Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:27][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (870 mg, 3.58 mM), a-bromo-m-xylene (662 mg, 3.58 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.18 g (95%) of the 9-[(3-methylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a dark oil. 1H NMR (DMSO-d6) δ 7.65 (dd, 1H, J=1 and 8 Hz), 7.3-7.1 (m, 3H), 7.05 (d, 1H, J=8 Hz), 7.0 (s, 1H), 6.85 (d, 1H, J=8 Hz), 5.5 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), 2.3 (s, 3H), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3010, 2953, 1724, 1652, 1605, 1465, 1442, 1288, 1174, and 1119. MS (ES) m/e 348.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].I[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1>CS(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Ic1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Oc2cnccn2)c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of 3-nitrophenol (0.151 g, 0.733 mmol) in DMSO (5 mL) was added NaH (35 mg of a 60% dispersion, 0.88 mmol) at 0° C. under Ar atmosphere. After stirring for 30 min, 2-iodopyrazine (0.133 mg, 0.953 mmol) was added and mixture heated to 85° C. for 4 h. To the mixture was added satd. NH4Cl solution (25 mL) and the product extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to yield a crude residue which was purified by column chromatography to afford (97 mg, 61% yield) 2-(3-nitrophenoxy)pyrazine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (brs, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.16-8.09 (m, 3H), 7.63 (t, J=8.0 Hz, 1H), 7.57-7.54 (m, 1H); MS (ESI) m/z: 218.0 (M+H+).
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:62]([O:64][C:65](=[O:74])[CH2:66][C@H:67]1[CH2:72][CH2:71][C@H:70]([NH2:73])[CH2:69][CH2:68]1)[CH3:63]>CN(C=O)C>[CH2:62]([O:64][C:65](=[O:74])[CH2:66][C@H:67]1[CH2:68][CH2:69][C@H:70]([NH:73][C:8](=[O:10])[CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:71][CH2:72]1)[CH3:63]
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Reactant: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H]1CC[C@H](NC(=O)C(C2CCCCC2)n2c([C@H](OC)c3ccccc3)nc3cc(F)ccc32)CC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of cyclohexyl-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid (350 mg, 0.88 mmol, 1.0 equiv) in DMF (5 mL) was added triethylamine (179 mg, 240 μL, 1.77 mmol, 2.0 equiv) and HATU (403 mg, 1.06 mmol, 1.2 equiv) and the mixture stirred at 40° C. After 15 min, trans-(4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (235 mg, 1.06 mmol, 1.2 equiv; [CAS RN 76308-26-4]) was added and stirring continued at 50° C. for 2 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was used in the consecutive step without further purification. MS (ISP): 564.7 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:13]2[CH2:18][CH2:17][C@@H:16]([OH:19])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1Cc2c(c(N)ccc2[C@H]2CC[C@@H](O)CC2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one (1.35 g, 5.23 mmol) was dissolved in MeOH (30 mL), and cooled to 0° C., followed by addition of sodium borohydride (0.198 g, 5.23 mmol). The reaction mixture was stirred at 0° C. for 1 h. The reaction was quenched with sat. aq. NH4Cl, diluted with EtOAc, washed with brine, and dried over anhydrous sodium sulfate. The compound was purified on an Isco Combiflash eluting with 0 to 4% MeOH in EtOAc to afford the trans isomer and the cis isomer. Trans-isomer: 1H NMR (400 MHz, DMSO-d6) δ 7.05 (d, J=8.34 Hz, 1H), 6.51 (d, J=8.34 Hz, 1H), 5.83 (s, 2H), 4.53 (d, J=4.29 Hz, 1H), 4.33 (s, 2H), 3.38-3.48 (m, 1H), 2.98 (s, 3H), 2.28-2.38 (m, 1H), 1.90 (d, J=9.35 Hz, 2H), 1.68 (d, J=12.38 Hz, 2H), 1.38-1.51 (m, 2H), 1.19-1.32 (m, 2H); MS (ES+): m/z: 262.1674 [MH+]. HPLC: tR=0.98 min (UPLC TOF MS: polar—3 min). Cis-isomer: 1H NMR (400 MHz, DMSO-d6) δ 7.07 (d, J=8.34 Hz, 1H), 6.54 (d, J=8.34 Hz, 1H), 5.83 (s, 2H), 4.33 (s, 3H), 2.99 (s, 3H), 2.34-2.43 (m, 1H), 1.70-1.87 (m, 4H), 1.38-1.57 (m, 4H); MS (ES+): m/z: 262.1693 [MH+]. HPLC: tR=1.04 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:37](F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:37][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(C(F)(F)F)c1)CC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 525.23 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[C:35](=O)[CH2:34][CH:33]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:32][C:31]=2[O:47]CC)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=O)=[CH:11][CH:10]=1)#[N:8].[OH2:50]>C(#N)C>[O:50]=[C:17]1[NH:16][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=2)[C:30]2[C:31](=[O:47])[CH2:32][CH:33]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:41][CH:42]=3)[CH2:34][C:35]=2[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2ccc(C(F)(F)F)cc2)C1
Reactant: O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC(c2ccc(C(F)(F)F)cc2)C3)cc1
Temperature: 25 °C

