Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([F:11])[CH:4]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][CH:2]([F:12])[C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:19]/[S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])=[C:5]([F:11])[CH:4]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(C(F)F)cc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(C(F)F)cc1F
Temperature: 55 °C
Yield: 103.1 %

Procedure:
To a mixture of 4-(difluoromethyl)-2-fluorobenzaldehyde (162 mg, 0.930 mmol) and (R)-2-methylpropane-2-sulfinamide (124 mg, 1.023 mmol) in DCE (3 mL) was added copper sulfate (223 mg, 1.396 mmol). Reaction mixture was heated in a preheated oil bath to 55° C. for 38 hours. The mixture was allowed to cool to room temperature, filtered through a pad of celites and washed with DCE. Combined filtrates were concentrated under reduced pressure to afford (R,E)-N-(4-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (266 mg) as a yellow oil, which was used without further purification. LCMS m/z 278.1 (M+H)+, Rt 0.98 min.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[C-:14]#[N:15].[K+]>CS(C)=O.CCOC(C)=O>[C:14]([CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)#[N:15]
Reactant: COC(=O)c1ccc(CCBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CCC#N)cc1
Reaction time: 20 h

Procedure:
Bromide 23-2 (0.52 g, 2.14 mmol) and KCN (167 mg, 2.57 mmol) were combined in 10 mL DMSO. After 20 h, at RT and 1.5 h at 70° the reaction mixture was diluted with EtOAc, washed with water, sat. NaHCO3, 10% KHSO4 and brine, dried (MgSO4), and concentrated providing 23-3 as a yellow solid. Rf 0.23 (30% EtOAc/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([OH:12])[CH:5]=1.[CH2:14](Br)[CH:15]=[CH:16][CH3:17]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH2:14][CH:15]=[CH:16][CH3:17])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: CC=CCBr
Product: CC=CCOc1cc(OC)cc(C(=O)OC)c1

Procedure:
3,5-Dimethoxy-4-(1-methyl) propyl-benzoyl chloride. Starting from 3-hydroxy-5-methoxy-benzoic acid methyl ester by reaction with 2-butenylbromide, 3-(2-butenyloxy)-5-methoxy-benzoic acid methyl ester is obtained. B.p. 156°-58°C/0.4 mmHg. By operating as described under C) the 3,5-dimethoxy-4-(3-methylpropen-3-yl)-benzoic acid is obtained. M.p. 140°-41°C (from diethyl ether/light petroleum). This compound is hydrogenated as under D) to give 3,5-dimethoxy-4-(1-methyl)propyl-benzoic acid, m.p. 125°-26°C (from diethyl ether/light petroleum). This compound is allowed to react with thionyl chloride, thus obtaining the title compound. M.p. 47°-48°C (from diethyl ether upon cooling).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:25]([CH:31]([CH3:33])[CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:25]([CH:31]([CH3:33])[CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCN1Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(C)C)N1CCN(Cc2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 40 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
1-(4-Benzyloxybenzyl)imidazolidin-2-one (1.0 g; 3.54 mmol) was dissolved in dimethylformamide (DMF, 10 ml). NaH (60% in mineral oil; 0.085 g; 3.54 mol) was added, and the mixture was heated at 40° C. for 1 h. Then ethyl 2-bromoisovalerate (0.74 g; 3.54 mmol) were added, and heating was continued at 60° C. for 4 h. The reaction was stopped by slow addition of water (1 ml). The solvent was removed under reduced pressure, and the residue was partitioned between water (50 ml) and EtOAc (50 ml). Dilute HCl was added until the pH of the aqueous phase was about 4. The phases were then separated, and the aqueous phase was extracted with EtOAc (2×; 30 ml). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (SiO2) resulted in ethyl 2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (0.38 g; 0.92 mmol). MS: 411.15 (M+H); Rt: 1.87 min (method: gradient 0 min 90% H2O (0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[CH:35]=[N:36][NH:37][CH:38]=4)=[CH:25][C:6]=3[N:7]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(C#N)cc1)C[C@H]2C
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1nnc2n1-c1ccc(-c3cn[nH]c3)cc1N(c1ccc(C#N)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
To a solution of (R)-4-(8-bromo-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (100 mg, 0.26 mmol) in DME/H2O (3:1, 2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70 mg, 0.36 mmol), cesium carbonate (164 mg, 0.50 mmol) and Tetrakis(triphenylphosphine)palladium(0)(22 mg, 0.02 mmol). The mixture was stirred in the microwave at 130° C. for 20 min. The reaction mixture was concentrated and purified by prep-TLC (elute: DCM:MeOH=15:1) to give (R)-4-(1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (15 mg, 15%).
