Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C:7]2[C:16]3[C:11](=CC=CC=3)[CH:10]=[C:9]3[C:17](O[C:20](=[O:21])[C:8]=23)=[O:18])C=CC=CC=1.[NH2:22][NH2:23]>>[C:17]1(=[O:18])[C:9]2[C:8](=[CH:7][CH:16]=[CH:11][CH:10]=2)[C:20](=[O:21])[N:23]=[N:22]1
Reactant: O=C1OC(=O)c2c1cc1ccccc1c2-c1ccccc1
Reactant: NN
Product: O=C1N=NC(=O)c2ccccc21

Procedure:
Later it was found (F. G. Baddar, M. F. El-Newaihy and M. R. Salem, J. Chem. Soc. 838, 1969) that in the reaction of 1-phenylnaphthalene-2,3-dicarboxylic anhydride (R=H in formula (XXX)) ##STR4## with hydrazine that a mixture of the N-amino compound and the phthalazine-1,4-dione were obtained. The 4'-7-dimethoxy anhydride (R=OMe) however gave the N-amino compound.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[N:31]1([CH2:37][CH2:38]Cl)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Reactant: ClCCN1CCCCC1
Product: COc1cc(-c2nc3ccc(OCCN4CCCCC4)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 2-(piperidin-1-yl)ethyl chloride essentially as previously described. mp 145° C., NMR, MS 579, 581, IR.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C@H:16]([CH2:28][NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[CH3:33][S:30]([N:29]1[CH2:28][C@H:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:4]2[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[CH:7][C:6]=3[N:15]=[C:3]2[CH2:2]1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)n1c(CCl)nc2cnc3ccccc3c21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3cnc4ccccc4c3n21
Yield: 82.2 %

Procedure:
tert-Butyl (4S)-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-5-[(methylsulfonyl)amino]pentylcarbamate (8.08 g, 16.3 mmol) was dissolved in 200 mL of CH2Cl2 and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.91 mL, 19.5 mmol) After 1 hour, the reaction mixture was washed successively with H2O and brine and the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 3% methanol/CHCl3) gave tert-butyl 3-[(11S)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (6.16 g) as a light yellow foam.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:6]=[N:7][N:8]([CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=1)C.Cl.CCOCC>C1COCC1.O>[CH3:14][Si:11]([CH2:10][N:8]1[CH:9]=[C:5]([CH:4]=[O:3])[N:6]=[N:7]1)([CH3:12])[CH3:13]
Reactant: CCOC(OCC)c1cn(C[Si](C)(C)C)nn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)Cn1cc(C=O)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a solution of 4-(diethoxymethyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazole (1.620 mg, 6.290 mmol) in 10.0 ml of THF was added 2.0N HCl in Et2O (9.44 ml, 18.88 mmol), and the mixture was stirred at RT for 15 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the crude title compound as a light yellow liquid (1.050 g, 91% crude). ES-MS [M+1]+: 184.1. This intermediate was carried over to the next step without further purifications and characterizations.
Reaction SMILES: [C:1]([N:4]([CH:13]([C:15]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:18][CH2:17][CH2:16]1)[CH3:14])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(=[O:3])[CH3:2].O.[OH-].[Na+]>O1CCCC1.CCOCC>[ClH:25].[OH2:3].[ClH:25].[ClH:25].[CH2:1]([N:4]([CH:13]([C:15]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:16][CH2:17][CH2:18]1)[CH3:14])[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)[CH3:2]
Reactant: CC(=O)N(CCN1CCOCC1)C(C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CCN1CCOCC1)C(C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Product: Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Borane-methyl sulphide complex (4 ml) was added under a nitrogen atmosphere to a solution of the amide prepared as above (0.63 g) in dry tetrahydrofuran (50 ml). The mixture was stirred for 16 hours. The residue as cooled to 0° C. and water (30 ml) added and then 2.5N sodium hydroxide solution (30 ml) added. The basic mixture was extracted with ether and the extract was washed, dried filtered and evaporated to give an oil which was dissolved in ether and the solution filtered. Passing hydrogen chloride gas through the solution gave N-ethyl-N-(2-morpholino-ethyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine dihydrochloride hydrate (m.p. 105°-115° C.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]([O:30][CH2:31][CH3:32])[C:17]3[C:22]([O:23][C:24]=2[CH:25]=1)=[CH:21][C:20]([O:26][C:27](=[O:29])[CH3:28])=[CH:19][CH:18]=3)(=[O:10])[CH3:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[C:27]([O:26][C:20]1[CH:19]=[CH:18][C:17]2[C:16]([CH2:4][CH2:3][C:2]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:1])([O:30][CH2:31][CH3:32])[C:15]3[C:24]([O:23][C:22]=2[CH:21]=1)=[CH:25][C:12]([O:11][C:8](=[O:10])[CH3:9])=[CH:13][CH:14]=3)(=[O:29])[CH3:28]
Reactant: OC1CCNCC1
Reactant: CCOC1c2ccc(OC(C)=O)cc2Oc2cc(OC(C)=O)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC1(CCC(=O)N2CCC(O)CC2)c2ccc(OC(C)=O)cc2Oc2cc(OC(C)=O)ccc21
Yield: 104 %

