Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=O)=[CH:19][C:14]=2[N:13]=[N:12]1.N1CCCCC1>CCO>[NH:11]1[C:15]2[CH:16]=[CH:17][C:18](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2[nH]nnc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]nnc2c1
Temperature: 90 °C
Yield: 74.8 %

Procedure:
A scintillation vial was charged with indolin-2-one (101 mg, 0.760 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (123 mg, 0.836 mmol), piperidine (7.5 uL, 0.076 mmol) and EtOH (4 mL). The reaction was then heated to 90° C. for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more EtOH (5 mL). The yellow solid was then filtered and washed with EtOH (20 mL) giving 149 mg, 75% of the title compound. 1H NMR (400 MHz, d6-DMSO) δ 15.94 (s, 1H), 10.65 (s, 1H), 8.27 (bs, 1H), 8.05 (bs, 1H), 7.80 (s, 1H), 7.77 (bs, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.09.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)([O-])=O.[H][H]>CC(O)=O.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2
Reactant: O=c1ccc2c([N+](=O)[O-])cccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cccc2[nH]c(=O)ccc12
Yield: 94.8 %

Procedure:
A solution of 2.1 g (11 mmol) of 5-nitro-1H-quinolin-2-one (Chem. Pharm. Bull. 1981, 29, 651) in 40 ml of AcOH is hydrogenated with 210 mg of 10% Pd/C in the presence of hydrogen for 24 h with vigorous stirring. The catalyst is filtered off and the mixture is evaporated. The residue is subjected to flash chromatography over SiO2 with a gradient of pure CH2Cl2 to CH2Cl2-MeOH 99-1. After evaporation, 1.67 g (yield 97%) of yellow crystals are obtained. 1H NMR (DMSO): 11.38 (s, 1H), 8.08 (d, 1H, J=8 Hz), 7.10 (t, 1H, J=7.6 Hz), 6.44 (d, 1H, J=8 Hz), 6.33 (d, 1H, J=8 Hz), 6.26 (d, 1H, J=10 Hz), 5.85 (s, 2H).
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[H][H]>CO.ClCCl>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Solvent: CO
Solvent: ClCCl
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In an analogous manner to Example 10 but in the presence of (S)-phenylethylamine (2.29 mmol) instead of NaOH as a base, 5 g (11.48 mmol) of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid were asymmetrically hydrogenated in 37 ml methanol/dichloromethane (3:2) in the presence of 0.93 mg of [Ru(OAc)2((S)-TMBTP)] (S/C molar ratio 10'000) under 30 bar of hydrogen for 4 h at 40°, then 2 h at 60° h to reach 99.9% conversion. Rotary evaporation of the reaction mixture afforded quantitatively (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid of 91.8% ee with 99.4% purity (HPLC area). In analogy to example 13, the experiments described in table 1 have been carried out with different substrate-to-catalyst ratios.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2.B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2
Reactant: COc1ccc2[nH]ncc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2[nH]ncc2c1
Temperature: 0 °C
Yield: 83.5 %

