Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[C:11]([O:20]S(C(F)(F)F)(=O)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O.Cl>[C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[C:11]([OH:20])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cc(OS(=O)(=O)C(F)(F)F)cc2c1CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cc(O)cc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of (5-oxo-3-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (XXIX, 140 mg, 0.33 mmol) in tetrahydrofuran (5 mL) was added a 1.0 M solution of tetrabutylammonium fluoride (660 μL, 0.66 mmol) in tetrahydrofuran at room temperature under nitrogen. The resulting light yellow solution was stirred for 5 h at room temperature, and then diluted with water (10 mL) and 1.0N hydrochloric acid (5 mL). The mixture was extracted with ethyl acetate (2×35 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by ISCO (40 g) column chromatography (gradient elution with 5-50% ethyl acetate in hexanes) to provide (3-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (82 mg, 85%) as a yellow solid: ES(+)-HRMS m/e calcd. for C16H20O5 (M+H)+293.1384, obsd. 293.1383.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:20][C:11]1[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=[C:17]([C:32]3[CH:31]=[CH:30][C:29]([CH2:28][N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)=[CH:34][CH:33]=3)[CH:18]=[C:13]2[CH:12]=1
Reactant: CN1CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: Cc1cc2cc(Br)cnc2n1S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc2cc(-c3ccc(CN4CCN(C)CC4)cc3)cnc2n1S(=O)(=O)c1ccccc1
Yield: 74.1 %

Procedure:
1-Benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (378 mg, 1.076 mmole) and 4-((4-methylpiperazin-1-yl)methyl)phenylboronic acid (303 mg, 1.29 mmole) are dissolved in acetonitrile (10 mL) and treated with 10 mL 1 M sodium carbonate solution. To this is added 40 mg of PdCl2(PPh3)2 catalyst, and the mixture is irradiated for 5 minutes at 150 degrees in a Biotage microwave reactor. After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate, dried, and concentrated. MPLC silica gel chromotagraphy 5-20% MeOH in dichloromethane gradient elution, provided 367 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][C:12](=[CH:14][CH3:15])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:11][C:12]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1)([CH3:13])[CH2:14][CH3:15]
Reactant: COC(=O)c1c[nH]nc1C
Reactant: CC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(C)(C)n1cc(C(=O)OC)c(C)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (10.8 g) synthesized in Example 1(3) was dissolved in acetonitrile (100 mL), 2-methyl-2-butene (16.3 mL) and p-toluenesulfonic acid monohydrate (4.4 g) were added, and the mixture was stirred in a sealed tube at 120° C. for 4 hr. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (4.6 g, 29%) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1>CN(C)C=O>[O:19]=[C:13]([N:10]1[CH2:11][CH2:12][N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)N1CCN(c2ncccn2)CC1
Yield: 70.7 %

Procedure:
A solution of 1-(2-pyrimidinyl)piperazine (3.28 g) and succinic anhydride (2.2 g) in dimethylformamide (15 ml) was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was recrystallized from ethanol/ethyl ether to give the titled compound (3.73 g) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:12]=[CH:13][CH:14]=2.[N:15]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:19]=[CH:18][N:17]=[CH:16]1>C(O)C>[Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Reactant: NCCCCCn1ccnc1
Solvent: CCO
Product: Brc1ccc2c3c(cccc13)C(NCCCCCn1ccnc1)=N2
Yield: 19.5 %

Procedure:
A mixture of 5.3 g of 6-bromo-benz[cd]indole-2-thiol, 3.1 g of 5-(1H-imidazol-1-yl)pentanamine, 100 ml of ethanol and 6.3 g of mercuric acetate was reacted as described in Example 1, giving 1.5 g of the desired product, mp 138°-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7](Cl)[N:8]=[N:9][C:4]=2[CH:3]=1.[OH:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=3)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Reactant: Clc1nnc2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2nnc3cc(Br)ccc3n2)cc1
Yield: 35.1 %