Procedure:
A solution of 4-hydroxypiperidine (506 mg, 5.00 mmol, 2.5 eq, Aldrich) and 9-(2-(N-succinimidyloxy-carbonyl))ethyl)-3,6-diacetoxy-9-ethoxy-9H-xanthene, 7a (1.023 g, 2.00 mmol, prepared according to Prober, et al., EP-A No. 252,683) in dry dichloromethane (20 ml) was stirred for 30 min. The reaction was added to 1M aqueous potassium phosphate buffer (30 mL; pH=7) and extracted with dichloromethane (3×30 mL). The organic extracts were dried over calcium sulfate, concentrated, and dried under vacuum overnight to afford crude amide 8a (1.039 g, 104%) as an off-white foam. This material was>90% pure according to NMR and TLC and was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:25][C:26]1[CH:27]=[C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:41][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]3)[O:35][N:34]=2)[CH:29]=[CH:30][C:31]=1[CH3:32]>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:25][C:26]3[CH:27]=[C:28]([C:33]4[N:37]=[C:36]([CH:38]5[CH2:41][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]5)[O:35][N:34]=4)[CH:29]=[CH:30][C:31]=3[CH3:32])=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(Br)ccn45)c3)no2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (24f) (400 mg, 1.67 mmol), in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (325 μL, 3.72 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 1.5 hour. The solvent was concentrated and the crude solid was added portion-wise to a stirring solution of methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (429 mg, 1.49 mmol) in anhydrous pyridine (1 mL) at 0° C. The reaction was stirred to room temperature under Argon for 30 minutes. Then, the reaction was quenched with water. The solvent was concentrated and the crude product was purified by silica chromatography to yield methyl 3-(3-(3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (42). MS m/z 511.1 (M+1)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccccc1OCc1ccccc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccccc3OCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 71.2 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0492 g, 0.168 mmol) and 1-[(3-bromopropyl)oxy]-2-[(phenylmethyl)oxy]benzene (0.0706 g, 0.220 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0735 g, 71.4%). EI-MS m/z 533 (M+) Rt (2.25 min).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](I)=[C:6]([CH3:9])[C:7]=1[CH3:8].[Cu](C#N)[C:12]#[N:13].ClCCl>C(#N)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:12]#[N:13])=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: N#C[Cu]C#N
Reactant: Cc1c(Cl)nnc(I)c1C
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(Cl)nnc(C#N)c1C
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
A mixture of D10 (0.225 g, 0.84 mmol), copper cyanide (0.15 g, 1.67 mmol) in acetonitrile (2 ml) was stirred at 160° C. for 20 min., under microwave irradiation. Dichloromethane was then added and the mixture filtered over celite. The solvent was evaporated in vacuo and the residue purified by column chromatography (silica gel; dichloromethane/heptane 1:1 to 7:3) to yield D11 (0.120 g, 85%) as a solid. C7H6ClN3 requires 167. Found 166 (MH−).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH3:13][NH:14][CH3:15].[H][H]>[Pt]=O.C(O)C>[CH3:13][N:14]([CH3:15])[CH2:10][CH2:9][CH:8]([CH:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)[CH3:12]
Reactant: CNC
Reactant: CC1=CCC(C(C)CC=O)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC1=CCC(C(C)CCN(C)C)CC1
Temperature: 25 °C

