Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:13](Br)=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:11]([CH:23]([CH3:25])[CH3:24])[N:10]=1)C1C=CC=CC=1.C([Li])CCC.[CH3:31][O:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:34]=1[CH:35]=O>O1CCCC1>[CH:23]([N:11]1[C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[C:13]([CH2:35][C:34]2[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:33]=2[O:32][CH3:31])[C:9](=[O:8])[NH:10]1)([CH3:24])[CH3:25]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COc1ccc(-c2c(Br)c(OCc3ccccc3)nn2C(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2c(Cc3ccc(OC)cc3OC)c(=O)[nH]n2C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-benzyloxy-4-bromo-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole in tetrahydrofuran (2 mL) was added n-butyllithium (2.6 mol/L hexane solution, 0.89 mL) at −78° C. under argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 2,4-dimethoxybenzaldehyde (0.51 g) in tetrahydrofuran (2 mL) was added to the reaction mixture, and the mixture was stirred at −78° C. for 1 hour. The reaction mixture was directly purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified [3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl (2,4-dimethoxyphenyl) methanol was dissolved in ethanol (9 mL), and a catalytic amount of 10% palladium-carbon powder was added to the solution. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. Dichloromethane was added to the reaction mixture, and the insoluble material was removed by filtration. The solvent of the filtrate was removed, and diethyl ether and hexane were added to the residue. The insoluble material was collected by filtration and dried under reduced pressure to give the title compound (0.09 g).
Reaction SMILES: [CH2:1]([C:4]1[C:5]2[CH:6]=[CH:7][C:8]([O:27][CH3:28])=[C:9]([O:25][CH3:26])[C:10]=2[CH2:11][NH+:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]4[O:24][CH2:23][O:22][C:17]=4[CH:18]=3)[C:13]=12)[CH:2]=[CH2:3].[Br-].[C:30]([Mg]Br)([CH3:32])=[CH2:31].O1CCCC1>C(OCC)C>[CH2:1]([C:4]1[C:5]2[CH:6]=[CH:7][C:8]([O:27][CH3:28])=[C:9]([O:25][CH3:26])[C:10]=2[CH:11]([C:30]([CH3:32])=[CH2:31])[N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]4[O:24][CH2:23][O:22][C:17]=4[CH:18]=3)[C:13]=12)[CH:2]=[CH2:3]
Reactant: C=C(C)[Mg]Br
Reactant: C=CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1=C2c3cc4c(cc3CCN2C(C(=C)C)c2c1ccc(OC)c2OC)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a suspension of 13-allyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; bromide (300 mg, 0.66 mmol) in anhydrous diethyl ether (20 mL) at 0° C. was added a solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 20 mL, 10 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with diethyl ether (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-allyl-8-isopropenyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (75 mg, 27%). LC/MS m/e calcd for C26H27NO4 (M+H)+: 418.51, observed: 418.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.64-2.80 (m, 2 H) 2.97-3.06 (m, 1 H) 3.18-3.25 (m, 1 H) 3.72 (s, 3 H) 3.79 (s, 3 H) 4.63 (s, 1 H) 4.73 (s, 1 H) 5.06-5.18 (m, 3 H) 6.02 (s, 2 H) 6.05-6.15 (m, 1 H) 6.81 (m, 1 H) 6.86 (s, 1 H) 6.91 (m, 1 H) 6.98 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(OO)(C)(C)C.[NH4+:22].[OH-]>CO.N>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:22])=[N:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CC1(c2cccc(Br)c2)COCC(=S)N1
Agent: CC(C)(C)OO
Agent: N
Agent: [OH-]
Solvent: CO
Product: CC1(c2cccc(Br)c2)COCC(N)=N1
Reaction time: 8 h