Procedure:
Sodium tert-butoxide (211 mg, 2.19 mmol) is added to a solution of 1-((4-cyanophenyl)-(2-ethoxy-6-oxo-4-(4-(trifluoromethyl)phenyl)cyclohex-1-enyl)methyl)-3-(3-(trifluorometh yl)phenyl)urea (intermediate 17, 825 mg, 1.37 mmol) in acetonitrile (12 mL) and the mixture is stirred at room temperature over night. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 100:0 to 0:100). Yield: 135 mg; ESI mass spectrum [M+H]+=556, Retention time HPLC: 1.27 min, 1.29 min (1:1 mixture of diastereomers) (V011_S01).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]1[C@@H:29]([CH2:33][CH:34]=[CH2:35])[C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:1]([N:8]([C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=[CH2:11])[C:30](=[O:31])[CH:29]([N:20]1[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]1=[O:18])[CH2:33][CH:34]=[CH2:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[C@H](NCc1ccccc1)c1ccccc1
Reactant: C=CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CCC(C(=O)N(Cc1ccccc1)[C@@H](C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-N-benzyl-1-phenylprop-2-en-1-amine (5a) (240 mg) in DCM (5 mL) at RT under N2 was added (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pent-4-enoic acid (4b) (263 mg) and EDAC.HCl (224 mg). The mixture was stirred overnight at RT, then diluted with 30% hexanes/EtOAc and washed with H2O, 0.2 N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and concentrated to a white foamy solid (233 mg, 48%). 1H NMR (300 MHz) The NMR of this compound in both CDCl3 and DMSO-d6 (with elavated temperatures) was complex, thus limiting interpretation. MS APCI, m/z=451 (M+1). LC/MS 3.13 min., Method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[N:21]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:28][CH2:29]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: c1cnc(N2CCNCC2)nc1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ncccn4)CC3)c(OC)nc2c1
Yield: 86 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 3.67-3.70 (m, 4H), 3.90 (s, 3H), 3.95-3.97 (m, 4H), 4.13 (s, 3H), 6.53 (t, J=4.8 Hz, 1H), 7.11-7.23 (m, 4H), 7.30 (d, J=9.3 Hz, 1H), 8.33 (d, J=4.8 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]([CH3:46])[C:41](=[O:47])[CH2:40][CH2:39]2.C[Si](Cl)(C)C>C(O)CCC>[CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:17][NH:16][C:11]=2[N:12]=[C:13]([NH:35][C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]([CH3:46])[C:41](=[O:47])[CH2:40][CH2:39]3)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(=O)CCc2cc(N)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CN1C(=O)CCc2cc(Nc3nc(NCc4ccccc4)c4c(-c5ccncc5)c[nH]c4n3)ccc21
Temperature: 116 °C
Reaction time: 40 h

Procedure:
A solution of N-benzyl-2-chloro-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (27 mg, 0.055 mmol), 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (20 mg, 0.11 mmol) and trimethylsilyl chloride (0.070 mL, 0.553 mmol) in nBuOH (1.5 mL) was stirred at 116° C. for 20 h. More trimethylsilyl chloride (0.100 mL, 0.790 mmol) was added. It was stirred at 116° C. for another 40 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound. MS 476.4 (M+H); UV 200.3, 268.7, 309.3 nm.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OC(=O)C)(=O)C.[O-2].[Mg+2].C(OC(C)C)(=O)C>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O

