Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:7][CH2:6][C:5]([C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4]1.Cl>>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:4]1
Reactant: CN(C)C1CCC(c2ccccc2)(c2ccc(Cl)cc2)C1
Agent: Cl
Product: CN(C)C1CCC(c2ccccc2)(c2ccccc2)C1

Procedure:
1-dimethylamino-3-(4-chlorophenyl)-3-phenylcyclopentane [PUN 123] Hydrochloride m.p. 168°-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[N+:13]([C:7]1[CH:6]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1])([O-:15])=[O:14]
Reactant: CC(C(=O)O)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a mixture of 8ml of nitric acid and 15ml of acetic acid 1g of 2-(4-hydroxyphenyl)propionic acid was added and stirred at -10° to -20° C for 4 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with a sodium hydrogen carbonate solution and water and then dried over magnesium sulfate. The chloroform solution was concentrated to give crystals, which were recrystallized from water. Yield, 700 mg (58%).
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].C(O)(C)(C)C.[OH:18][C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[N:21][C:20]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:25][C:23]1[N:22]=[N:21][C:20]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:19]([OH:18])[CH:24]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1[O-]
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a mixture of 25.5 g (150 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of t-butanol in an autoclave was added 2.5 g (purity: 99%; 15.0 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 80.0 g of pure water and 90.0 g of toluene were added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.74 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 90.1%) and 12.5 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.3%) were obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[CH:32]([C:35]1[S:36][CH:37]=[C:38]([C:40]([N:42]2[CH2:66][C:46]3([CH2:49][N:48]([CH2:50][CH2:51][C:52]4[CH:53]=[C:54]([CH:63]=[CH:64][CH:65]=4)[CH2:55][CH2:56][O:57][CH2:58][CH2:59][C:60]([OH:62])=O)[CH2:47]3)[O:45][CH2:44][CH2:43]2)=[O:41])[N:39]=1)([CH3:34])[CH3:33].[CH2:67]([NH:69][CH2:70][CH:71]([O:74][CH3:75])[O:72][CH3:73])[CH3:68].C(N(CC)CC)C>CN(C=O)C>[CH3:73][O:72][CH:71]([O:74][CH3:75])[CH2:70][N:69]([CH2:67][CH3:68])[C:60](=[O:62])[CH2:59][CH2:58][O:57][CH2:56][CH2:55][C:54]1[CH:63]=[CH:64][CH:65]=[C:52]([CH2:51][CH2:50][N:48]2[CH2:49][C:46]3([CH2:66][N:42]([C:40]([C:38]4[N:39]=[C:35]([CH:32]([CH3:33])[CH3:34])[S:36][CH:37]=4)=[O:41])[CH2:43][CH2:44][O:45]3)[CH2:47]2)[CH:53]=1
Reactant: CCNCC(OC)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCOCCC(=O)O)c4)C3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC(OC)OC)C(=O)CCOCCc1cccc(CCN2CC3(C2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
HATU (0.201 g) was added in one portion to a stirred solution at 0° C. of 3-(3-(2-(8-(2-isopropylthiazole-4-carbonyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethyl)phenethoxy)propanoic acid trifluoroacetate salt (0.25 g) (example 176 step b), N-ethyl-2,2-dimethoxyethanamine (0.059 g) (U.S. Pat. No. 2,707,186) and triethylamine (0.283 ml) in DMF (4 mL). The mixture was stirred at 20° C. for 3 hours and then partitioned between ethyl acetate and aq brine, the organic layer was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.250 g.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc21
Yield: 71 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 71% of theory, C27H27N5O3 (469.6) ##EQU41##
Reaction SMILES: [Cl-:1].[Na+].[C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:5])=[CH2:4].CS(O)(=O)=[O:24].[OH-].[Na+]>O>[ClH:1].[OH:24][C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4]
Reactant: C=C(C)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Reactant: CS(=O)(=O)O
Reactant: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(C)(C)O)c2)nc1
Product: Cl
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of the sodium chloride salt of 3-isopropenyl-5-(5-methylpyridin-2-yl)benzoic acid (2.114 g, 4.93 mmol) in water (49.3 mL) at 0° C. was added methanesulfonic acid (23.7 mL, 247 mmol) and the mixture was heated to 50° C. After 16 h, the mixture was cooled to 0° C. and sodium hydroxide (9.86 g, 247 mmol) added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→65% water/acetonitrile with 0.1% trifluoroacetic acid). Treatment with 2 M hydrochloric acid in diethyl ether gave the title compound as a hydrochloride salt (1.252 g). MS 272.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:5]2[C:10]([C:11]=1[CH:12]=O)=[CH:9][C:8]([O:14][CH3:15])=[C:7]([O:16][CH3:17])[CH:6]=2.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28]CN.[CH3:32][N:33](C)C=O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:5]2[C:10]([C:11]=1[CH2:12][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])=[C:9]([CH2:32][NH2:33])[C:8]([O:14][CH3:15])=[C:7]([O:16][CH3:17])[CH:6]=2
Reactant: COc1cc2c(-c3ccc(Cl)cc3)nc(Cl)c(C=O)c2cc1OC
Reactant: CN(C)CCCN
Reactant: CN(C)C=O
Solvent: CO
Product: COc1cc2c(-c3ccc(Cl)cc3)nc(Cl)c(CCCN(C)C)c2c(CN)c1OC
Reaction time: 3 h