Procedure:
To a solution of 5-(3-bromo-phenyl)-5-methyl-morpholine-3-thione (5 g, 17.5 mmol) in MeOH/NH3 (110 ml) were added at room temperature t-BuOOH (28 ml, 65%) and NH4OH (47 ml, 25%). The mixture was stirred overnight, quenched with aqueous Na2S2O3 solution, concentrated in vacuo to remove the methanol solution and extracted with EtOAc (3×30 ml). The organic phase was dried with Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC [column: Venusil XBP-C18, 250×21.2 mm, 10 μm; injection volume: 10 ml/injection; mobile phase: CH3CN/H2O=10 to 35% (0.1% formic acid) gradient for 15 min, washed with 95% CH3CN for 4 min, back to 10% balance for 4 min] to give the title compound in the form of a formic acid salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O-].[Na+].CI.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CO
Product: CSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-bromobenzenethiol (5 g, 26.44 mmol) was added to a solution of sodium methoxide (1.43 g, 26.48 mmol) in 20 ml of anhydrous methanol. The mixture was stirred for 30 min under nitrogen at room temperature and a solution of methyl iodide (4.51 g, 31.77 mmol) in 20 ml anhydrous methanol was then added. The reaction mixture was stirred overnight at room temperature, poured into 2 M aqueous NaOH solution (30 ml) and extracted three times with ether (60 ml×3). The combined organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of solvent, the product was purified by distillation at 80° C. (0.3 mmHg) and isolated in 86.1% (4.62 g) yield. 1H NMR(CDCl3, 500 MHz) δ ppm: 2.44 (s, 3H, CH3), 7.1-7.4(m, 4H, Ar—H)GC-MS(relative intensity %): 202, 204(1:1, 100, M+), 187, 189(1:1, 11, 3-BrPhS+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:48](Cl)=[O:49])=[CH:43][CH:42]=1>O>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:48]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:13][C:14]3[C:17](=[O:18])[C:16](=[O:19])[C:15]=3[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)=[O:49])=[CH:43][CH:42]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CCCNc1c(N[C@@H](Cc2ccc(N)cc2)C(=O)O)c(=O)c1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCNc1c(N[C@@H](Cc2ccc(NC(=O)Oc3ccc(OC)cc3)cc2)C(=O)O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 1.1 %

Procedure:
To the derivatised resin (5), (120 mg) was added 1,4-dioxan (4.5 ml), DIPEA (0.2 ml, 1.2 mmol), water (0.5 ml) and 4-methoxyphenylchloroformate (0.2 ml, 0.6 mmol). The solution was agitated for 12 h at RT then filtered and washed thoroughly with DCM. The resin was treated with 60% trifluoroacetic acid in DCM (1.5 ml) for 3 h with agitation and then filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC to afford the title compound (2 mg).
Reaction SMILES: Cl.[CH3:2][Si:3]1([CH3:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.O>C(OC(=O)C)C>[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:6]1[CH2:7][CH2:8][Si:3]([CH3:9])([CH3:2])[CH2:4][CH2:5]1
Reactant: C[Si]1(C)CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si]1(C)CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
To a solution of 4 (500 mg, 3.85 mmol) in ethylacetate, triethylamine (973 mg, 9.63 mmol) is added and stirred at 25° C. for 10 min. The reaction mixture is cooled to 0° C. and 3,4-difluoronitrobenzene (612 mg, 3.85 mmol) is added dropwise and allowed to stir at 25° C. for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc and the solvent is removed. The product is purified by column chromatography using hexanes-EtOAc mixtures to obtain the product as a crystalline yellow solid 9 (721 mg) in 70% isolated yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH:18](Cl)(Cl)Cl>>[CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]2[CH2:11][CH2:13][CH2:12][CH2:18]2)=[O:8])[CH:3]1[C:14]([O-:16])=[O:15]
Reactant: ClC(Cl)Cl
Agent: CC1(C)C(C=CC(=O)OCC2CC2)C1C(=O)O
Product: CC1(C)C(C=CC(=O)OC2CCCC2)C1C(=O)[O-]

Procedure:
Using the procedure of Example 9, the product of Step B and (3-propyn-2-yl-2,5-dioxo-imidazolidinyl)-methanol were reacted to obtain (3-propyn-2-yl-2,5-dioxo-imidazolidinyl)-methyl (1R, cis, ΔZ) 2,2-dimethyl-3-(3-cyclopentyloxy-3-oxo-1-propenyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+15.5°±1.5° (c=1% in chloroform).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[C:5]([NH:26][C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[O:4][N:3]=1.O[CH:36]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:37]([O:39][CH3:40])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[N:26]([C:27]([O:29][CH2:30][C:31]([Cl:32])([Cl:33])[Cl:34])=[O:28])[C@H:36]([C:37]([O:39][CH3:40])=[O:38])[CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)C(O)CC(C)C
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1onc(C)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To tert-butyl 4-[4-(3-methyl-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}isoxazol-4-yl)phenyl]piperazine-1-carboxylate (617 mg, 1.16 mmol), methyl 2-hydroxy-4-methylpentanoate (255 mg, 1.74 mmol) and triphenyl phosphine (460 mg, 1.74 mmol) in dry DMF (15 mL) at 0° C. under dry nitrogen was added diisopropyl azodicarboxylate (0.35 mL, 1.74 mmol) dropwise over ½ hour and the reaction mixture was stirred for 2 days at rt. The reaction was poured into water and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 25/75) to afford methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH3:20][CH:19]([NH:22][CH2:15][CH:14]([OH:16])[CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:18][CH:17]=1)[CH3:21]
Reactant: CC(C)N
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: CC(C)NCC(O)COc1ccc(CCOCC2CC2)cc1