Procedure:
A solution of 5-methoxy-1H-indazole [0.410 g, Reference Example 24(a)] in dichloromethane (7.5 ml) was treated with a solution of boron tribromide in dichloromethane (7.5 ml, 1M). The mixture was then heated to reflux for 4 hours, then cooled to 0° C. and then treated dropwise with water (2 ml). The pH of this mixture was adjusted to 7-8 by addition of 10% aqueous sodium hydrogen carbonate. The mixture was then extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated. The residual brown oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) to give 5-hydroxy-1H-indazole (0.310 g) as a yellow solid. LC-MS (METHOD B): RT=1.96 minutes; 135 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[I:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[S:31])[CH:24]=1>C(#N)C>[I:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[S:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:21])[NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:13][CH:12]=3)=[CH:6][CH:7]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: S=C=Nc1cccc(I)c1
Reactant: Nc1ccc(NC(=S)Nc2ccc(S(N)(=O)=O)cc2)cc1
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC(=S)Nc2ccc(NC(=S)Nc3cccc(I)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 4-(3-(4-aminophenyl)thioureido)benzenesulfonamide (0.322 g, 1.0 mmol) in acetonitrile was added 1-iodo-3-isothiocyanatobenzene (0.261 g, 1.0 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and water was added into the crude reaction mixture. The precipitate which formed was filtered, and dried to afford the title product as a white solid (0.452 g, 78%). 1H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 10.02 (s, 1H), 9.90 (s, 1H), 9.81 (s, 1H), 7.94 (t, J=1.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.48-7.41 (m, 5H), 7.12 (t, J=8.0 Hz, 1H); MS (ESI), 584 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:36]([O:40][C:41](=[O:44])[CH2:42]Br)([CH3:39])([CH3:38])[CH3:37]>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:15]([CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(CCCCC1CCCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 76.5 %

Procedure:
A solution of (4S)-4-benzyl-3-(5-cyclohexylpentanoyl)-1,3-oxazolidin-2-one (70.0 g, 204 mmol) in anhydrous tetrahydrofuran (650 ml) was cooled to −70° C. and treated dropwise with sodium hexamethyldisilazide (1M in tetrahydrofuran, 224 ml, 224 mmol) over 45 minutes. The mixture was stirred for a further 45 minutes before being treated with t-butylbromoacetate (31.6 ml, 214 mmol). This mixture was stirred at −70° C. for 30 minutes then warmed to −30° C. and quenched with an aqueous solution of ammonium chloride (20%w/v, 400 ml) and warmed to room temperature. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The solid was recrystallised from hexane to afford the title compound as a white solid (71.4 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccsc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccsc2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a mixed solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (264 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 165 mg, 72%).
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>O>[CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][Cl:25])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(C2CCCCCC2)cc1
Solvent: c1ccncc1
Solvent: O
Product: ClCCc1ccc(C2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
73.6 g of β-(p-cycloheptyl-phenyl)-ethanol are mixed with 31.6 ml of absolute pyridine. 29.5 ml of thionyl chloride are added dropwise to this mixture, whilst cooling with ice. Thereafter, the reaction mixture is slowly heated to 100°-110°C and kept at this temperature for 2 hours. The reaction solution is again cooled to room temperature, 69 ml of water are added, and the whole is extracted with a mixture of ether and chloroform. The organic phase is washed twice with 2 N sodium carbonate solution, three times with 2 N hydrochloric acid and finally once with 2 N sodium carbonate solution, dried over sodium sulphate, filtered and evaporated. The residue, a brown oil, is distilled in a high vacuum. Hereupon, β-(p-cycloheptyl-phenyl)-ethyl chloride is obtained as a light yellow oil of boiling point 130°-5°C/0.2 mm Hg.
Reaction SMILES: [C:1]1([CH:7]([CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[NH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:1]1([C@@H:7]([C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[NH:8][C:9]([NH2:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)NC(c1ccccc1)C1CCCO1
Solvent: CO
Product: NC(=O)N[C@@H](c1ccccc1)[C@@H]1CCCO1
Reaction time: 0.04 h

Procedure:
The enantiomers of 1-(phenyl(tetrahydrofuran-2-yl)methyl)urea (150 mg, 0.681 mmol) were separated by SFC (Berger Multigram II, Column: Chiral Technology OZ-H 2.1×25 cm, SuM, UV wavelength: 220 nM, mobile phase: 40%/60% Methanol+0.25% dimethyl ethylamine/CO2(1), flow rate: 70 mL/Min, 7 min run time). Elution was observed at 2.46 min. The fractions were collected and the solvent evaporated in vacuo to afford 1-((S)-phenyl((S)-tetrahydrofuran-2-yl)methyl)urea and Intermediates 149A-151A. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 7.23 (m, 4H), 7.18 (m, 1H), 6.43 (d, J=9.5, 1H), 5.57 (br s, 2H), 4.68-4.47 (dd, J=3.5, J=5.5, 1H), 3.97 (m, 1H), 3.76 (q, J=8.0 1H), 3.56 (q, J=7.0, 1H), 1.79-1.75 (m, 3H), 1.73 (m, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[CH:7][C:6]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH:28]=[CH2:29]>CC(C)=O>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:9][C:8]([O:15][CH2:29][CH:28]=[CH2:27])=[CH:7][C:6]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1