Procedure:
A 250 ml hydrogenation flask was charged with 50g (0.3 mole ) of 3-(4-methyl-3-cyclohexenyl)butyraldehyde, 15g (0.33 mole) of dimethylamine, 0.5 of platinum oxide and 80 ml of 95% ethanol. Cooling was required to control the initial exotherm. The reaction mixture was then shaken at ambient temperature under 20-40 lbs. of hydrogen until 0.3 mole of hydrogen was consumed. The mixture ws filtered and concentrated, and the residue was distilled yielding 38.4g of pure N,N-dimethyl-N-[3-(4-methyl-3-cyclohexenyl)butyl]amine: bp 95-101 (0.4mm); ir (τ max. film) 3.5 (s), 6.9 (s), 7.3 (s), 12.5 (m) micron; nmr (8 CDCl3), 5.40 (m, 1H), 2.28 (s, 8H), 2.0 to 0.8 (m, 16H) ppm; ms (molecular ion) 195.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[Br-].[CH:15]1([Zn+])[CH2:17][CH2:16]1.C(OCC)(=O)C.O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]1([C:2]2[C:11]([F:12])=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]3)=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: [Zn+]C1CC1
Reactant: Cc1ccc2ccc(Br)c(F)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc2ccc(C3CC3)c(F)c2n1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A solution of 7-bromo-8-fluoro-2-methylquinoline (0.15 g, 0.63 mmol), Pd(PPh3)4 (0.072 g, 0.063 mmol) and 0.5 M cyclopropylzinc(II) bromide (2.50 ml, 1.25 mmol) in THF was stirred at reflux for 12 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 2:1) to give 7-cyclopropyl-8-fluoro-2-methylquinoline (0.10 g, 80.3%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]([NH:37][C:38](=[O:40])[CH3:39])([CH3:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([CH3:35])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[OH:7][C:3]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[C:4]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:27]1[NH:28][C:29]2[C:34]([C:26]=1[CH2:25][C:24]([NH:37][C:38](=[O:40])[CH3:39])([CH3:23])[CH3:36])=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NC(C)(C)Cc1c[nH]c2cc(C)ccc12
Product: CC(=O)NC(C)(C)Cc1c(C(C2=C(O)C(C)(c3ccc(C)cc3)C2=O)c2ccccc2)[nH]c2cc(C)ccc12

