated by filtration, washed with water and methanol, dried under reduced pressure, thereby obtaining 4.5 g of 6-bromo-2′-(N-phenylamino)-picoline anilide (yield: 49%).