Procedure:
4-Acetoxy-3,5-di-tert-butylphenol (10 g) and potassium carbonate (15.6 g) were dissolved in acetone (300 ml). After addition of 3-bromo-1-propene (6.55 ml), the mixture was refluxed for 24 h. The reaction mixture was concentrated under reduced pressure and water was added to the concentrate. The mixture was subjected to extraction with diethyl ether and the organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-1-(2-propenyloxy)benzene (11 g) as a colorless liquid in a quantitative yield.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccc(Br)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(Br)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.67 g of 4,5-bis(4-methoxyphenyl)-2-(4-bromophenylthio)imidazole in 100 ml of dichloromethane. The reaction mixture is agitated for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, yielding 4.36 g of 4,5-bis(4-methoxyphenyl)-2-(4-bromophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][OH:9].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:9][CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[C:2]=1[Br:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCc1sc2ccccc2c1Br
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1c(CCOCc2ccccc2)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
To a cooled solution (0° C.) of 2-(3-bromo-benzo[b]thiophen-2-yl)-ethanol (7.7 g, 29.9 mmol) in DMF (40 mL), NaH (1.44 g, 59.8 mmol, 95%) was added and the mixture was stirred for 20 min at 0° C. Subsequently benzylbromide (5.3 mL, 45 mmol) was added and the mixture was stirred overnight while the temperature gradually reached room temperature. After quenching with MeOH, the mixture was concentrated in vacuo, dissolved in EtOAc, washed with sat NaHCO3, brine, dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (eluent: EtOAc/Hexanes=1/1) afforded 9.1 g of 2-(2-benzyloxy-ethyl)-3-bromo-benzo[b]thiophene (87% yield).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.[C:6]1(C)[CH:11]=[CH:10][C:9](S(O)(=O)=O)=[CH:8][CH:7]=1.C1C=CC=CC=1>O>[CH2:2]1[CH2:1][O:4][CH2:9][CH:10]([CH2:11][CH2:6][CH:7]=[CH2:8])[O:3]1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=CCCC1COCCO1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 5-oxy-1-hexene (9.8 g.), ethylene glycol (18.6 g.), p-toluene sulfonic acid monohydrate (1.56 g.) and benzene (250 ml.) is heated at reflux under a Dean-Stark water separator. After 2 hrs., the reaction mixture is washed with water and the organic layer is separated, dried with magnesium, and evaporated in vacuo. Distillation of the residue gives 5-ethylenedioxy-1-hexene (90% yield) b.p. 34°-37°/1.5 mm. nmr (CDCl3) δ: 1.27 (s, CH3), 1.5-2.4 (m, CH2 --CH2); 2.83 (s, --O--CH2 --CH2 --O); 4.80-6.1 (m, CH2 =CH--). IR (film) μ: 6.06 (CH2 =CH--).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>CCOC(C)=O>[CH3:33][O:32][C:28]1[CH:27]=[C:25]([NH:26][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)[CH:24]=[C:23]([O:22][CH3:21])[C:29]=1[O:30][CH3:31]
Reactant: Clc1cncc(Oc2ccccc2-c2ccccc2)n1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccccc3-c3ccccc3)n2)cc(OC)c1OC
Yield: 60 %