Procedure:
A mixture of 7-bromo-3-chloro-1,2,4-benzotriazine (1.93 g), ethyl 2-(4-hydroxyphenoxy)propionate (1.69 g), anhydrous potassium carbonate (1.20 g) and methyl ethyl ketone (50 ml) was heated under reflux overnight. The solvent was removed by distillation under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was separated, dried (over anhydrous magnesium sulfate) and the solvent was removed by distillation under reduced pressure to give an oil. The crude product was purified by chromatography over silica gel (eluent dichloromethane) and the product was recrystallised from aqueous ethanol to give the title compound (1.16 g) as yellow crystals, mp 104° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH:32]([C:35]5[N:39]=[C:38]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=6)[NH:37][N:36]=5)[CH2:31][CH2:30]4)=[CH:24][CH:23]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[C:16]#[C:17][Si](C)(C)C)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].ClCCl>CO>[C:16]([C:15]1[CH:14]=[N:13][N:11]2[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][N:29]4[CH2:30][CH2:31][CH:32]([C:35]5[N:39]=[C:38]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=6)[NH:37][N:36]=5)[CH2:33][CH2:34]4)=[CH:26][CH:27]=3)=[N:9][C:10]=12)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1cnn2cc(-c3ccccc3)c(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cnn2cc(-c3ccccc3)c(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)nc12

Procedure:
250 mg 6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-[(trimethylsilyl)ethynyl]pyrazolo[1,5-a]pyrimidine and 114 mg K2CO3 are stirred in 5 ml methanol and 5 ml dichloromethane for 7 h. The solvent is removed by evaporation and the residue is purified by chromatography on silica gel (dichloromethane/methanol) to yield the desired compound
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:18][CH:19]([OH:30])[CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[CH3:31]I>CN(C=O)C.C(OCC)(=O)C>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:18][CH:19]([O:30][CH3:31])[CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: CI
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(NCC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)OC)c1
Reaction time: 2.5 h

Procedure:
Sodium hydride (9.0 mg, 0.23 mmol) was added to a stirring solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (99.3 mg, 0.20 mmol) in DMF 0.5 ml, 0.39 M). The solution was stirred at room temperature for about 70 minutes before the dropwise addition of a solution of methyl iodide (14 ml. 0.22 mol) in DMF (1.0 ml). The reaction was monitored by 1 c/ms for the consumption of SM and the appearance of O and N-methyl products. After 2.5 hours of stirring at r.t, conversion was about 30% and about 5% N-methyl product had formed. The reaction was stopped when an increase of N-Me to O-Me had been observed and conversion was about 50%. The brown solution was diluted with ethyl acetate and washed several times with water and finally brine. The organic layer was dried over Na2SO4, filtered and condensed. The mixture was purified by preparative TLC 30% EtOAc/hexanes.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]1([CH2:19][CH:20]([NH:24][C:25](=[N:27][S:28]([CH3:31])(=[O:30])=[O:29])C)[C:21]([OH:23])=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[NH2:32][C@@H:33]([CH2:45][CH3:46])[CH:34]([C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1)[OH:35].CN1CCOCC1>C(Cl)Cl.Cl>[O:37]1[C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=[C:36]1[CH:34]([OH:35])[C@@H:33]([NH:32][C:21](=[O:23])[CH:20]([NH:24][CH:25]=[N:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:19][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:45][CH3:46]
Reactant: CC[C@H](N)C(O)c1nc2ccccc2o1
Reactant: CC(=NS(C)(=O)=O)NC(CC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)C(CC1CCCCC1)NC=NS(C)(=O)=O)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.1 %

