Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9]>C1COCC1.Cl[Ni](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>[CH3:3][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9]
Reactant: Cc1ccccc1Cl
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1C

Procedure:
To a suspension of magnesium turnings (12.15 grams, 0.5 mole) in THF (150 mL) was added 2-chlorotoluene (50.6 grams, 0.40 mole). The mixture was refluxed for 18 hours, cooled to ambient and added dropwise to a solution of 2-chlorotoluene (44.3 grams, 0.35 mole) and bis(triphenylphosphine)-nickel (II) dichloride (2.0 grams) in THF (250 mL). The reaction mixture warmed upon mixing and was heated to reflux for 4 hours after completion of the addition. The reaction mixture was cooled and quenched by the addition of toluene (400 mL) and a saturated ammonium chloride solution (200 mL). The layers were separated and the organic phase was washed sequentially with 10 percent HCl (200 mL), water (3×100 mL), and then stripped under nitrogen to give a thick oil. The oil was distilled under vacuum to give the product as a fraction boiling in the range of 85° to 90° C. at 1 mm Hg. The yield was 43.40 grams (68 percent of theory) of 2,2'-dimethyl-1,1'-biphenyls containing 93 percent of the 2,2'-isomer and 3.5 percent of other isomers.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].N[C@@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CC(=O)N.N[C@@H](C(O)=O)CC(=O)N.N[C@H](C(O)=O)CCC(=O)N.N[C@@H](C(O)=O)CCC(=O)N>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: NC(=O)CC[C@@H](N)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: NC(=O)C[C@@H](N)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
replace with: D-Glu, D-Asp, Asp, Asn, D-Asn, Gln, D-Gln;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.Cl.[NH2:14][OH:15]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[N:14][OH:15]
Reactant: NO
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=NO)cc1F
Temperature: 62.5 °C
Yield: 77.3 %

Procedure:
A mixture of 3-fluoro-4-nitro-benzaldehyde (9.5; 56.21 mmol) and hydroxylamine hydrochloride (4.29 g; 61.83 mmol) in ethanol (50 mL) was heated at 60-65° C. for 2 hours. The solvent was distilled off. The residue was purified by flash chromatography over silica gel with 10-15% ethyl acetate in light petroleum to give 8 g of the title compound (77.4%); IR (KBr): 3091, 3056, 2501, 2431, 1597, 1513, 1488, 1400 cm−1; MS (m/z): 185 (M++1); 1H NMR (CDCl3) δ: 7.62-7.70 (m, 2H), 8.14-8.19 (m, 1H), 8.24 (s, 1H NH), 11.99 (s, 1H, NHOH).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 1-fluoro-4-nitro-benzene (500 mg, 3.54 mmol), morpholine (620 mg, 7.08 mmol) and K2CO3 (733 mg, 5.3 mmol) in DMSO (5 mL) was irradiated in a microwave (160 W) for 30 seconds (3×10 seconds). The reaction mixture was cooled to room temperature and poured onto ice. The resulting precipitated was filtered to afford 490 mg (66%) of 4-(4-nitro-phenyl)-morpholine. 1H NMR: (DMSO-d6): δ 8.1 (m, 2H), 7.1 (m, 2H), 3.42 (t, 4H), 3.4 (t, 4H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([CH:14]([OH:44])[C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[C:23]([C:24]([N:26]=[CH:27][N:28]=3)=[NH:25])=[N:22][C:21]2=[SiH2:30])[C@H:17]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:16]1[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:13])([CH3:12])[CH3:11].N1CCOCC1>N1C=CC=CC=1>[C:10]([CH:14]([OH:44])[C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[C:23]([C:24]([N:26]=[CH:27][N:28]=3)=[N:25][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:22][C:21]2=[SiH2:30])[C@H:17]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:16]1[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)O[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=N)O[C@@H]1C(O)C(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCN1
Solvent: c1ccncc1
Product: CC(C)(C)O[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=NC(=O)c2ccccc2)O[C@@H]1C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Benzoyl chloride (8 ml, 68.86 mmol) was added dropwise to a stirred suspension of (50) (17.89 g, 34.28 mmol) in anhydrous pyridine (100 ml) at 0° C. After 5 min the reaction was warmed to room temperature and stirred for 2.5 hr. After that the mixture was cooled to 0° C. and morpholine (12 ml, 137.9 mmol) was added slowly with stirring. After 45 min at 0° C. the reaction mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate and evaporated in vacuo. Crystallization from acetonitrile (100 ml) furnished (51) as crystalline material. Yield 16.47 g (76.8%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:34]1[CH2:39][CH2:38][S:37](=[O:40])[CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:34]5[CH2:39][CH2:38][S:37](=[O:40])[CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S1CCNCC1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=S1CCN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (5 mL) was added thiomorpholine 1-oxide (155 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (280 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (87 mg, yield 36%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 568 (MH+).
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[C:5]([NH:9][CH2:10][CH2:11][OH:12])([CH3:8])([CH3:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([N:9]1[CH2:10][CH2:11][O:12][P:1]1[Cl:4])([CH3:8])([CH3:7])[CH3:6]
Reactant: ClP(Cl)Cl
Reactant: CC(C)(C)NCCO
Solvent: Cc1ccccc1
Product: CC(C)(C)N1CCOP1Cl
Yield: 56.7 %