Procedure:
reacting 1-{4-[2-(Cyclopropylmethoxy)ethyl]phenoxy}-2,3-epoxypropane with isopropylamine to produce Betaxolol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15](=[O:30])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH:22]([C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[CH3:23])([CH3:13])([CH3:12])[CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:30])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:22]([C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[CH3:23])[CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(NCCCCNC(=O)OC(C)(C)C)c1nccn1C
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)C(C)c1nccn1C

Procedure:
Using General Procedure B, reaction of 3-methylpyridine-2-carboxaldehyde, {4-[1-(1-methyl-1H-imidazol-2-yl)-ethylamino]-butyl}-carbamic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave {4-[[1-(1-methyl-1H-imidazol-2-yl)-ethyl]-(3-methylpyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a light yellow oil. 1H NMR (CDCl3) δ 1.10-1.35 (m, 4H), 1.37 (s, 9H), 1.53 (d, 3H, J=7.5 Hz), 2.11 (s, 3H), 2.51 (m, 1H), 2.62 (m, 1H), 2.90 (br, 2H), 3.37 (s, 3H), 3.62 (d, 1H, J=13.5 Hz), 3.95 (d, 1H, J=13.5 Hz), 4.04 (q, 1H, J=7.5 Hz), 4.57 (br, 1H, NH), 6.76 (s, 1H), 6.92 (s, 1H), 7.09 (m, 1H), 7.40 (d, 1H, J=7.5 Hz), 8.38 (d, 1H, J=4.5 Hz). Conversion to the HBr salt using General Procedure D gave COMPOUND 231 as a white solid. 1H NMR (D2O) δ 1.50 (br, 4H), 1.52 (d, 3H, J=6.9 Hz), 2.44 (s, 3H), 2.72 (br, 2H), 2.89 (br t, 2H), 3.89 (s, 3H), 4.24 (s, 2H), 4.68 (q, 1H, J=6.9 Hz), 7.38 (d, 1H, J=1.8 Hz), 7.40 (d, 1H, J=1.8 Hz), 7.85 (t, 1H, J=6.6 Hz), 8.36 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 14.17, 16.90, 24.18, 25.00, 35.16, 39.54, 50.20, 52.57, 53.23, 119.09, 124.44, 125.99, 137.29, 138.34, 146.69, 148.46, 152.08. ES-MS m/z 302 (M+H). Anal. Calcd. for C17H27N5.3.5HBr.1.9H2O.C4H10O: C, 34.45; H, 5.95; N, 10.80; Br, 43.12. Found: C, 34.57; H, 5.73; N, 10.77; Br, 42.98.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(Cl)s1
Product: ClCc1coc(-c2ccc(Cl)s2)n1
Yield: 51 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-chloro-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(5-chloro-2-thienyl)oxazole. The yield was 51%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 90-91° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:9]=2[N:10]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: OCc1ccc2nc(-c3cccs3)oc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2nc(-c3cccs3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.7 g (16.0 mmol) (2-thiophen-2-yl-benzoxazol-6-yl)-methanol are dissolved in 200 ml DCM, 15.0 g (10.78 mmol) manganese dioxide are added and the suspension is stirred overnight at RT. The next day the suspension is filtered through kieselguhr and the filtrate is concentrated completely by rotary evaporation i. V.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([CH2:33][OH:34])=[CH:30][C:29]=2[CH:35]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:67][C:68]([F:72])([F:71])[CH2:69]O>C1C=CC=CC=1>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([CH2:33][O:34][CH2:69][C:68]([F:72])([F:71])[F:67])=[CH:30][C:29]=2[CH:35]=1
Reactant: OCC(F)(F)F
Reactant: Cc1c(COc2ccc3oc(CO)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cc1c(COc2ccc3oc(COCC(F)(F)F)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound of Example 40 (60 mg) and 1,1′-(azodicarbonyl)dipiperidine (64 mg) were suspended in dry benzene (2 ml). To the suspension was added tributylphosphine (63 μl) at room temperature. The mixture was stirred at room temperature for 15 minutes. To the mixture was added 2,2,2-trifluoroethanol (74 μl). The mixture was stirred at room temperature overnight. After removing the solvent the reaction mixture was separated by silica gel column chromatography developed by the solvent mixture of dichloromethane and methanol. The title compound (57 mg) was obtained as a colorless oil. ESI-MS: m/z 555 (MH+); 1H-NMR (CDCl3): δ 2.05 (2H, quintet, J=6.5 Hz), 2.33 (3H, s), 2.87 (2H, t, J=7 Hz), 3.83 (2H, s), 3.91 (2H, q, 8.5 Hz), 4.14 (2H, t, J=6 Hz), 4.74 (2H, s), 5.10 (2H, s), 6.60 (1H, d, J=7 Hz), 6.71 (1H,s), 6.95-7.25 (5H, m), 7.38 (1H, d, J=9 Hz), 7.66 (1H, dt, J=7.5 Hz, 2 Hz), 8.48 (1H, dd, J=1.5 Hz, 4.5 Hz), 8.56 (1H, d, J=1.