Procedure:
Reaction of 22.8 parts N-acetoacetyl-L-aspartic acid with 11.25 parts acetic anhydride, 0.059 parts magnesium oxide, and 2.1 parts by volume glacial acetic acid in 32 parts by volume isopropyl acetate at 45°-50° C. for 100 minutes as described above in Example 6-H above afforded 19.5 parts N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])=[O:9])(=[O:3])[CH3:2].[Cl-].[C:27](OC1C(=CC=CC=1)C(O)=O)(=[O:29])[CH3:28].C(O)CCCCCO>>[C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:28][CH2:27][OH:29])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(=O)c1ccc(C(=O)OCCOCCOCCO)c(O)c1C(C)=O
Agent: OCCCCCCO
Agent: [Cl-]
Product: CC(=O)c1ccc(C(=O)OCCOCCOCCOCCO)c(O)c1C(C)=O

Procedure:
The compound was prepared according to the procedure described in Example 1 for the synthesis of (XIX), prepared starting from 6 g of the chloride of acetylsalicylic acid, 4.6 ml of TEA and 1.9 g of 1.6-hexandiol. The product was purified by flash chromatography utilizing an eluent mix constituted by ethylether/hexane 7:3 (v/v). The intermediate fractions were collected, the solvent was evaporated under reduced pressure and a solid residue was obtained which, triturated with isopropyl ether, produced 1 g of 1.6-hexandiol bis-acetylsalicylate (II) with m.p.=96° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15].Cl>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1

Procedure:
A solution containing 0.55 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.36 g of acetophenone in 10 ml of methanol was saturated with gaseous hydrogen chloride. After standing over night at 5° C. the product was filtered and washed with methanol. Yield 0.55 g (68%), m.p. 192°-195° C.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=1[CH2:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([N+:29]([O-])=O)=[CH:24][CH:23]=1)([CH3:3])[CH3:2]>CCO.C1COCC1.[Pt]=O>[CH:1]([C:4]1[CH:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:17])[F:18])[C:5]=1[CH2:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[CH:24][CH:23]=1)([CH3:3])[CH3:2]
Reactant: Cc1nc(OCc2c(C(C)C)cnn2-c2ccccc2OC(F)(F)F)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(OCc2c(C(C)C)cnn2-c2ccccc2OC(F)(F)F)ccc1N
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To an ambient temperature solution of 6-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-3-nitro-pyridine (2.73 g, 6.25 mmol) in EtOH/THF (100/100 mL) is added platinum (II) oxide (142 mg, 0.625 mmol, 10 mol %). The reaction is placed under an atmosphere of hydrogen gas. After 3 h, the reaction is filtered through diatomaceous earth, concentrated, and chromatographed (0% to 30% EtOAc/Hex) to yield the title compound (2.15 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.53 (dd, 1H, J=7.9, 1.8 Hz), 7.46-7.41 (m, 1H), 7.39-7.31 (m, 2H), 7.08 (d, 1H, J=8.8 Hz), 6.33 (d, 1H, J=8.4 Hz), 5.17 (s, 2H), 3.06 (sept, 1H, J=7.0 Hz), 2.32 (s, 3H), 1.27 (d, 6H, J=7.0 Hz).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]1([S:7]([NH:10][C:11](=[O:24])[C:12]2[CH:13]=[CH:14][C:15]([C:18]#[CH:19])=[CH:16][CH:17]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Yield: 121.3 %