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>ClCCCl>[Cl:41][C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(O)ncnc2s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCc1cc2c(Cl)ncnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a solution of tert-butyl N-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (2.3 g, 7.79 mmol, 1.00 equiv) in DCE (300 mL) was added PPh3 (4.1 g, 15.63 mmol, 2.00 equiv). The solution was stirred for 1 h at room temperature under nitrogen. Then CCl4 (3.6 g, 23.38 mmol, 3.00 equiv) was added and the resulting solution was stirred at 72° C. overnight. After cooling, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:3) to give tert-butyl N-(2-[4-chlorothieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (1.0 g) as a light yellow solid. MS (ES): m/z 314 and 316 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:6]=1[F:20])[CH2:3][OH:4].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24](O)=O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24]1[O:4][CH2:3][CH:2]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:6]=2[F:20])[N:1]=1
Reactant: CCCCCCCCCc1ccc(C(N)CO)c(F)c1
Reactant: O=C(O)c1c(F)cccc1F
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccc(C2COC(c3c(F)cccc3F)=N2)c(F)c1
Temperature: 25 °C

Procedure:
To a mixture of 2.81 g (10 millimoles) of 2-amino-2-(2-fluoro-4-n-nonylphenyl)ethanol, 1.77 g (10 millimoles) of 2,6-difluorobenzoic acid and 20 ml of toluene, 3 g (30 millimoles) of concentrated sulfuric acid was added and refluxed for 7 hours with stirring. After cooling again to room temperature, the reaction mixture was washed successively with 30 ml of a 10% aqueous sodium hydroxide solution and then 30 ml of a saturated sodium chloride solution, desiccated over anhydrous sodium sulfate and concentrated under reduced pressure. This concentrate was purified by silica-gel column chromatography using a 8/2 solvent mixture of n-hexane/ethyl acetate to obtain 2-(2,6-difluorophenyl)-4-(2-fluoro-4-n-nonylphenyl)-2-oxazoline (Compound Number 42).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].[Br:20][C:21]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3([CH2:34][CH2:35][CH2:36][CH2:37]Br)[CH2:31][CH2:32][CH2:33][C:22]=1[C:23]=23>CN(C=O)C>[Br:20][C:21]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3([CH2:34][CH2:35][CH2:36][CH2:37][N:2]4[CH2:3][CH2:4][C:5]5[C:13]6[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=6)[NH:7][C:6]=5[CH2:1]4)[CH2:31][CH2:32][CH2:33][C:22]=1[C:23]=23
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=C1Nc2ccc(Br)c3c2C1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Br)c3c2C1(CCCCN1CCc2c([nH]c4ccccc24)C1)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A 31 mg (0.18 mmol) portion of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and 62 mg (0.54 mmol) of potassium carbonate were added to 1 ml of DMF solution containing 58 mg (0.15 mmol) of 6-bromo-2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one and stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate and washed with water. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the residue was recrystallized from acetone-diisopropyl ether to obtain 50 mg of the title compound (70% in yield).
