Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH2:32]([O:39][NH2:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:39][NH:40][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:21](=[O:22])[C:20]2=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NOCc1ccccc1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 85.8 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propanoic acid (1.30 g, 3.14 mmol), N,N′-carbonyldiimidazole (533 mg, 3.28 mmol) and O-benzylhydroxylamine hydrochloride (550 mg, 3.45 mmol) in tetrahydrofuran (10 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide as a yellow solid (1.4 g, 86% yield): mp, 137.0-139.0° C.; 1H NMR (DMSO-d6) δ1.30 (t, J=6.8 Hz, 3H, CH3), 3.05-3.16 (m, 2H, CH2), 3.72 (s, 3H, CH3), 4.09 (q, J=6.8 Hz, 2H, CH2), 4.64 (s, 2H, PhCH2), 5.68 (t, J=7.8 Hz, 1H, NCH), 6.87-7.02 (m, 3H, Ar), 7.23-7.41 (m, 5H, Ar), 8.11 (d, J=8.1 Hz, 1H, Ar), 8.48 (s, 1H, Ar), 8.62 (dd, J=1.8, 8.2 Hz, 1H, Ar), 11.24 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.64, 34.17, 50.76, 55.45, 63.71, 76.67, 111.68, 112.37, 118.02, 119.76, 124.70, 128.16, 128.62, 129.75, 130.42, 132.52, 135.74, 135.79, 147.73, 148.69, 151.50, 165.73, 165.99, 166.17. Anal. Calcd for C27H25N3O8: C, 62.42; H, 4.85; N, 8.09. Found: C, 62.34; H, 4.71; N, 8.05.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>C(O)CCC>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: OCCCCCCCl
Solvent: CCCCO
Product: OCCCCCCN(CCCCCCO)c1ccccc1
Yield: 70 %

Procedure:
Using a modified literature method (Moon, K.-J.; Shim, H.-K.; Lee, K.-S.; Zieba, J.; Prasad, P. N. Macromolcules 1996, 29, 861), the reaction of aniline with 6-chloro-1-hexanol in butanol provided N,N-bis(6-hydroxyhexyl)-aniline in 70% yield. A 100 mL two-necked flask containing 15 mL of dry DMF was cooled down to 0° C. with an ice bath. To this solution, 4.7 g (30.7 mmol) of phosphorous oxychloride was added dropwise and the mixture was stirred for 30 min at 0° C. 3 g (10.2 mmol) of N,N-bis(6-hydroxyhexyl)-aniline in dry DMF (15 mL) was added to the above solution and heated to 90° C. for 2 hrs. The reaction solution was cooled down to room temperature, poured into ice water and neutralized to pH 6-8 with saturated sodium hydroxide aqueous solution. The resulting solution was extracted with methylene chloride and then dried over magnesium sulfate. The crude compound was purified by silica gel column chromatography (ethyl acetate/hexane=1:5) to yield 2.3 g (63%) of pure light brown oil, (9). 1H-NMR (200 MHz, CDCl3): δ 9.71 (s, 1H, —CHO), 7.71 (d, 2H, J=9.0 Hz), 664 (d 2H, J=9.0 Hz), 3.55 (t, 4H, —CH2Cl, J=6.6 Hz), 3.35 (t, 4H, —NCH2—, J=7.6 Hz), 1.80 (m, 4H), 1.68-1.37 (m, 12H). 13C-NMR (100 MHz, CDCl3): δ 190.2, 152.7, 132.5, 124.9, 110.9, 51.1, 45.2, 32.7, 27.2, 26.9, 26.5. HRMS (EI): m/z=357.1617 (M+), Δ=2.6 ppm.
