Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:28]([NH2:30])=O.C(O)(=O)C>C(Cl)Cl.O>[CH:13]1([NH:12][C:10](=[O:11])[C:9]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:7]([N:6]3[CH:5]=[N:4][C:3]4[C:2]3=[N:1][CH:28]=[N:30][C:20]=4[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:8]=2)[CH2:15][CH2:14]1
Reactant: NC=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccccc3)ncnc21
Temperature: 200 °C
Yield: 59 %

Procedure:
The mixture of 3-(5-amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (33 mg, 0.09 mmol), formamide (0.5 mL, excess), and acetic acid (0.1 mL) was heated in the microwave at 200° C. for 20 min. After cooling, the mixture was diluted with CH2Cl2 and water, and the CH2Cl2 layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparatory HPLC to provide the title compound (20 mg, 59%) as a white solid: HPLC tR=2.20 min; MS m/z 370.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:6]=1)[CH3:2].[N:19]([Si](C)(C)C)=[N+:20]=[N-:21].Cl[Sn](Cl)(Cl)Cl>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([N:19]=[N+:20]=[N-:21])[O:14][CH2:15][CH2:16][OH:17])[CH:6]=1)[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)c1cccc(OCC2OCCO2)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cccc(OCC(N=[N+]=[N-])OCCO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-([1,3]-dioxolan-2-ylmethoxy)-benzoic acid ethyl ester (2.02 g, 8 mmol) and azidotrimethylsilane (1.17 ml, 8.8 mmol) was added SnCl4 (60 μl) at room temperature under nitrogen. After 2 hr, 2% aqueous methanol (10 ml) was added to the reaction mixture and the reaction was stirred at room temperature for 30 minutes. All the solvents were evaporated under reduced pressure. The residue was co-evaporated with ethanol (2×10 ml). The residue was purified by a column chromatography (3×20 cm). The product was eluted with 0 to 1% methanol in DCM. The title compound was obtained as a colourless oil (2.01 g, 85.1%). APCI-MS, m/z 267.90 (M−N2+1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([CH3:42])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([NH:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[NH:18][C:17]=3[CH:16]=[C:15]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:40])[F:39])=[O:31])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:43]I>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[C:5]([CH3:42])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([NH:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[N:18]([CH3:43])[C:17]=3[CH:16]=[C:15]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:39])([F:40])[F:41])=[O:31])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(NCC(C)(C)CO)nc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2c1nc(NCC(C)(C)CO)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide powder (6.2 mg) was added to a solution of N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (80 mg) in DMF (2 mL), the solution was stirred at room temperature for 30 minutes, methyl iodide (8.7 μL) was added, and it was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (20 mg) as white powder. This was suspended in MeOH, 2N hydrogen chloride/EtOH (1 Eq) was added, it was stirred to obtain a solution, and the solvent was removed under reduced pressure. The residue was washed with diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (15 mg) as white powder.
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)(C[C:4](O)=[O:5])C.[CH3:17][O:18][C:19](=[O:43])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]([C:28](=[O:42])[CH2:29][N:30](C(OCC1C=CC=CC=1)=O)[CH3:31])[CH3:27].[ClH:44]>CCCCCC>[ClH:44].[CH3:4][OH:5].[CH3:17][O:18][C:19](=[O:43])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]([CH3:27])[C:28](=[O:42])[CH2:29][NH:30][CH3:31].[ClH:44]
Reactant: COC(=O)c1ccccc1N(C)C(=O)CN(C)C(=O)OCc1ccccc1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCCCCC
Product: CNCC(=O)N(C)c1ccccc1C(=O)OC
Product: CO