Reaction SMILES: [C:1]([N:5]1[CH2:29][CH2:28][CH2:27][CH2:26][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:22][CH3:23])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:30])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C.O>[C:1]([N:5]1[CH2:29][CH2:28][CH2:27][CH2:26][C:8]2[C:9]([Br:38])=[C:10]3[C:19]4[CH:18]=[C:17]([S:20]([CH2:22][CH3:23])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCS(=O)c1cc2c(cc1OC)CCn1c-2cc2c1C(=O)N(C(C)(C)C)CCCC2
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
A solution of 350 mg of 23c in 4 ml of DMF was treated with 155 mg of NBS. After stirring for 10 min. the reaction was diluted with 25 ml of water and extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated, and the residue was treated with diisopropyl ether, to give 360 mg of 23d, Mp: 140-145° C. Rf 0.18 (heptane/ethyl acetate 1/1). LC-MS-ESI: [M+1] 506.97 and 524.99. NMR (CDCl3) δ 1.24 (t, 3, ethyl), 2.82 and 3.08 (2×m, 2, ethyl), 3.88 (s, 3, OCH3), 6.77, 8.78 (2×s, 2, Ar—H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]Cl.[N+:9]([C:12]1[O:16][C:15]([CH:17]=[CH:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:23]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:18]=[CH:17][C:15]1[O:16][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=1
Reactant: ClCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Product: O=[N+]([O-])c1ccc(C=Cc2nccn2Cc2ccccn2)o1

Procedure:
Using the same general procedure of Example 1, the captioned compound was prepared using 2-picolyl chloride and 2-[2-(5-nitro-2-furyl)vinyl]imidazole. The resulting yellow product was recrystallized from benzene-petroleum ether and melted at 141°-142°.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][O:7][C:8]1[CH:16]=[C:15]([CH:17]=[C:18]([CH3:20])[CH3:19])[CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>C1C=CC=CC=1.CN(C)C=O.[Cu].[Zn].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>[CH3:6][O:7][C:8]1[CH:16]=[C:15]([CH:17]=[C:18]([CH3:20])[CH3:19])[CH:14]=[CH:13][C:9]=1[C:10](=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCI
Reactant: COc1cc(C=C(C)C)ccc1C(=O)Cl
Agent: [Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCC(=O)c1ccc(C=C(C)C)cc1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A mixture of 1-iodobutane (185 mg) and zinc-copper couple (101 mg) in benzene (3 ml) and N,N-dimethylformamide (0.2 ml) was stirred at 60° C. for 2 hours. To the mixture, a solution of tetrakis(triphenylphosphine)palladium (31 mg) and 2-methoxy-4-(2-methyl-1-propenyl)benzoyl chloride (prepared from 138 mg of 2-methoxy-4-(2-methyl-1propenyl)benzoic acid and 0.07 ml of oxalyl chloride) in benzene (2 ml) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (9:1) to give 2'-methoxy-4'-(2-methyl-1-propenyl)valerophenone (91 mg) 10 as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][N:12](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][NH:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CNC1
Yield: 67.1 %

Procedure:
3.4 g (9.6 mmol) of 3-(N-tert-butyloxycarbonylaminomethyl)-1-benzhydryl azetidine was dissolved in 170 mL MeOH and hydrogenated over 0.30 g Pd(OH)2 at 5 MPa over night. The catalyst was filtered off and the solvent evaporated. The crude product was purified by flash chromatography using MeOH/CH2Cl2, 1/9, followed by MeOH (saturated with NH3 (g))/CH2Cl2, 1/9, as eluent to yield 1.2 g (67%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11](=[N:18][C:19]2[C:28]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)[NH:12][C:13]([O:15]CC)=O)[CH:10]=1)=[O:5])[CH3:2].ClCCCl>[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:12][C:13](=[O:15])[C:20]3[C:19](=[C:28]4[C:23](=[CH:22][CH:21]=3)[O:24][CH2:25][CH2:26][O:27]4)[N:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(=Nc1cccc2c1OCCO2)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCCl
Product: CCOC(=O)c1cnn(-c2nc3c4c(ccc3c(=O)[nH]2)OCCO4)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Titanium (IV) chloride (1.2 mL, 11 mmol) was carefully added to a solution of 1-[(2,3-dihydro-benzo[1,4]dioxin-5-ylimino)-ethoxycarbonylamino-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (1.39 g, 3.58 mmol) and DCE (11 mL), and the resulting solution was heated to 110° C. for 2 h. The reaction mixture was cooled to room temperature and ethanol (60 mL) was added. The resulting slurry was stirred at room temperature for 30 min; the precipitate was then collected to yield the titled compound (0.970 g, 78% yield). MS (ESI/Cl): mass calcd. for C16H14N4O6, 342.1; m/z found, 343.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.78 (s, 1H), 8.90 (d, J=0.5 Hz, 1H), 8.31 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 4.48-4.35 (m, 4H), 4.30 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:61])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([OH:60])[CH2:45]2)[CH:7]([CH3:62])[CH:6]([OH:63])[CH2:5][C:4]1=[O:64])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:61])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]([OH:60])[CH2:45]2)[CH:7]([CH3:62])[CH:6]([OH:63])[CH2:5][C:4]1=[O:64])[CH3:2]