Reaction SMILES: C1(CC(=O)CC2C=CC=C(C(F)(F)F)C=2)C=CC=CC=1.C(OCC)=O.Cl.C(N)C.[CH2:30]([N:32]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[C:35](=[O:48])[C:34]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:33]1)[CH3:31].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:30]([N:32]1[CH2:37][CH:36]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:45])[F:46])[CH:39]=2)[C:35](=[O:48])[CH:34]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:33]1)[CH3:31]
Reactant: CCn1cc(-c2ccccc2)c(=O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: CCN
Agent: Cl
Agent: O=C(Cc1ccccc1)Cc1cccc(C(F)(F)F)c1
Solvent: CCOC=O
Product: CCN1CC(c2ccccc2)C(=O)C(c2cccc(C(F)(F)F)c2)C1

Procedure:
An 11.5 g. portion of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone was reacted with ethyl formate and ethylamine hydrochloride as described in Examples 1-3 to produce 6.8 g. of 1-ethyl-3-phenyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinone, which was reduced with 2 g. of lithium aluminum hydride as described above. After column chromatography as described in the examples above, the products of Examples 27 and 28 were recovered as a mixture. Mass spectroscopy of the mixture showed a molecular weight of 345, and the yield was 1.2 g. The molecular weight of the product of Example 29 was indicated as 347 by mass spectroscopy, yield 1.9 g.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][S:7][C:8]2[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=2[OH:14])=[CH:4][CH:3]=1.[OH:19]O>C(O)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][S:7]([C:8]2[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=2[OH:14])=[O:19])=[CH:4][CH:3]=1
Reactant: OO
Reactant: Cc1cc(O)c(SCc2ccc(Cl)cc2)c(=O)o1
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)Cc2ccc(Cl)cc2)c(=O)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-p-Chlorobenzylthio-4-hydroxy-6-methyl-2-pyrone (11.3 g., 0.0400 mol), 30% hydrogen peroxide (5.14 g., 0.0440 mol) and 50 ml. glacial acetic acid were combined and stirred at room temperature for 4 hours. Then stored at room temperature over night. The reaction mixture, containing a crystalline solid, was added to 200 ml. of icewater. The precipitate was collected and dried. The solids were recrystallized from a mixture of cyclohexane-toluene to recover 8.6 g. (72 percent) of the desired compound, m.p. 150°-151°C. One additional recrystallization from cyclo-hexane-toluene gave the pure compound as white platelets, m.p. 151°-152°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:5])[CH3:2].[CH2:17]([OH:22])[CH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][O:22][C:7]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])=[O:16]
Reactant: OCCCCO
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Product: CCOC(=O)NC(=O)c1ccccc1C(=O)OCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-ethoxycarbonylphthalimide with 1,4-butanediol under conditions shown in Table 19, ethyl N-{2-(4-hydroxybutoxycarbonyl)benzoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 6.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23](O)=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.O>CN(C)C=O>[N:38]1([C:23](=[O:24])[CH2:22][CH2:21][C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:11]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=Cc1[nH]c2c(c1CCC(=O)N1CCOCC1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Morpholine (5.2 g) in 30 mL of dimethylformamide was added and the stirring continued overnight. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid that formed was slurry-washed with 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 9.6 g (80%) of 3-[3-(3-morpholin-4-yl-3-oxopropyl)-4,5,6,7-tetrahydro-1H-indol-2-ylmethylene]-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:59]=[C:60]([CH:63]=[CH:64][CH:65]=2)[C:61]#[N:62])[CH2:53][CH2:52]1>CN(C=O)C.O>[C:61]([C:60]1[CH:59]=[C:58]([CH:65]=[CH:64][CH:63]=1)[O:57][CH:54]1[CH2:55][CH2:56][N:51]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:52][CH2:53]1)#[N:62]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: N#Cc1cccc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(OC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 0.03 h