Procedure:
To a solution of 8.7 ml (0.10 mol) of phosphorus trichloride in 200 ml of toluene in a 500 ml three neck flask equipped with a mechanical stirrer, a condenser and an addition funnel is added a solution of 11.72 g (0.10 mol) of 2-tert-butylaminoethanol in 50 ml of toluene. After refluxing for 16 hours, the orange solids are filtered off and the filtrate concentrated in vacuo. Distillation under reduced pressure gives 10.3 g (56.7%) of clear liquid: b.p. 82° C./1.0 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:22]#[C:23][CH2:24][N:25]3[CH2:30]COC[CH2:26]3)=[CH:17][CH:18]=2)[C:13]1=[O:31].CO.C(OCC)(=O)C>C(O)C.[Pd]>[CH3:30][N:25]([CH3:26])[CH2:24][CH2:23][CH2:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][N:12]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:13]2=[O:31])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(C#CCN4CCOCC4)cc3c2=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(CCCN(C)C)cc3c2=O)c1
Yield: 91.2 %

Procedure:
Methyl 4-methyl-3-[7-(3-morpholin-4-ylprop-1-yn-1-yl)-1-oxoisoquinolin-2(1H)-yl]benzoate (292 mg) and 10% Pd/C (30 mg) were stirred in a mixture of ethanol (2 ml)/methanol (4 ml)/ethyl acetate (2 ml) under an atmosphere of hydrogen at room temperature for 17 hours. The catalyst was removed by filtration through a microfibre filter and the filtrate was concentrated to yield an oil. The oil was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to yield methyl 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoate as a brown oil (242 mg); NMR Spectrum: (DMSOd6) 1.79 (m, 2H), 2.14 (s, 3H), 2.28-2.36 (m, 6H), 2.77 (t, 2H), 3.57 (m, 4H), 3.86 (s, 3H), 6.72 (d, 1H), 7.30 (d, 1H), 7.59 (d, 1H), 7.67 (m, 2H), 7.83 (s, 1H), 7.98 (d, 1H), 8.08 (s, 1H); Mass Spectrum: M+H+ 421.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[C:9]3[NH:25][N:26]=[CH:27][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:29][CH2:30][CH2:31][OH:32]>>[C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[C:9]3[N:25]([CH2:29][CH2:30][CH2:31][OH:32])[N:26]=[CH:27][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc3[nH]ncc3c(-c3ccccc3)c2-c2ccncc2)cc1
Reactant: OCCCI
Product: OCCCn1ncc2c(-c3ccccc3)c(-c3ccncc3)c(-c3ccccc3)nc21

Procedure:
Following a similar procedure to that described in examples 6 and 7, but using 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 2) instead of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and 3-iodopropanol instead of iodoethane, the title compounds were obtained.
Reaction SMILES: [O-][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C[Si]([C:21]#[N:22])(C)C.CN(C)C(Cl)=O.C(OCC)(=O)C>[N+](CC)([O-])=O.O>[C:21]([C:7]1[N:2]=[C:3](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1)#[N:22]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc[n+]1[O-]
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
tert-Butyl (E)-3-(1-oxido-2-pyridyl)-2-propenoate (2.10 g, 9.5 mmol) was dissolved in nitroethane (10 ml), and trimethylsilyl cyanide (1.88 g, 19.0 mmol) and N,N-dimethylcarbamoyl chloride (2.04 g, 19.0 mmol) were added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (2.18 g, ca. 100%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[C:24](OC)=[N:23][S:22](=[O:27])[N:21]=1>CO>[NH2:19][C:20]1[C:24]([NH:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)=[N:23][S:22](=[O:27])[N:21]=1
Reactant: COC1=NS(=O)N=C1N
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Solvent: CO
Product: NC1=NS(=O)N=C1NCCCOc1cc(CN2CCCCC2)ccn1
Yield: 66.8 %