Procedure:
Analogously, from Z-Sar-OH and methyl N-methyl was prepared 2-[[(Benzyloxycarbonyl-methyl-amino)-acetyl]-methyl-amino]-benzoic acid methyl ester as light yellow oil (Rf 0.3 hexane:EtOAc1:2), MS: 370 (M), which was deprotected according to 6.1. and transferred into its HCl.salt by treatment with HCl/MeOH to give 2-(Methyl-methylaminoacetyl-amino)-benzoic acid methyl ester·hydrochloride, MS: 237 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[NH2:25])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([C:21]([F:22])([F:23])[F:24])=[CH:16][C:15]=2[NH:25][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][N:26]=[CH:31][CH:30]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)CCCc1ccncc1
Reactant: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2N)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2NC(=O)CCCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (step 2, 250 mg, 0.67 mmol), 4-(4-pyridinyl)butanoic acid (200 mg, 1 mmol), and WSC (191 mg, 1 mmol) in dichloromethane (7 ml) was stirred at room temperature for 1.5 h. The mixture was added water (5 ml) and extracted with dichloromethane(30 ml). The organic layer was washed with brine (5 ml), then dried (Na2SO4). The solvent was removed under reduced pressure to afford the title compound as pale brown amorphous.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.C(O)(C)(C)C.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)CCl>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH:10]=[CH:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12

Procedure:
2.3 g. of 11β-fluoro-4-androstene-3,17-dione is stirred under reflux in 25 ml. of tert.-butanol and 15 ml. of ethylene chloride with 4 g. of chloranil and 50 mg. of p-toluenesulfonic acid for 6 hours. After the reaction mixture has been worked up as described in Example 16 and chromatographed on silica gel with acetone/hexane, 1.2 g. of 11β-fluoro-4,6-androstadiene-3,17-dione is obtained. UV: ε280 = 25,600.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[B:5]1([OH:15])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][O:6]1>>[N+:1]([C:12]1[CH:13]=[CH:14][C:9]2[CH2:8][CH2:7][O:6][B:5]([OH:15])[C:10]=2[CH:11]=1)([O-:4])=[O:2]
Reactant: OB1OCCc2ccccc21
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2c(c1)B(O)OCC2
Temperature: -42.5 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To 4.0 mL fuming HNO3 at −45° C. was added 3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (497 mg, 3.4 mmol) in small portions while maintaining the reaction temperature between −40 to −45° C. Once the addition was complete the resulting solution was allowed to stir at −45° C. for an additional 10 min before poured into crushed ice (20 g). The ice mixture was allowed to warm up to room temperature gradually and the precipitate was collected by filtration and washed with H2O to give 7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol as a white powder. 1H NMR (acetone) δ: 8.51 (d, J=2.5 Hz, 1H), 8.24 (dd, J=8.3, 2.6 Hz, 1H), 7.75 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.19 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz, 2H). Amount obtained: 286 mg, 44% yield.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[O:18][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1]
Reactant: Oc1cc(F)ccc1Br
Reactant: BrCc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Br)c(OCc2ccccc2I)c1
Yield: 102.5 %

Procedure:
Stir a mixture of 2-iodobenzyl bromide (90 g, 0.29 mol), 2-bromo-5-fluorophenol (57.9 g, 0.29 mol), and potassium carbonate (63 g, 0.46 mol) in N,N-dimethylformamide (750 mL) at room temperature for 16 h. Add water (1 L), stir the resulting mixture for one hour, filter off solids, rinse with water and dry in a vacuum oven (20 mm Hg/60° C.) to obtain the title compound (121 g, >100%). 1H NMR (400 MHz, DMSO-d6) δ 5.11 (s, 2H), 6.81 (t, 1H), 7.13 (t, 1H), 7.19 (dd, 1H), 7.46 (t, 1H), 7.59 (d, 1H), 7.62 (t, 1H), 7.93 (d, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:10]=1)=[O:5])C.[OH-].[K+]>CO.O>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)cn2)CC1
Reaction time: 27 h
Yield: 82 %