Procedure:
A mixture of ethyldimethylaminopropyl carbodiimide hydrochloride (0.198 g, 1.14 mmol), hydroybenzotriazole (0.114 g, 0.742 mmol), 3-cyclohexyl-2-(1-methanesulfonyliminoethylamino)-propionic acid (0.205 g, 0.742 mmol) and 2(S)-amino-1-benzoxazol-2-ylbutan-1-ol (0.153 g, 0.743 mmol) in methylene chloride (6 mL) was cooled in an ice bath and then N-methylmorpholine (0.155 g, 1.55 mmol) was added to the reaction mixture which was then stirred at room temperature for 40 min. The reaction mixture was diluted with ice water and dilute hydrochloric acid and the product extracted with ethyl acetate. The extracts were washed with aqueous sodium bicarbonate, then brine, then dried over magnesium sulfate and evaporated to give of N-[1(S)-(benzoxazol-2-ylhydroxymethyl)propyl]-3-cyclohexyl-2-[(methanesulfonyliminomethyl)-amino]propionamide (0.314 g). Exact mass 464.21. Found: M+H=465.3, M+Na=487.3, M−H=463.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:15][CH2:14][CH2:16][NH:17][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: NCCO
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1cccc([N+](=O)[O-])c1)NCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
To a solution of 3-nitrophenylacetic acid (3.21 g, 17.7 mmol), ethanolamine (2.8 g, 46 mmol), and triethylamine (3.0 mL, 22 mmol) in anhydrous DMF (110 mL) was added a solution of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP, 9.37 g, 18.0 mmol) in anhydrous DMF (80 mL). After stirring 16 hours at ambient temperature (under nitrogen), the reaction mixture was concentrated in vacuo, dissolved in DCM and filtered. The filtrate was washed with 10% aqueous citric acid, saturated aqueous NaHCO3, pH 7 buffer, and brine, dried over Na2SO4 and filtered. The evaporated filtrate was then purified by flash chromatography (10% methanol in DCM) giving the title compound (1.02 g, 26%) as a light yellow solid. 1H NMR (300 MHz, CDCl3/CD3OD) δ 8.18 (m, 1H), 8.11 (ddd, 1H, J=8.1 Hz, 2.4 Hz, 1.1 Hz), 7.72 (m, 1H), 7.60 (t, 1H, J=7.8 Hz), 3.62 (s, 2H), 3.44 (t, 2H, J=5.9 Hz), 3.16 (t, 2H, J=5.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].FC(F)(F)C[O:29][C:30](=O)[NH:31][C:32]1[N:33]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:37]([C:35]1[CH:36]=[C:32]([NH:31][C:30]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[O:29])[N:33]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: NCc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(CN4CCCC4)noc3c2)cc1
Temperature: 85 °C
Yield: 33.5 %

Procedure:
5-Fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzylamine (6v) (50 mg, 0.15 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trifluoro-ethyl ester (b) (75 mg, 0.18 mmol) and diisopropylethylamine (0.038 mL, 0.22 mmol) were combined in DMF (1.5 mL) and heated at 85° C. for 3 hours. The reaction was cooled and concentrated in vacuo and purified by column chromatography (silica, 40 to 60% EtOAc/hexanes/0.25% Et3N) to provide 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzyl]-urea (8v) (30 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.6 Hz, 1H), 7.31 (d, J=7.0 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 7.02-6.88 (m, 5H), 6.17 (s, 1H), 6.02 (s, 1H), 5.30 (t, J=8.6 Hz, 1H), 4.36 (d, J=5.5 Hz, 2H), 3.98 (s, 2H), 2.60 (s, 4H), 2.36 (s, 3H), 1.80 (s, 4H), 1.32 (s, 9H); MS (ESI+) m/z 597 (M+H) detected; HPLC (5 to 95%) 2.93 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:41][C:38]3[C:39]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3cccc(Cl)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 544.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].CO.[CH2:5]([N:9]([C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH:6]([CH3:8])[CH3:7].Cl>O>[CH2:5]([N:9]([C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)CCCC(=O)N(CCc1c[nH]c2ccccc12)CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
1.5 ml of an aqueous 10% sodium hydroxide solution and 10 ml of a mixture of methanol and water (1:1) were added to 0.63 g of N-isobutyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-isobutyl-4-methoxycarbonylbutanamido)ethyl]-indole). The mixture was stirred at 60° C. for 30 minutes. After the reaction was completed, the mixture was evaporated to remove solvent. The residue thus obtained was adjusted to a pH of 2.0 with 10% hydrochloric acid, and then extracted with chloroform. The extract was washed with water and concentrated. 0.6 g of N-isobutyl-N-(4-carboxybutyryl)-tryptamine (i.e., 3-[2-(N-isobutyl-4-carboxybutanamido)ethyl]-indole) were thereby obtained. Yield: 99.3%
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[CH:11]=[C:3]([CH:4]=[C:5]([O:6][CH3:7])[C:8]=1[OH:9])[CH:2]=[O:1]
Reactant: BrBr
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(Br)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
To a solution of vanillin (30.40 g, 0.20 mol) in glacial acetic acid (200 ml) was added bromine (46.79 g, 0.29 mol) in glacial acetic acid (20 ml) at 100 over a period of 1 h. Additional acetic acid (100 ml) was added to the thickening mixture and the reaction was stirred for 24 h at ambient temperature. The reaction was diluted with ice-water (300 ml) and then the precipitate was filtered and washed with water and dried in vacuo to give the desired compound (40.69 g, 89%).
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=2)=[CH:21][C:20]=1[C:36]1[CH:45]=[CH:44][C:43]2[C:42]([CH3:47])([CH3:46])[CH2:41][CH2:40][C:39]([CH3:49])([CH3:48])[C:38]=2[CH:37]=1.O.Cl>C(O)C>[NH2:6][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:30]=2)=[CH:21][C:20]=1[C:36]1[CH:45]=[CH:44][C:43]2[C:42]([CH3:47])([CH3:46])[CH2:41][CH2:40][C:39]([CH3:48])([CH3:49])[C:38]=2[CH:37]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCN)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reaction time: 8 h
Yield: 37.1 %