Procedure:
3.62 g 3-Chloro-1-(4-chlorophenyl)-6,7-dimethoxy-isoquinoline-4-aldehyde is heated to 80° C. within 4 hours in conjunction with 3.06 g of 3-dimethylaminopropylamine in 100 ml dimethylformamide (DMF) and 50 ml CH3OH. The solvent is removed in vacuo, the residue is dissolved in 150 ml of anhydrous methanol and 1.53 g of sodium boron hydride are added portionwise at 10° C. The reaction mixture is stirred for 3 hours, the solvent is removed in vacuo and the residue is stirred with water. Filtration of the resulting mixture gives 4.2 g 3-chloro-1-(4-chlorophenyl)-6,7-dimethoxy-4-(3-dimethylaminopropyl)-aminomethyl-isoquinoline having a melting point from 126° to 127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[CH3:21][C:22]1([CH3:32])[O:26][C:25](=[CH:27][C:28](Cl)=[O:29])[C:24](=[O:31])[O:23]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:28](=[O:29])[CH:27]=[C:25]1[C:24](=[O:31])[O:23][C:22]([CH3:21])([CH3:32])[O:26]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: Clc1ccc(CNCCCc2ccccc2)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC1(C)OC(=O)C(=CC(=O)N(CCCc2ccccc2)Cc2ccc(Cl)c(Cl)c2)O1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred mixture of (3,4-dichloro-benzyl)-(3-phenyl-propyl)-amine; hydrochloride (330 mg, 1.0 mmol) and (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (206 mg, 1.08 mmol) in CH2Cl2 (10 mL) at room temperature was added diisopropylethylamine (386 μL, 2.2 mmol). After 30 min, the reaction mixture was diluted with ether (50 mL), washed with dilute aqueous HCl (1×5 mL), water (1×10 mL), and saturated aq. NaCl (1×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the desired amide (447 mg, 100% yield) as a viscous oil. 1H NMR (300 MHz, CDCl3) δ: 7.41–6.94 (8H, m), 6.08 (0.66H, s), 6.01 (0.34H, s), 4.53 (1.33H, s), 4.48 (0.67H, s), 3.41 (0.67H, t, J=7.5 Hz), 3.26 (1.33H, t, J=7.8 Hz), 2.61 (2H, t, J=7.3 Hz), 1.95–1.85 (2H, m), 1.71 (6H,s). MS calcd for C23H23Cl2NO4Na (M+Na): 470.09. Found: 470.09.
Reaction SMILES: [P:1](Cl)(Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[ClH:12].[NH2:13][C@@H:14]([CH3:22])[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][P:1](=[N:13][C@@H:14]([CH3:22])[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])=[O:9]
Reactant: CCCCOC(=O)[C@H](C)N
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOC(=O)[C@H](C)N=[P+]([O-])Oc1ccccc1Cl

Procedure:
1-Butanol (1200 mL) was cooled to −20° C. and 50 mL of SOCl2 added with stirring followed by 50 g (33.67 mmol) of (S)-2-aminopropanoic acid. The solution was heated 24 hrs at reflux, most of the solvent stripped off, and the residue was dissolved in 800 mL of diethyl ether. The mixture was left for 1 hr at 0° C. to afford (S)-butyl 2-aminopropanoate hydrochloride (intermediate 11.47 g). Phenyl phosphorodichloridate (48.9 g, 232 mmol) and (S)-butyl 2-aminopropanoate hydrochloride (42 g, 232 mmol) were suspended in anhydrous CH2Cl2 (200 mL). N,N-diisopropylethylamine (59.9 g, 464 mmol) was added drop wise at −78° C., and after 4 hrs the reaction was concentrated. Diethylether (Et2O, 500 mL) was added and the resulting precipitate was filtered off and washed with dry Et2O (twice 100 mL). The filtrate was evaporated to dryness. (2S)-butyl 2-(chloro(phenoxy)phosphorylamino)propanoate (12) was stored as 0.5 M solution in THF at −18° C. until further reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([NH:10][C:11]([C:13]1[C:14](=[O:28])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:12])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.CN(C)C=O.[Br:35]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3](=[O:29])[CH:4]([C:5]1[S:6][C:7]([Br:35])=[CH:8][CH:9]=1)[NH:10][C:11]([C:13]1[C:14](=[O:28])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(Br)s1
Temperature: 25 °C