Procedure:
A solution of the product of Step A (6.5 g; 26.0 mmoles) in 90 ml of methanol was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (3.84 g; 26.0 mmoles) according to the general procedures described in U.K. Patent Application 2,067,987 to give 6.33 g of product. Recrystallization from methanol-acetonitrile yielded the title compound, mp 154°-158° C.
Reaction SMILES: C(O[C:4](=[O:19])[NH:5][S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH2:13][CH2:12]2)(=[O:8])=[O:7])C.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:4]([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[CH2:13][CH2:12]3)(=[O:7])=[O:8])=[O:19])=[CH:23][CH:22]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc2c(c1)CCN2C
Reactant: Nc1ccc(Cl)cc1
Product: CN1CCc2cc(S(=O)(=O)NC(=O)Nc3ccc(Cl)cc3)ccc21
Yield: 60 %

Procedure:
Following the procedure of Example 3B, the title product was prepared in 60% yield from [(2,3-dihydro-1-methyl-1H-indol-5-yl)sulfonyl]carbamic acid ethyl ester and 4-chloroaniline, m.p. 145°-147° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](OB(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(COC)OC>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: COc1ccc(OB(O)O)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc(-c2ccc(OC)c(OC)c2)n1

Procedure:
To a mixture of methyl 6-chloropyridine-2-carboxylate, 3,4-dimethoxyphenylboric acid, dimethoxyethane and water were added palladium acetate, triphenylphosphine and sodium carbonate, and they were reacted at 100° C. for 1 hour to obtain methyl 6-(3,4-dimethoxyphenyl)pyridine-2-carboxylate. Thus obtained compound was reacted at 60° C. for 30 minutes in a mixed solution of THF-methanol with adding a 1M aqueous sodium hydroxide solution, whereby 6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid was obtained.
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1C(=O)N([Br:28])C(=O)C1>CN(C=O)C>[Br:28][C:16]1[CH:17]=[CH:18][C:19]2[N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[CH:12]=[CH:13][C:14]=2[C:15]=1[NH2:20]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N)cccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(Br)ccc32)cc1
Temperature: -20 °C

Procedure:
To 1-tosyl-1H-indol-4-amine (9.1 g, 31.8 mmol) in DMF (300 mL) at −20° C. was added NBS (5.60 g, 31.5 mmol) and the mixture was stirred at −20° C. After 5 minutes the reaction was quenched with sat. aq. NaHCO3, then with sat. sodium thiosulfate, extracted with EtOAc (three times), dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 364.9, 366.9 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10].[CH:18](=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].O>O1CCCC1>[CH:12]1([O:11][C:9]([O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH:18]=[O:26])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccccc1O
Reactant: O=C(Cl)OC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1OC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
6.3 ml (45 mmol) of triethylamine and then 7.4 g (45 mmol) of cyclohexyl chloroformate are added dropwise to a solution containing 5 g (41 mmol) of salicylaldehyde in 50 ml of tetrahydrofuran at 0° C. After stirring at ambient temperature for 2 hours, the medium is treated with water and then extracted with a heptane/ethyl acetate 1/1 mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. 10.3 g of 2-(cyclohexyloxycarbonyl-oxy)benzaldehyde are obtained in the form of a yellow oil with a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.Cl.C(OCC)C.C([O-])([O-])=O.[K+].[K+]>O.CN1C(=O)CCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: BrCCCCCBr
Reactant: Oc1ccnc2cc(Cl)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc2c(OCCCCCBr)ccnc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 12.3 %