Procedure:
Using Method EE with 2-chloro-6-[(2-phenyl)-phenyl-oxy]-pyrazine (110 mg, 0.39 mmol) and 3,4,5-trimethoxyaniline (84 mg, 0.46 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (101 mg). Yield: 60%. 1H NMR (250 MHz, DMSO-d6) δ 3.41 (s, 6H, [CH3O]3+5), 3.55 (s, 3H, [CH3O]4), 6.79 (s, 2H, Harom2′+6′), 7.22-7.49 (m, 9H, Harom), 7.66 (s, 1H, HPz 5) 7.88 (s, 1H, HPz 3), 9.51 (s, 1H, NH).
Reaction SMILES: [CH:1]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]3[C:14](O[C:17](=[O:18])[C:10]=3[CH:9]=2)=[O:15])=[CH:5][C:4]2[C:19](O[C:22](=[O:23])[C:3]=2[CH:2]=1)=[O:20].[CH2:24]([NH2:27])[CH:25]=[CH2:26].O>C(O)(=O)C>[CH2:24]([N:27]1[C:19](=[O:20])[C:4]2=[CH:5][C:6]([O:7][C:8]3[CH:9]=[C:10]4[C:17](=[O:18])[N:27]([CH2:24][CH:25]=[CH2:26])[C:14](=[O:15])[C:11]4=[CH:12][CH:13]=3)=[CH:1][CH:2]=[C:3]2[C:22]1=[O:23])[CH:25]=[CH2:26]
Reactant: O=C1OC(=O)c2cc(Oc3ccc4c(c3)C(=O)OC4=O)ccc21
Reactant: C=CCN
Solvent: CC(=O)O
Solvent: O
Product: C=CCN1C(=O)c2ccc(Oc3ccc4c(c3)C(=O)N(CC=C)C4=O)cc2C1=O
Temperature: 115 °C

Procedure:
N,N′-Bis(2-Propenyl)-4,4′-Oxydiphthalimide [ODPA-Bis (N-Allyl)] was synthesized in the following manner. A reaction flask was charged with 4,4′-oxydiphthalic dianhydride (21.7 g, 70 mmoles) in glacial acetic acid solvent (120 ml). Allyl amine (7.98 g, 140 mmoles) was added slowly to the flask while the reaction mixture temperature was controlled at 18° to 22° C. with external cooling. After addition was complete, the reaction mixture was heated to reflux (ca. 115° C.) for 90 min and the solution gradually turned to clear from cloudy. After cooling, the product mixture was poured into water (450 to 500 ml), The resulting mixture was then brought to boiling briefly. After cooling, product precipitated out of solution and was collected by filtration, washed several times with water, and finally with methanol. Product was then dried in a vacuum oven (150 mm Hg, room temperature). The white solid product was obtained in 76%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cu](C#N)[C:12]#[N:13]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[C:12]#[N:13]
Reactant: COc1ccc(Br)cc1F
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C#N)cc1F
Temperature: 25 °C
Yield: 78 %

Procedure:
20 g of the 2-fluoro-4-bromoanisole thus obtained and 9.8 g of copper cyanide were dissolved in 100 ml of dimethyl formamide and heated under reflux for ten hours. To the reaction mixture, was added an aqueous solution of 20 g of ferric chloride in 100 ml of water. The reaction mixture was allowed to cool to room temperature and the reaction product was extracted with toluene. The organic layer was successively washed with water, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of common salt. Then the organic layer was separated. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=10:1) and further recrystallized from ethanol. Thus 10.0 g of 3-fluoro-4-methoxybenzonitrile was obtained. Yield: 68%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10]([C@@H:12]1[C@@H:16]([N:17]=[N+:18]=[N-:19])[C@@H:15]([OH:20])[C@H:14]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][CH:24]=[N:25][C:26]=3Cl)[O:13]1)=[O:11].[C:31]([O:35][C:36](=[O:48])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1[CH2:46][NH2:47])([CH3:34])([CH3:33])[CH3:32]>C(O)C>[C:31]([O:35][C:36](=[O:48])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1[CH2:46][NH:47][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[C:27]=1[N:28]=[CH:29][N:21]2[C@H:14]1[C@H:15]([OH:20])[C@H:16]([N:17]=[N+:18]=[N-:19])[C@@H:12]([C:10](=[O:11])[NH:9][CH3:8])[O:13]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CN
Reactant: CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC(=O)OC(C)(C)C)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Temperature: 70 °C
Yield: 81.3 %