Procedure:
100 μl of hydrazine monohydrate (2.05 mmol) are added to a solution of 650 mg (1 mmol) of ethyl 4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 50 ml of ethanol. The reaction mixture is stirred overnight at reflux. The reaction is stopped by adding water and hydrochloric acid to pH 4, and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off. The residue is purified by chromatography on silica gel (eluent: 70/30 ethyl acetate/methanol). 180 mg of ethyl 4′-(3-aminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a whitish solid (m.p.=155° C., yield=35%).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]([C:18]([NH:23][CH3:24])=[CH:19][N+:20]([O-:22])=[O:21])[CH3:17])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([OH:4])[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([N:16]([CH2:15][C:12]1[CH:13]=[N:14][C:9]([Cl:8])=[CH:10][CH:11]=1)[CH3:17])[NH:23][CH3:24]
Reactant: CNC(=C[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=C(C(O)C(Cl)(Cl)Cl)[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Chloral hydrate (0.40 g) was added slowly in 40 minutes to a mixture of 1-[N-(6-chloro-3-pyridylmethyl)-N-methylamino]-1-methylamino-2-nitroethylene (0.26 g), triethylamine (0.1 g) and acetonitrile (3 ml). The mixture was stirred at room temperature for 21 hours and under refluxing for 9 hours. The resultant crystals were collected by filtration to give 1,1,1-trichloro-4-[N-(6-chloro-3-pyridylmethyl)-N-methylamino]-4-methylamino-3-nitro-3-buten-2-ol (Compound No. 11) (0.23 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[C:14]([CH2:16][N:17]([CH3:19])[CH3:18])=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cn(-c2ccc(Cl)cc2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(Cl)cc2C#N)c1CN(C)C
Yield: 17 %

Procedure:
In analogy to example 5b, 5-chloro-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and crystallization from Ethyl acetate afforded the title compound as a white solid (yield: 17%). MS: m/e=275.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:33])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:33])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1c(CO)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCOc1c(CCl)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Yield: 94.8 %

Procedure:
To a suspension of 6-benzyloxy-4-butoxy-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (6.96 g, 17 mmol) in toluene (50 mL)) was added thionyl chloride (2.5 mL, 34 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-4-butoxy-3-chloromethyl-2-isobutyl-1(2H)-isoquinolinone (6.90 g, 94.8%) as crystals.