Procedure:
tert-Butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate described in Production Example 13-2 (2.11 g, 6.53 mmol) was dissolved in methanol (60 mL), then potassium hydroxide (1.46 g, 26.1 mmol) dissolved in water (16 mL) was added, and then the mixture was stirred for 27 hours. The reaction mixture was concentrated under vacuum and diethyl ether was added for partition. Ethyl acetate was added to the aqueous layer for dilution, then a 5% aqueous potassium hydrogensulfate solution was added for acidification, and the mixture was extracted with ethyl acetate twice. The combined organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated to obtain the title compound (1.58 g, 82%).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>C(Cl)Cl>[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH:21][C:9]([C:8]2[CH:12]=[CH:13][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:10])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCc1ccc(F)cc1
Solvent: ClCCl
Product: O=C(NCCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TEA (474 μL, 3.4 mmol), is added dropwise to a suspension of the title A compound, 4-chlorosulfonyl-benzoyl chloride in DCM (10 mL) at −78° C. To this mixture is added p-fluorophenethylamine over 5 min. After another 10 min at −78° C., the solution is allowed to warm to 0° C. and stirring is continued at this temperature for 1 h. The reaction is quenched by adding it to ice-water (30 mL), and the mixture is extracted with DCM (3×10 mL). The combined organic phases are dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to obtain the crude product which is chromatographed on silica gel using EtOAc as the eluent to give 4-[2-(4-fluoro-phenyl)-ethylcarbamoyl]-benzenesulfonyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@H:9](O)[CH2:8]2)[CH:2]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@@H:9]([N:17]3[C:16](=[O:18])[C:15]4=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]4[C:13]3=[O:23])[CH2:8]2)[CH:2]=1
Reactant: O[C@H]1CC[C@@H](c2cccnc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CC[C@@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A solution of (1S,3R)-3-(3-pyridyl)cyclopentanol (3.95 g, 24.2 mmol) in THF (80 mL) was cooled to 4° C. and treated with phthalimide (3.91 g, 26.6 mmol), Diisopropylazodicarboxylate (5.24 mL, 26.6 mmol) and triphenylphosphine (6.98 g, 26.6 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layers was dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (Hexane/EtOAc=4/1) to yield (1R,3R)-N-[3-(3-pyridyl)cyclopentyl]phthalimide (6.27 g, 89%) as colorless powder.
Reaction SMILES: [CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[NH:4][C:5](=[O:28])[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][C:8]1=2.FC(F)(F)C(O)=O.C(Cl)[Cl:42]>>[ClH:42].[CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[NH:4][C:5](=[O:28])[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:8]1=2
Reactant: ClCCl
Reactant: Cc1cccc(NC(=O)Cn2c3c(c4ccccc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NC(=O)Cn2c3c(c4ccccc42)CCNCC3)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
tert-Butyl 6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.02 g, 2.27 mmol) was disolved in CH2Cl2 (15 mL), then trifluoroacetic acid (3.0 mL, 4.44 g, 38.9 mmol, 17.2 equiv.) was added. The resulting solution was stirred at rt for 1.5 h. The reaction mixture was concentrated to dryness, then the residue was partitioned between EtOAc (100 mL) and 1N NaOH (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL) The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was combined with EtOAc (20 mL) and 1M HCl in Et2O (20 mL), then the salt was collected by filtration. The salt was dried under vacuum over P2O5. N-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide hydrochloride (0.7739 g) was obtained in 89% yield. 1H NMR (300 MHz, CD3OD) δ 2.11, 2.29, 3.23-3.26, 3.32-3.35, 3.47-3.56, 5.12, 7.06-7.15, 7.22, 7.44, 7.53; MS (ESI+) for C22H25N3O m/z 348.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([S:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2]
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Reactant: COc1ccc(S)cc1
Product: CCCCCCCCCCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Yield: 98 %

Procedure:
2-(4-Methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from the corresponding ethyl-2-bromomyristate (5.0 g, 14.9 mmol) and 4-methoxythiophenol (1.9 g, 13.4 mmol), 5.0 g of the product was isolated. Yield 98%; Light yellow oil; MS: 393 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH2:34])[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].[N-:36]=[N+:37]=[N-:38].[Na+].[CH:40](OCC)(OCC)OCC>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH:40]=[N:38][N:37]=[N:36]3)[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-n3cnnn3)CC2O)CCCCC1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.3 %

Procedure:
The mixture of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-aminophenyl)piperidin-3-one (2 g, 4 mmol) obtained in Step 2 of Example 43, sodium azide (NaN3; 409 mg, 6.2 mmol) and triethyl orthoformate (1.1 ml, 6.7 mmol) was refluxed in 10 ml of acetic acid for about 4 hours. The reaction mixture was cooled to room temperature. 10 ml of ice water was added to the reaction mixture, which was then stirred for about 48 hours. The resulting residue was filtered and dried to give 0.6 g of the titled compound.
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:17]([O:10][CH:7]1[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4][C:3]([CH2:1][CH3:2])([CH3:14])[CH:8]1[CH3:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1(C)CC(OCc2ccccc2)C(C)C(C)(CC)N1
Yield: 48.3 %