Procedure:
Triethyl amine (0.3 mL, 2.1 mmol) was added to a solution of (2S,3S,4R,5R)3-azido-5-(6-chloro-purin-9-yl)-4-hydroxy-tetrahydro-furan-2-carboxylic acid methylamide (302 mg, 0.9 mmol) and 2-aminomethyl-4-chloro-phenoxy acetic acid tert-butyl ester (290 mg, 1.07 mmol) in ethanol at ambient temperature. The reaction was heated to 70° C. for 2.5 hours, cooled, and the resultant solid was washed with cold ethanol, and dried to afford 420 mg (81%) of the title compound as a colorless solid. Alternatively, the product could be purified by flash chromatography (2-5% methanol/dichloromethane). MS 574 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.28 (bs, 1H); 8.24 (s, 1H); 7.32 (bs, 1H); 7.18 (dd, 1H, J=8.9, 2.6 Hz); 6.92 (d, 1H, J=8.9 Hz); 5.95 (d, 1H, J=7.1 Hz); 5.03 (dd, 1H, J=7.1, 4.9 Hz); 4.82 (bs, 2H); 4.83 (s, 2H); 4.39 (m, 2H); 3.0 (s, 1H); 2.8 (s, 3H); 1.4 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[OH-].[K+].[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH3:10])[N:5]=[C:6]([O:16][CH2:15][C:14]([F:18])([F:17])[F:13])[N:7]=1
Reactant: CNc1nc(N)nc(Cl)n1
Reactant: OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: CNc1nc(N)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-chloro-6-methylamino-1,3,5-triazine (0.2 mole) was slurried in 80 ml of 2,2,2-trifluoroethanol at room temperature. Potassium hydroxide pellets (0.2 mole) were added portionwise and the mixture was stirred at room temperature overnight. The following day the reaction was heated at gentle reflux for 2 hours during which time the solids gradually dissolved. The solution was cooled and the solvent was removed under vacuum. The residue was washed with water and filtered to give 20.9 g shining off-white crystals of the product named above with the following characteristics: m.p. 204°-205° C. NMR (DMSO-d6): δ2.75, d, (NHCH3); 4.8, q, (OCH2CF3); 6.5-7.3, m, (NH2 +NHCH3).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[H-].[Na+].[H-].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]=[C:17](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:16][N:15]=[C:14]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:13]=2[CH:40]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17](=[CH:4][N+:1]([O-:3])=[O:2])[CH2:16][N:15]=[C:14]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:13]=2[CH:40]=1
Reactant: C[N+](=O)[O-]
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.0 ml. of nitromethane and 5 ml. of dry dimethylformamide was added 53 mg. of a 50% dispersion of sodium hydride in mineral oil (1.1 mmole hydride). After 1 hour at room temperature, under nitrogen, 489 mg. (1.0 mmole) of 7-chloro-2-di-(morpholino)phosphinyloxy-5-phenyl-3H-1,4-benzodiazepine was added. After stirring at room temperature for 2 hours, dimethylformamide was evaporated (about 80°). The residue was partitioned between methylene chloride and an aqueous layer which is acidified with a slight excess of acetic acid. The methylene chloride layer was dried (Na2SO4) and evaporated. Separation of the product mixture by preparative tlc (silica gel, developed in 10% methanol in ethylacetate v/v) afforded pure final product, which upon crystallization from methanol, had a m.p. of 178°-180°.