Yield: 14.6 %

Procedure:
DIPEA (316 mg, 2.5 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (181 mg, 0.7 mmol) in DMF (3 mL) followed by HOBt (108 mg, 0.8 mmol) and EDCI.HCl (160 mg, 0.8 mmol). After 2 minutes of stirring, 3-(piperidin-4-yloxy)-benzonitrile hydrochloride (50 mg, 0.7 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) afford 44 mg (14.3% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(3-cyano-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 473.17, 99.16%, 1H NMR (300 MHz, DMSO-d6): δ 8.1 (m, 1H), 7.8 (m, 2H), 7.6 (m, 4H), 7.4 (m, 3H), 7.1 (b, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 4.0 (m, 1H), 3.8 (m, 1H), 2.0 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18]N(C)C)=[CH:6]1.ClC(OCC)=O.[C:33]1([SH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18][S:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6]1
Reactant: COC(=O)c1cc2c(CN(C)C)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: Sc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(CSc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reaction time: 0.33 h
Yield: 37.9 %

Procedure:
To a stirring solution of methyl 1-(2,4-difluorobenzyl)-3-[(dimethylamino)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.906 g, 2.52 mmol) in DCM (20 mL) was added ethyl chloroformate (0.240 mL, 2.52 mmol). The pale yellow homogeneous solution was stirred for 20 minutes. To this stirring solution was added a solution of benzenethiol (0.416 g, 3.78 mmol) and diisopropyl ethylamine (0.814 g, 6.3 mmol) in DMF (10 mL). The reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated in vacuo and purified by flash chromatography yielding a white powder (0.405 g, 40%). 1H NMR (400 MHz, CDCl3) δ ppm 4.01 (s, 3H) 4.27 (s, 2H) 5.32 (s, 2H) 6.74-6.80 (m, 1H) 6.81-6.90 (m, 2H) 7.12 (s, 1H) 7.17-7.24 (m, 3H) 7.26-7.29 (m, 2H) 8.50 (s, 1H) 8.78 (s, 1H). LCMS (APCI, M+H): 425.1.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:19][CH:20]=3)[N:15]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:14]=2)=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[N:22]1([C:18]2[CH:17]=[C:16]3[C:21]([C:13]([C:10]4[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=4)=[CH:14][N:15]3[C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[CH:20][CH:19]=2)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1
Reactant: COc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCNCC4)ccc23)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCNCC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
Boron tribromide (BBr3, 17 μL, 0.182 mmol) was added to a mixture solution of 3-(4-methoxyphenyl)-6-(piperazin-1-yl)-1-(pyridin-4-yl)-1H-indole (14 mg, 0.036 mmol) in methylene chloride (0.5 mL) at −78° C. After stirring at room temperature for 15 hours, the reaction solution was added to a mixture solution of saturated sodium bicarbonate aqueous solution and ethyl acetate and then extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound (12 mg) was obtained as yellow solid.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C>C1COCC1>[Si:30]([O:29][CH2:28][CH2:27][CH:21]1[N:14]2[C:15]3[C:11]([CH:12]=[CH:13]2)=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:17][C:16]=3[CH2:18][NH:19][CH2:20]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC1CNCc2cc(CCc3ccccc3)c(C(F)(F)F)c3ccn1c23
Temperature: 80 °C
Yield: 81.9 %

Procedure:
A mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 100 mg, 0.26 mmol), 2-bromoethoxy t-butyl(dimethyl)silane (63 mg, 0.26 mmol) and diisopropylethylamine (0.09 mL, 0.53 mmol) in THF was heated at 80° C. for 5 h. The solvent was evaporated to yield 2-(2-((tert-butyldimethylsilyl)oxy)ethyl-6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (107 mg, MS m/z 503 (MH+)).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[I-:10].[Na+].[OH-].[Na+].Cl[O-].[Na+].Cl.[Na]>CO>[I:10][C:6]1[CH:5]=[CH:4][C:2]([OH:3])=[C:1]([O:8][CH3:9])[CH:7]=1
Reactant: [I-]
Reactant: COc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc(I)ccc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-Iodo-2-methoxyphenol was prepared according to the method described by K. J. Edgar and N. Falling, J. Org. Chem. 55, 5287 (1990). Guaiacol (50.0 g, 402 mmol), sodium iodide (60.5 g, 402 mmol) was dissolved in methanol (800 ml) and cooled to 0° C., and sodium hydroxide (16.0 g, 402 mmol) was added at such a rate that the temperature did not exceed 5° C. An aqueous solution of sodium hypochlorite (750 ml, 72% solution, 402 mmol) was added during 45 min. The temperature was not allowed to exceed 0° C. After completed addition it was stirred for another 10 minutes at 0° C. First aqueous hydrochloric acid (100 ml, 4 M solution) and then sodium sulifite (200 ml saturated aqueous solution) was added. The product was extracted with ether was followed by drying over magnesium sulfate. Evaporation of the solvent was followed by distillation and the fraction at 105-106° C. at 0.1 mm Hg was collected. Yield 55 g, 54%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:69])[C@H:4]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:5][C:6](=[O:61])[C@H:7]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=1)[NH:8][C:9](=[O:52])[C@H:10]([CH2:31][S:32][C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:11]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)(=O)C.O>[CH3:1][O:2][C:3](=[O:69])[C@H:4]([CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)[NH:5][C:6](=[O:61])[C@H:7]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=1)[NH:8][C:9](=[O:52])[C@H:10]([CH2:31][S:32][C:33]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:11]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
Water (445 ml) is added dropwise to a solution of N,S-ditrityl-cysteinyl-tyrosyl-phenylalanine methyl ester (21.9 g, 23.5 mmoles, described in Example 1) in glacial acetic acid (1780 ml) at room temperature. The solution is stirred at 45° C for 1.5 hour and diluted with water (2200 ml). The precipitate is removed by filtration and the filtrate is evaporated. The last traces of acetic acid are removed by repeated evaporation with benzene to give (S-trityl)cysteinyl-tyrosyl-phenylalanine methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:22]([Br:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=[O:31]>C(#N)C.O>[CH2:1]([O:8][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:22]([Br:23])=[CH:21][N:20]=[C:19]([NH:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=[O:31])[N:18]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(NCCCCCNc1nc(Cl)ncc1Br)OCc1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(NCCCCCNc1nc(Nc2cccc(C(=O)O)c2)ncc1Br)OCc1ccccc1

Procedure:
A reaction mixture of 1.20 g (2.8 mmol) of [5-(5-bromo-2-chloro-pynmidin-4-ylamino)-pentyl]-carbamic acid-benzyl ester and 0.37 g (2.7 mmol) of 3-aminobenzoic acid in acetonitrile/water (8 ml/1.5 ml) is stirred under reflux for 20 hours. The reaction mixture is spun in, and the remaining residue is purified by chromatography (dichloromethane/methanol 9:1, Flashmaster II). 1.27 g (2.4 mmol, corresponding to 86% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:6].CN(C=O)C.[F:24][C:25]([F:29])([F:28])[CH2:26]I>>[CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[C:13]([O:14][CH2:26][C:25]([F:29])([F:28])[F:24])=[CH:12][CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])(=[O:6])=[O:7]
Reactant: CN(C)C=NS(=O)(=O)c1c(O)cccc1[N+](=O)[O-]
Reactant: FC(F)(F)CI
Solvent: CN(C)C=O
Product: CN(C)C=NS(=O)(=O)c1c(OCC(F)(F)F)cccc1[N+](=O)[O-]
Reaction time: 20 h

Procedure:
To a solution of N-(1-dimethylamino-methylidene)-2-nitro-6-hydroxy-benzenesulfonamide (847 mg, 3.1 mmol) in DMF (10 mL) NaH (135 mg, 55% dispersion in Nujol, 3.1 mmol) is added under argon. After stirring for 15 min 2,2,2-trifluoro-ethyl iodide (2777 mg, 12.4 mmol) is added, and stirring is continued for 20 h. Volatiles are evaporated under reduced pressure, and the residue is partitioned between EtOAc and water. The organic phase is washed with saturated brine, dried (Na2SO4) and evaporated. Chromatography of the residue (silica gel, hexanes/EtOAc/acetone 2:1:3) gives N-(1-dimethylamino-methylidene)-2-nitro-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[CH3:16]>S1(CCCC1)(=O)=O>[C:15]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:21][CH2:20]1)(=[O:17])[CH3:16]
Reactant: CC(=O)NC1CCNCC1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(=O)NC1CCN(c2cccc(Br)n2)CC1
Temperature: 150 °C
Reaction time: 20 h
Yield: 56 %

Procedure:
A mixture of 0.042 mole of 2,6-dibromopyridine, 0.056 mole of anhydrous potassium carbonate and 0.052 mole of 4-acetamidopiperidine in 75 ml of sulfolane is heated to 150° C. with stirring for 20 hours, then the sulfolane is concentrated to 1/5th of its volume, the reaction mixture is poured in 100 ml of water and extracted with diethyl ether (4×150 ml). The organic phase is washed with water, dried over anhydrous sodium sulfate, concentrated to dryness and the residue is crystallised in 40 ml of ethyl acetate. The 4-acetamido-1-(6-bromo-2-pyridyl)piperidine is thus obtained; m.p. 158° to 160° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:14]=4[N:15]=3)[C:6]=2[CH:23]=1.[O:24]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25]1.C1([SiH3])C=CC=CC=1.C([Sn](Cl)(Cl)CCCC)CCC>C1COCC1>[CH3:22][C:17]1([CH3:21])[CH2:16][C:14]2[N:15]=[C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][CH2:29][CH:26]5[CH2:27][CH2:28][O:24][CH2:25]5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)[S:12][C:13]=2[C:19](=[O:20])[CH2:18]1
Reactant: O=CC1CCOC1
Reactant: CC1(C)CC(=O)c2sc(N3CCOc4ccc(N)cc43)nc2C1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CC(=O)c2sc(N3CCOc4ccc(NCC5CCOC5)cc43)nc2C1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A mixture of Example 12 (50 mg, 0.15 mmol), tetrahydrofuran-3-carboxaldehyde (30 mg, 0.15 mmol), phenylsilane (0.04 mL, 0.3 mmol) and dibutyltin dichloride (5 mg, 0.015 mmol) in THF (3 mL) was heated to 100° C. under microwave irradiation for 40 min. After cooling to r.t., the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organics were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude material was purified by prep HPLC to give the title compound as a yellow solid (14 mg, 22%). δH (CDCl3) 1.08 (6H, s), 1.56-1.71 (2H, m), 1.98-2.13 (1H; m), 2.35 (2H, s), 2.43-2.57 (1H, m), 2.68 (2H, s), 3.03 (1H, d, J 6.8 Hz), 3.52-3.59 (1H, m), 3.65-3.76 (1H, m), 3.78-3.91 (2H, m), 4.08-4.15 (2H, m), 4.16-4.22 (2H, m), 6.32 (1H, dd, J 8.7, 2.4 Hz), 6.73 (1H, d, J 8.7 Hz), 7.10 (1H, d, J 2.6 Hz). LCMS (ES+) 414 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.C(=O)=O.[OH:18][C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]([N:22]1[CH2:23][CH2:24][C:19]([OH:18])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:21]1)=[O:14]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C(O)CC1COc2ccccc2O1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(CC1COc2ccccc2O1)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred solution of 11.64 g of 2-(1,4-benzodioxan-2-yl)-acetic acid in 60 ml of tetrahydrofuran is added 12 g of 1,1-carbonyldiimidazole. After the evolution of carbon dioxide has ceased, 10.6 g of 4-hydroxy-4-phenylpiperidine are added and the mixture stirred overnight at room temperature. It is evaporated, the residue taken up in ethyl acetate, the solution washed with water, N hydrochloric acid and water, dried and evaporated, to yield the 1-[2-(1,4-benzodioxan-2-yl)-acetyl]-4-hydroxy-4-phenylpiperidine.