Procedure:
Under the conditions of example 21 C, a solution of 3.1 g of N-benzenesulfonyl-4-(2-trimethylsilylethinyl)-benzoic acid amide in 200 ml of tetrahydrofuran is reacted with 9.5 ml of a 1-molar solution of tetrabutylammonium fluoride in tetrahydrofuran and worked up. 3 g of N-benzenesulfonyl-4-ethinylbenzoic acid amide is obtained as crude product.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH:34]=[O:35])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([OH:6])=[O:35])[CH2:26]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccccc2C=O)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of sodium chlorite (1.85 g; 20.43 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.6 g; 13.37 mmol; 3.6 eq.) in water (10 mL) was added dropwise to a mixture of 2-methyl-2-butene (3.71 mL) and 3-(2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.03 g; 3.71 mmol; 1 eq.) in 1,4-dioxane (10 mL). and the reaction mixture was stirred at room temperature for 2 hours. The dioxane was evaporated in vacuo, the mixture diluted with water and the pH made acidic with 0.1M HCl. The precipitate was filtered off, washed with water and dried to afford the title compound (1.02 g, 94%) as a white solid. UPLC/MS: (MS−) 292.4 ([M−H]−).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][CH:7]=1>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:18][C:19]=1[N+:1]([O-:4])=[O:2]
Reactant: CC(CC(=O)O)C(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Product: CC(CC(=O)O)C(=O)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To 300 ml of fuming nitric acid was added by small portions 51 g of 3-(4-bromobenzoyl)butyric acid with stirring over 2 hours, during which the internal temperature of the reaction mixture was maintained at 10° to 20° C. The resulting mixture was poured into 1 liter of ice water and then extracted with chloroform. The chloroform layer was washed with water and concentrated. The residue was crystallized from water to give 46 g (77%) of 3-(4-bromo-3-nitrobenzoyl)butyric acid [Compound a; Compound (IV) wherein R3 =CH3 ].
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:15].[CH2:17]1[CH2:24][O:23][S:20](=[O:22])(=[O:21])[CH2:19][CH2:18]1>>[S:20]([CH2:19][CH2:18][CH2:17][CH2:24][N:4]1[C:5]2[CH:6]=[CH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[C:2]([CH3:16])([CH3:1])[CH:3]1[CH3:15])([OH:23])(=[O:22])=[O:21]
Reactant: CC1=Nc2ccc3ccccc3c2C1(C)C
Reactant: O=S1(=O)CCCCO1
Product: CC1N(CCCCS(=O)(=O)O)c2ccc3ccccc3c2C1(C)C

Procedure:
1,1,2-Trimethylbenzo[e]indole (1.0 g, 4.8 mmol) and 1,4-butane sultone (0.50 mL, 4.8 mmol) were heated for 2.5 h at 130° C., filtered off after cooling, washed with acetone and dried for 3 h at 100° C. Yield: 1.13 g (70%) gray-white solid, melting point 263° C. (Lit. review: H. Langhals, C. Haritoglou, Der Ophthalmologe 2009, 106, 16-20: 266° C.). IR (ATR): {tilde over (ν)}=3435 (m), 2939 (w), 1636 (w), 1584 (w), 1523 (w), 1468 (m), 1199 (s), 1034 (s), 872 (w), 824 (m), 791 (w), 758 (m), 737 cm−1 (w). 1H NMR (400 MHz, CD3OD): δ=8.32 (d, 1H, Haromatic, 3J=8.5 Hz), 8.24 (d, 1H, Haromatic, 3J=8.9 Hz), 8.16 (d, 1H, Haromatic, 3J=8.2 Hz), 8.06 (d, 1H, Haromatic, 3J=9.0 Hz), 7.80 (ddd, 1H, Haromatic, 4J=1.3 Hz, 3J=6.9 Hz, 3J=8.4 Hz), 7.71 (ddd, 1H, Haromatic, 4J=1.1 Hz, 3J=6.9 Hz, 3J=8.1 Hz), 4.70-4.64 (m, 2H, NCH2), 2.91 (t, 2H, CH2SO3−, 3J=7.1 Hz), 2.26-2.18 (m, 2H, CH2), 2.03-1.94 (m, 2H, CH2), 1.84 (s, 6H, 2×CH3), 1.30 ppm (s, 3H, CH3). 13C NMR (100 MHz, CD3OD): δ=196.6, 138.7, 137.5, 134.1, 131.3, 129.9, 128.5, 127.9, 127.5, 123.2, 112.7, 56.1, 49.9, 26.4, 23.0, 22.1, 21.2 ppm. HRMS (ESI) (C19H24NO3S): calculated 346.1471. found 346.1473, Δ=0.2 mmu.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:15]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)CCc1ccc(O)cc1
Yield: 92.9 %

Procedure:
Following the same procedure of Example 4 except that 3-(4-hydroxyphenyl)propionic acid (1.0 g, 6.0 mmol) and glycine ethyl ester hydrochloride (0.94 g, 6.7 mmol) were used, 1.4 g of the title compound was obtained. The compound was finally purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)). The results of analyses of the compound are as follows:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.F[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17][OH:18].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>O>[N+:23]([C:20]1[CH:21]=[CH:22][C:15]([N:31]2[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]2)=[C:16]([CH2:17][OH:18])[CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Temperature: 140 °C
Reaction time: 14 h

Procedure:
4.24 g of potassium carbonate was added to N-methylpyrrolidone (4.24 mL) solution of 4.24 g of 2-fluoro-5-nitrobenzyl alcohol and 4.24 g of N-ethylpiperazine, and stirred at 140° C. for 14 hours. Water was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water in that order, then dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the entitled compound as a yellow solid.