Reactant: [H][H]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccccc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (37 mg in 2 ml ethanol) is added 4 mg of 5% rhodium on carbon catalyst. The reaction flask is fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours, the mixture is filtered over diatomaceous earth, concentrated and purified by preparative TLC on silica gel
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[K+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:19])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
39.5 g of the 2-benzyloxy-4-fluoronitrobenzene (0.16 mol) prepared as described in Example 1 are added to a mixture of an aqueous potassium hydroxide solution prepared from 27.2 g of potassium hydroxide (0.48 mol) and 180 ml of distilled water, and 150 ml of dimethyl sulfoxide in a three-neck flask fitted with reflux condenser, stirrer and nitrogen inlet, and the mixture is then heated to 100° C. After 4 hours, the reaction solution is allowed to cool to room temperature, and the residue is filtered off via a fluted filter. The dark-orange solution is then added to 800 ml of water, and concentrated hydrochloric acid is added with vigorous stirring until the mixture is acidic. Within about 1 hour, a white-yellowish, flaky reaction product precipitates; this is filtered off via a Büchner funnel and washed three times with water. The reaction product is recrystallized from ethanol and then dried for 48 hours under nitrogen at 40 ° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:20]([N:27]1[C:31]([C:32](=[O:43])[CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:30][N:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:20]([N:27]1[C:31]([C:32]([OH:43])([C:11]2[CH:12]=[CH:13][C:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][CH:10]=2)[CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:30][N:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CCCc1ccc(F)cc1)c1cncn1Cc1ccccc1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccc(F)cc2)c2cncn2Cc2ccccc2)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
9,9 g of p-tert-butylaminocarbonylphenyl bromide is dissolved in 200 ml of dry tetrahydrofuran and cooled to -70° C. To the solution is added dropwise n-butyl lithium (5,3 g) in hexane and the mixture is stirred for one hour. 1-benzyl-5-[4-(4-fluorophenyl)-1-oxobutyl]-1H-imidazole (10,4 g) in 200 ml of tetrahydrofuran is added to the mixture at -70° C. and the mixture is allowed to warm to room temperature and stirring is continued over night. Saturated ammonium chloride is added to the mixture and the solution is extracted with ethyl acetate. Ethyl acetate fractions are combined and evaporated to dryness.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:21])([F:20])[CH:9]([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(=O)=O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].CN1CCCC1=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:20][C:8]([F:21])([CH:9]([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:7][N:28]1[C:24](=[O:34])[C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]1=[O:29]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cccc(C(F)C(F)(F)COS(=O)(=O)C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [K]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To 2,2,3-trifluoro-3-(3-nitrophenyl)propyl trifluoromethanesulfonate (C32, 709 mg) and potassium phthalimide (1.07 g), N-methylpyrrolidone (4 mL) was added at room temperature, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 30% hexane in ethyl acetate) to obtain 2-(2,2,3-trifluoro-3-(3-nitrophenyl)propyl)isoindoline-1,3-dione (C33, 531 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].N1C=CN=C1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][O:8][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 2-(3-Bromo-phenoxy)-ethanol (2.0 g, 9.2 mol) in dichloromethane (15 mL) at ice water bath temperature was added (1.25 g, 1.84 mmol) imidazole followed by the addition of TBSCl (1.67 g, 11 mmol) under nitrogen protection. TLC showed reaction was complete in 1 h. The reaction mixture was filtered. The filtrate was washed with water and dried over Na2SO4. The crude product was purified by column chromatography eluted with hexanes/ethyl acetate to afford titled product as a light color oil (2.65 g, 87%).