Procedure:
{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-thiophen-2-yl-acetic acid methyl ester (0.190 g, 0.000454 mol;) was dissolved in N,N-Dimethylformamide (6 mL, 0.07 mol;) and N-Bromosuccinimide (0.089 g, 0.00050 mol;) was added. The reaction was allowed to stir at room temperature o/n. LC-MS showed the formation of product at 1.89 498.45. The reaction was concentrated and dissolved in ethyl acetate. The reaction was then washed 1× with saturated bicarbonate and 1× with brine before drying with magnesium sulfate and concentrating. The crude was then dissolved in methylene chloride and injected onto the combiflash and eluted using a 0-100% hexanes ethyl acetate gradient. The pure fractions were combined and concentrated to give the product. ES (+) MS m/e=498.45
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH:13]=[N:14][OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([OH:21])[C:19]#[CH:20].[O-]Cl.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[CH:20]=[C:19]([CH2:18][OH:21])[O:15][N:14]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ON=Cc1ccc(OCc2ccccc2)cc1
Reactant: C#CCO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
2.27 g of 4-benzyloxy-benzaldehydeoxime (10 mmol; 92% purity) was dissolved in 40 ml of methylenechloride (0.25 M), and 1.77 ml of propargyl alcohol (30 mmol) was then added to the resulting solution. 13.7 ml of 10% NaOCl (20 mmol) was then dropwise added very slowly to the resulting solution by using a dropping funnel at 0° C. After the addition of NaOCl was completed, the resulting mixture was stirred for about 5 hours while the temperature was slowly raised to room temperature. Subsequently, the completion of the reaction was confirmed by liquid chromatography, the resultant was subjected to distillation under reduced pressure to evaporate methylenechloride therefrom, 200 ml of water was added to the residue, and the obtained solid was then filtered. The filtered compound was washed with a large amount of water, and then washed with diethylether to obtain a solid compound. The obtained solid compound was purified with an ethylacetate/hexane solution (1:2) to obtain a white, solid [3-(4-benzyloxy-phenyl)-isoxazole-5-yl]-methanol (yield: 2.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=1>C1COCC1>[F:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:33])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=3)=[CH:4][CH:3]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(N)cc2)no1)C(C)C
Reactant: O=C=Nc1cccc(F)c1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3cccc(F)c3)cc2)no1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate (500 mg) dissolved in THF (10 ml) was added 1-fluoro-3-isocyanatobenzene (260 mg) and stirred at RT overnight. The solid was filtered and washed with THF to yield 460 mg (64%) white solid. MS (ES+): m/z 455 (M+1); 1H NMR (DMSO-d6, 300 MHz): δ 9.19 (d, 1H), 9.16 (s, 1H), 9.13 (s, 1H), 7.84 (d, 2H), 7.67 (s, 1H), 7.62 (d, 2H), 7.5 (dd, 1H), 7.31 (m, 1H), 7.13 (dd, 1H), 6.78 (m, 1H), 4.29 (m, 1H), 3.66 (s, 3H), 2.2 (m, 1H), 0.95 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][OH:14])[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].O>O1CCCC1>[CH2:15]([O:14][CH2:13][CH2:12][N:8]([CH:9]([CH3:10])[CH3:11])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)N(CCO)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(CCOCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
A solution of 2-(N-tert-butoxycarbonyl-N-isopropylamino)-ethanol (3.00 g, 14.8 mmol) and benzyl bromide (2.6 ml, 22.1 mmol) in anhydrous tetrahydrofuran (30 ml) was added to a solution of 60% sodium hydride (885 mg, 22.1 mmol) in anhydrous tetrahydrofuran (20 ml) under ice-cooling, and the mixture was stirred at 60° C. for four hours. Water (100 ml) was added to the reaction mixture under ice-cooling, the temperature was returned to room temperature, and the whole was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine (100 ml) and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the obtained oily matter was purified by silica gel column chromatography (mobile phase:hexane/ethyl acetate=4/1) to give 1.30 g (30%) of the target compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[N:4]=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:24][C:25](=[NH:27])[CH3:26]>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]2[O:9][N:27]=[C:25]([CH3:26])[N:24]=2)=[C:5]([CH3:10])[N:4]=[CH:3]1
Reactant: Cc1ncn(C)c1C(=O)O
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1noc(-c2c(C)ncn2C)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
A solution of 3,5-dimethyl-3H-imidazole-4-carboxylic acid (1.0 g, 7.14 mmol) and 1,1′-carbonyldiimidazole (1.74 g, 10.7 mmol) in DMF (35 ml) was stirred at RT for 3 h. N-hydroxy-acetamidine (0.68 g, 9.18 mmol) was added, the reaction mixture was stirred at 16 h at 80° C., evaporated and dissolved in acetic acid (30 ml). The solution was stirred at 100° C. for 2 h, evaporated, poured into sat. NaHCO3 solution (50 ml) and extracted with dichloromethane (7×30 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated to give the title compound (0.78 g, 61%) as a white solid, m.p. 95° C. and MS: m/e=178.2 (M+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=[C:12]([C:24](OCC)=[O:25])[C:11]3=[O:29])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:24]([C:12]2[C:11](=[O:29])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:9]=3)[N:14]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:13]=2)=[O:25])=[CH:33][CH:32]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C2CCNCC2)c2ccc(CN3CCOCC3)cc2c1=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CCNCC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 180 °C