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione was reacted with benzaldehyde and N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-acetamide (from Example 1.2) to give N-(2-{2-[(2-hydroxy-3-methyl-4-oxo-3-p-tolyl-cyclobut-1-enyl)-phenyl-methyl]-6-methyl-1H-indol-3-yl}-1,1-dimethyl-ethyl)-acetamide as a pale yellow solid. MS: 519.5 ([M−H]−).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:11][C:12]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1>C(N(CC)CC)C>[OH:21][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
In the manner of Example 57 were reacted 3.4 ml of octanoyl chloride, 3.0 g of 5-amino salicylic acid and 2.8 ml of triethylamine. Recrystallization from methanol gave the title compound--m.p. ca. 200°-204° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:23][CH:24]2[CH2:29][CH2:28]S[CH2:26][CH2:25]2)=[C:8]([CH:22]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])([O-:3])=[O:2].ClC1C=CC=C(C(OO)=O)C=1.[S:41]([O-:45])([O-])(=[O:43])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[O:43]=[S:41]1(=[O:45])[CH2:28][CH2:29][CH:24]([NH:23][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[O:10])[CH2:25][CH2:26]1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCSCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(tetrahydro-2H-thiopyran-4-ylamino)benzamide (50.0 mg) in anhydrous dichloromethane (1 mL) was added m-chloroperbenzoic acid (41.5 mg), and the mixture was stirred for 4 hours at ambient temperature. To the mixture were added an aqueous saturated sodium thiosulfate solution and an aqueous sodium bicarbonate solution. The resulting precipitates were collected by filtration and washed with water, methanol and ethyl acetate to give 2-(1,1-dioxotetrahydro-2H-thiopyran-4-ylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (40.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)=[CH:4][CH:3]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl.C(O)(=O)C>[CH2:27]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:7][N:8]2[C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)=[CH:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(N)cc32)n1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(NCc4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of the compound of Example 4 (10 mg) in dichloromethane (350 μL, manufactured by Kanto Chemical Co., Inc.), acetic acid (10 μL, manufactured by Wako Pure Chemical Industries, Ltd.), benzaldehyde (4 mg, manufactured by Nacalai Tesque, Inc.) and sodium triacetoxyborohydride (17.7 mg, manufactured by Sigma-Aldrich Corp.) were added, and the mixture was stirred overnight at room temperature. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×2 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 2.4 mg of the title compound. LC-MS: HPLC retention time 5.83 minutes, m/z 519 (M+H), condition B-1.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].ClCCl.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=O>ClCCCl>[Cl:27][CH2:28][C:29]1[N:4]([CH2:3][CH:2]([CH3:16])[CH3:1])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)Cn1c(CCl)nc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
N4-(2-Methylpropyl)quinoline-3,4-diamine (41 g), dichloromethane (550 mL), triethylamine (40 mL, 1.5 eq), and chloroacetyl chloride (16.7 mL, 1.1 eq.) were combined and then stirred at ambient temperature over the weekend. The reaction mixture was diluted with 1,2-dichloroethane (75 mL) and then washed with saturated aqueous sodium bicarbonate (3×400 mL). The organic layer was dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 52.81 g of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: OCCCCNC1CCCNCC1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCCCCNC1CCCN(c2cccc(Br)n2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
545 mg (2.3 mmol) of 2,6-dibromopyridine, the product from step c (428 mg, 2.3 mmol) and 954 mg of potassium carbonate (6.9 mmol) are suspended in 20 ml of DMSO and stirred at 120° C. overnight. Water is then added to the mixture, which is then extracted with EA. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue formed is purified by means of RP flash chromatography on C18 silica gel.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])=[CH:17][CH:16]=1.N1C=CC=CC=1.C(OC)(C)(C)C>C1(C)C=CC=CC=1>[F:13][C:14]([F:28])([F:29])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[CH:19][CH:20]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)Nc2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At room temperature, 0.29 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride was added dropwise to a solution of 0.36 g of 4′-trifluoromethyl-2-aminobiphenyl and 0.18 g of pyridine in 10 ml of toluene, after which the mixture was stirred at room temperature for 16 hours. 30 ml of methyl tert-butyl ether were added, and the organic phase was washed successively with 2% strength hydrochloric acid, 2% strength aqueous sodium hydroxide solution and then with dilute sodium chloride solution. The organic phase was dried and concentrated under reduced pressure. The crude product was stirred with 5 ml of diisopropyl ether. The solid that remained was separated off and dried. This gave 0.45 g of the desired product as a white powder; m.p. 164-165° C.
Reaction SMILES: C([N:8]([CH2:22][CH:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19](=[O:21])[NH2:20])[CH:13]=1)C1C=CC=CC=1.C(O)C>CO.[Pd]>[C:19]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[OH:18])[O:11][CH2:10][CH2:9][NH:8][CH2:22][CH:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:21])[NH2:20]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)c2ccccc2)ccc1O
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)c2ccccc2)ccc1O

Procedure:
Analogously to Example 4, a solution of 45 g of crude α-[N-benzyl-N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]benzyl alcohol in 500 ml of methanol is hydrogenated with the addition of 5 g of palladium-on-charcoal catalyst (5%) and the reaction mixture is worked up. α-[N-[2-(3-Carbamoyl-4-hydroxy-phenoxy)-ethyl]aminomethyl]-benzyl alcohol with a melting point of 174°-175° (from ethanol) is obtained. The methanesulfonate melts at 182°-183° (from methanol).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: NCCCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Br)c(CNCCCO)c1
Reaction time: 4 h

Procedure:
To a stirring solution of 2-bromo-5-nitrobenzaldehyde (1 eq) in methylene chloride (0.1 M) at room temperature was added 3-amino-1-propanol (2 eq). After stirring for 4 hr, sodium triacetoxyborohydride (2 eq) and acetic acid (5 eq) was added. The reaction mixture was stirred for 3 hr and carefully quenched with methanol. The organic phase was washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (10% EtOAc/Hexane). EI-MS m/z 289 (M+H)+.