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22](C)[CH2:21][C@H:20]1[C:25]([OH:27])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:25]([O:27][CH2:7][C:6]([C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])=[O:26])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(Br)cc1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a mixture of p-bromophenacyl bromide (242 mg, 0.87 mmol) in DCM (1.5 mL) and DMA (1.5 mL), under nitrogen, was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.87 mmol) and N,N-diisopropylethylamine (531.8 μL, 3.05 mmol) and the resulting mixture was stirred at 35° C. for 3 h, concentrated under vacuum, dissolved in DCM (30 mL), and washed with water (2×5 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title intermediate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:34]C)=[C:15]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=2)[CH:16]=1.[CH:36]1[C:44]2[C:43]3[CH:45]=[CH:46][CH:47]=[CH:48][C:42]=3[O:41][C:40]=2[C:39]([C:49]([OH:51])=O)=[CH:38][CH:37]=1.C(Cl)Cl>CC(C)=O>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:15]2[CH:16]=[C:11]([NH:10][C:49]([C:39]3[C:40]4[O:41][C:42]5[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=5[C:44]=4[CH:36]=[CH:37][CH:38]=3)=[O:51])[CH:12]=[CH:13][C:14]=2[CH3:34])=[O:33])[CH2:27][CH2:28]1
Reactant: O=C(O)c1cccc2c1oc1ccccc12
Reactant: CCc1ccc(N)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
Diisopropylethylamine (0.4 ml) was added to a stirred mixture of N-(5-amino-2-ethylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide (0.2 g), dibenzofuran-4-carboxylic acid (0.133 g), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.22 g) and methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was dissolved in acetone and reprecipitated by the addition of isohexane. There was thus obtained the title compound (0.164 g); NMR Spectrum: (DMSOd6) 1.15 (t, 3H), 2.25 (s, 3H), 2.35-2.5 (m, 8H), 2.6 (m, 2H), 3.55 (s, 2H), 7.3 (d, 1H), 7.4-7.6 (m, 5H), 7.65 (m, 1H), 7.8-7.9 (m, 5H), 8.2 (d, 1H), 8.35 (d, 1H), 9.95 (s, 1H), 10.43 (s, 1H); Mass Spectrum: M+H+ 547.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]23[CH2:17][CH:16]([CH2:18]2)[C:15](=[O:19])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:13]3=[O:20])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCCCCI
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitropenyl)-3-azabicyclo[3.1.1]heptane-2,4 -dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 2.96 g of n-pentyl iodide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation, the product is obtained having a melting point of 75°-79°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)[CH2:8][CH2:7][CH2:6]2)#[N:2]>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)[CH2:8][CH2:7][CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1ccns1
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CCCC2c1ccns1

Procedure:
Analogously to Example 4, 6-cyano-1-hydroxy-1-(5-isothiazolyl)-1,2,3,4-tetrahydronaphthalene (Example 15) in glacial acetic acid is convened into the title compound using tin(II) chloride and 36.5% hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH2:24]([O:26][C:27](=[O:31])[CH:28]([CH3:30])[NH2:29])[CH3:25].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:13][C:14]=1[S:19]([NH:29][CH:28]([CH3:30])[C:27]([O:26][CH2:24][CH3:25])=[O:31])(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: CCOC(=O)C(C)N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)NS(=O)(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 58 %

Procedure:
4.0 g of 3-chloro-2-(4-chloro-3-chlorosulfonylphenyl)-5-trifluoromethylpyridine, 2.4 g of D,L-alanine ethyl ester hydrochloride and 5.2 g of triethylamine in 50 ml of anhydrous tetrahydrofuran were stirred at 23° C. for 18 hours, after which the mixture was concentrated. The residue was taken up in 100 ml of methylene chloride. The solution was extracted twice with 30 ml of water each time, dried over sodium sulfate and concentrated. Chromatography of the residue on silica gel with cyclohexane/ethyl acetate (4:1) resulted in 2.8 g of a colorless oil. Yield: 58%;