Procedure:
A flask containing crude ethyl 6-(4-morpholinylmethyl)-4-oxo-1-(4-piperidinyl)-1,4-dihydro-3-quinolinecarboxylate (0.14 g) is treated with 4-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 180° C. for 2 hours. The reaction is cooled to room temperature and flash column chromatographed on silica eluting with 2% to 10% methanol saturated with ammonia in dichloromethane and then by recrystallization from acetonitrile to afford 0.10 g of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1.[OH:17][CH2:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][C:22]=2[CH:23]=1>C(#N)C>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:26]=[CH:27][C:21]3[O:20][C:19]([CH2:18][OH:17])=[CH:23][C:22]=3[CH:24]=2)[CH2:33][CH2:32]1
Reactant: OCc1cc2cc(N3CCNCC3)ccc2o1
Reactant: COc1ccc2[nH]cc(CCCCCl)c2c1
Solvent: CC#N
Product: COc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(CO)cc5c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1.8 g of 3-(4-chlorobutyl)-5-methoxyindole [obtainable by diazotization of p-methoxyaniline, reaction with ethyl cyclohexanone-2-carboxylate according to Japp-Klingemann to give 4-(2-carbethoxyindol-3-yl)butyric acid, alkaline hydrolysis, decarboxylation, reduction with LiAlH4 and reaction with SOCl2 ] and 1.9 g of 1-(2-hydroxymethylbenzofuran-5-yl)piperazine [obtainable by reaction of N,N-bis(2-chloroethyl)amine with 2-hydroxymethyl-5-aminobenzofuran] are dissolved in 200 ml of acetonitrile and the mixture is stirred at room temperature for 10 hours. Customary working up gives 1-[4-(5-methoxyindol-3-yl)butyl]-4-(2-hydroxymethylbenzofuran-5-yl)piperazine, m.p. 159°.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[O:10])=[CH:6][CH:5]=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C@@H:9]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[OH:10])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)[C@H]2CCCO2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([C@H](O)C2CCCO2)o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
2.27 g (59.9 mmol; 1.20 eq) of sodium borohydride were added in small portions to a solution of 9.00 g (49.9 mmol; 1.0 eq) of (5-methylfuran-2-yl)-(R)-tetrahydrofuran-2-ylmethanone in 100 ml of tetrahydrofuran cooled to 0° C. The reaction medium was stirred at ambient temperature for 3 hours. The reaction medium was poured into 200 ml of ethyl acetate and then 100 ml of water were added. The aqueous phase was extracted with ethyl acetate and then the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. 8.10 g de (5-methylfuran-2-yl)-(R)-tetrahydrofuran-2-ylmethanol were obtained. Yield=92%.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:26])=[C:5]([CH:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:6]([O:11]C)=[C:7]([CH3:10])[C:8]=1[CH3:9].[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.O>[CH3:26][C:4]1[C:3](=[O:2])[C:8]([CH3:9])=[C:7]([CH3:10])[C:6](=[O:11])[C:5]=1[CH:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCC(c1cccnc1)c1c(C)c(OC)c(C)c(C)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCCCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1cccnc1
Temperature: 0 °C
Yield: 63.1 %

Procedure:
To a solution of 1.1 g (3.09 mmol) of 1-(3,6-dimethoxy-2,4,5-trimethylphenyl)-1-(3-pyridyl)heptane in 20 ml of acetonitrile-water (1:1), the solution of 4.5 g (8.2 mmol) of cerium ammonium nitrate (CAN) in 15 ml of acetonitrile-water was added dropwise with stirring at 0° C. and stirred for 30 minutes after the completion of addition. The reaction product was isolated by a routine method, to give 635 mg (63%) of 1-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-1-(3-pyridyl)heptane. The physical data are shown in Table 2-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH3:15][C:16]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][C:3]=2[CH3:14])=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)c(C)c2)o1

Procedure:
Example 23 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 27).