Procedure:
To a solution of 3.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidinol (Compound 1) in 30 ml of dry toluene was added, at 0°-5° C., 0.65 g of sodium hydride (purity 52.9%). The mixture was refluxed by heating for 6 hours. After cooling the mixture, 1.9 g of benzyl chloride were added dropwise at 0°-5° C. and the resulting mixture was refluxed by heating for 4 hours. The reaction mixture was then washed with water and dried over anhydrous magnesium sulphate; the solvent was then distilled off. The residue was purified by column chromatography on silica gel using benzene as eluent, followed by distillation under reduced pressure. There were obtained 2.1 g of Compound 95 as a pale yellow oil (bp 120°-124° C./0.2 mmHg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][OH:20].C(N(CC)CC)C>ClCCl>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH:19]=[O:20]
Reactant: OCCCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCc1ccccn1
Reaction time: 0.33 h

Procedure:
Dimethyl sulphoxide (3.3 ml) was added dropwise to a solution of oxalyl chloride (3.9 ml) in dichloromethane (25 ml) at -78° under nitrogen. After gas evolution had ceased (5 min) a solution of 2-pyridinepropanol (4.0 g) in dichloromethane (20 ml) was added over 5 min and the solution stirred at -78° for 20 min. Triethylamine (5 ml) was added dropwise to the solution, then the resulting dark green mixture warmed to 20° and washed with 2M sodium carbonate solution (20 ml). The organic phase was dried and evaporated in vacuo to give 2-pyridinepropanal. This aldehyde was immediately dissolved in THF (30 ml) and added dropwise to a 3M solution of methylmagnesium chloride in THF (20 ml) at 0°-5° under nitrogen. After 1 h, water (10 ml) was cautiously added followed by sufficient 2M hydrochloric acid to dissolved all the magnesium residues (resulting pH~7 ). The solution was extracted with dichloromethane (3×30 ml) and the organic extracts dried and evaporated in vacuo to a dark oil. Kugelrohr bulb to bulb distillation (b.p. 130°-135°/0.7 mm) afforded the title compound as a pale yellow oil (0.91 g), t.l.c. ethyl acetate Rf 0.17.
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:23]([N:30]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([NH:37]/[C:3](=[C:10]2\[C:11](=[O:22])[NH:12][C:13]3[C:18]\2=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=3)/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:38][CH:39]=1)[CH3:31])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Product: CN(Cc1ccccc1)Cc1ccc(N/C(=C2\C(=O)Nc3cc4c(cc32)OCO4)c2ccccc2)cc1

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10](=[O:13])([SH:12])[CH3:11]>C1COCC1>[C:10](=[O:13])([S:12][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9])[CH3:11]
Reactant: CC(=O)S
Reactant: BrCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)SCCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of NaOH (2.1 g, 52.6 mmol) in dry THF (15.8 mL) was added 1,5-dibromopentane (21.75 g, 95 mmol), followed by ethanethioic S-acid (4 g, 52.6 mmol). The mixture was stirred at rt overnight. It was quenched by adding Et2O (20 mL). The reaction mixture was filtered through a pad of celite, and rinsed with Et2O. The filtrate was concentrated to afford crude product, which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([F:17])[CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: Nc1cccc(F)c1
Solvent: CCN(CC)CC
Product: Fc1cccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)c1

Procedure:
2-Chloro-6-(3-fluorophenylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-fluoroaniline, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:28][O:29][C:30]1[C:31](=O)[C:32](=[O:36])[C:33]=1[O:34]C>>[CH3:28][O:29][C:30]1[C:33](=[O:34])[C:32](=[O:36])[C:31]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NC(=O)c2cccc(F)c2)c2cccc(N)c2)cc1
Agent: Cl
Product: COc1ccc(C(NC(=O)c2cccc(F)c2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 98.1 %

Procedure:
In a similar manner to that described in Example (46e) N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]-3-fluorobenzamide hydrochloride (244 mg) [prepared as described in step (b) above] and 3,4-dimethoxy-3-cyclobutene-1,2-dione (107 mg) were reacted, to afford the title compound (285 mg) as a white solid.