Procedure:
7-Chloro4-quinolinol (2 g, 11.1 mmol), Li2CO3 (1.7 g, 22.3 mmol) and NMP (16 mL) were charged in a 100 ml round-bottomed flask equipped with a magnetic stirrer. 1,5-Dibromopentane (13.5 g, 55.7 mmol) was added and the reaction mixture was stirred for 1 h at 90° C. The reaction mixture was poured in 100 mL of H2O, extracted with EtOAc (300 mL). The organic layer was washed with water (30 mL), brine (2×30 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. HCl 1M in diethyl ether (15 mL, 15 mmol) was added and the bis-alkylated product was precipitated and filtered. The precipitate was dissolved in water with K2CO3 (1.5 g, 11.1 mmol), extracted with EtOAc (300 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=99.5:0.5 to 95:5) to give after evaporation 4-(5-bromopentyloxy)-7-chloroquinoline 33 (0.45 g, 12% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.[CH2:45]([O:47][CH2:48][CH2:49]Cl)[CH3:46]>>[CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[N:30]([CH2:46][CH2:45][O:47][CH2:48][CH3:49])[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2ccc(Cl)cc2)cc(OC)c1OC
Reactant: CCOCCCl
Product: CCOCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3cc(OC)c(OC)c(OC)c3)c3ccc(Cl)cc3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 21.1 using N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-chlorophenyl)butyl)-3,4,5-trimethoxybenzamide and 2-chloroethyl ethyl ether to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=1[CH3:17]>C(O)C.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=1[CH3:17])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1nn(C)c(C)c1N
Solvent: CCO
Solvent: O
Product: Cc1nn(C)c(C)c1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (7.47 mL, 70.9 mmol) in ethanol (35 mL) and H2O (105 mL) was added 4-amino-1,3,5-trimethylpyrazole (8.8 g, 70.9 mmol). The solution was refluxed for 15 h, then cooled to room temperature. The precipate was separated by filteration and washed with 25% aqueous ethanol to yield the title compound (8.6 g): 1HNMR (CDCl3, 300 MHz) δ 8.81 (s, 1H), 8.18 (dd, 2H, J=1.6, 8.7), 6.69(m, 1H) 6.61 (dd, 1H, J=1.2, 8.7), 3.77 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H); low resolution MS(FAB) m/z 247(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][N:17]1[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(CCl)c(Cl)c1
Reactant: CC1CCNCC1
Solvent: CCOC(C)=O
Product: CC1CCN(Cc2ccc([N+](=O)[O-])cc2Cl)CC1
Reaction time: 0.25 h

Procedure:
1 g (4.85 mmol) of 2-chloro-4-nitrobenzylchloride is slowly added dropwise to 2 mL (16.22 mmol) of 4-methylpiperidine at ambient temperature and the mixture is stirred for 15 minutes. The reaction mixture is diluted with ethyl acetate and extracted twice with water. The organic phase is dried over sodium sulfate and evaporated down. Yield: 1.3 g (99.7% of theory); C13H17ClN2O2 (M=268.74); calc.: molecular ion peak (M+H)+: 269/271; found: molecular ion peak (M+H)+: 269/271; Rf value: 0.4 (Alox, petroleum ether).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:50]=[CH:49][C:10]([CH2:11][N:12]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([CH:40]=2)=[CH:38][CH:37]=[C:36]([O:41]CC2C=CC=CC=2)[CH:35]=3)[C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:15]=2)=[CH:9][CH:8]=1>C1(OC)C=CC=CC=1.CO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([CH:40]=2)=[CH:38][CH:37]=[C:36]([OH:41])[CH:35]=3)[C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:15]=2)=[CH:49][CH:50]=1
Reactant: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2cnc3cc(OCc4ccccc4)ccc3c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CO
Product: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2cnc3cc(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of AlCl3 (44 mg, 0.33 mmol) in anhydrous anisole (150 μl) was added to 32 (43 mg, 0.07 mmol) in anhydrous anisole (150 μl) and the resulting solution was stirred at room temperature for 18 hours. The reaction was diluted with MeOH (150 μl) and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 80:20:1 EtOAc:Hexanes:MeOH) to give 33 as a yellow amorphous solid in quantitative yield: 1H NMR (CDCl3, 500 MHz) δ 8.35 (s, 1H), 7.74 (s, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.52 (bs, 1H), 7.37 (m, 1H), 7.31 (m, 1H), 7.25-7.11 (m, 5H), 6.84-6.77 (m, 3H), 6.74 (d, J=8.6 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 6.64 (s, 1H), 5.16 (s, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.3, 159.4, 159.3, 158.0, 138.8, 135.5, 132.3, 130.4, 130.3, 130.1 (2C), 129.6, 129.1 (2C), 127.1, 123.0, 122.0, 114.9, 114.3 (2C), 113.3, 110.7, 55.8, 55.4, 53.9; IR (film) νmax 2926, 1601, 1506, 1248, 1177, 1030, 818 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C32H28N2O5, 521.2076. found, 521.2030.