Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12](F)=[CH:11][N:10]=1>CN(C)C=O>[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][N:10]=1
Reactant: OCC1CC1
Reactant: Fc1cnc(Cl)nc1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(Cl)ncc2OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.948 mL cyclopropanemethanol in 13 mL dimethylformamide was added 0.468 g sodium hydride 55% in mineral oil and the reaction mixture was stirred at room temperature for 15 min. The resulting solution was added drop wise to a solution of 2.586 g 2-chloro-4-(4-chloro-phenyl)-5-fluoro-pyrimidine at 0° C. and the mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=10:90 to 80:20 to yield 2.50 g of the title compound as white solid, MS 295.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:10][O:11][CH2:12][CH:13]=O.CN(C)C>C1C=CC=CC=1.CO>[CH3:10][O:11][CH2:12][CH:13]=[N:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1N
Reactant: COCC=O
Agent: CN(C)C
Solvent: c1ccccc1
Solvent: CO
Product: COCC=Nc1c(C)cccc1C

Procedure:
A solution of 24.2 (0.2 mole) of 2,6-dimethylaniline and 17.8 g (0.24 mole) of methoxy-acetaldehyde in 150 ml of benzene is treated with 1 ml of 25% trimethylamine solution in methanol and the mixture is refluxed for 5 hours using a steam trap. The reaction mixture is evaporated in vacuo and vacuum distillation of the residue yields the 1-(2'-methoxy-ethylidene-amino)-2,6-dimethylbenzene with a boiling point of 58°-61° C. at 0.1 Torr.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.C=O.Cl.[C:23](O)(=O)C>C1C=CC=CC=1.CO>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH2:23][O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: CC(=O)O
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Agent: C=O
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C1C(CO)COCN1CC2
Yield: 89 %

Procedure:
A suspension of 6 mmoles (1.6 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in 50 ml of absolute benzene is admixed with a suspension of 7 mmoles (0.02 g) of paraformaldehyde in 10 ml of absolute methanol. The reaction mixture is refluxed for two hours in the presence of a catalytic amount of hydrochloric acid or acetic acid, whereupon the obtained pale-yellow solution is evaporated in vacuo. The residual oily product is triturated with a small amount of acetone to yield the aimed compound in crystalline form in a yield of 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:12][CH2:13]OCC2C=CC=CC=2)=[O:10])=[CH:4][CH:3]=1.Br.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)N(CCOCc1ccccc1)Cc1cccnc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1N(Cc2cccnc2)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To 5.81 g (14.7 mmol) of N-(4-chlorophenyl)-N'-(3-pyridylmethyl)-N'-2-(benzyloxy)ethyl urea in a 100 ml round-bottomed flask were added 65 ml of 48% hydrobromic acid at room temperature. The mixture was heated gradually and then heated for 4 hours at 95° to 100° C. The reaction mixture was cooled to room temperature, 20 ml of water were added, and further 50 ml of ethyl acetate were added to extract. The ethyl acetate layer was extracted with 30 ml of 6N hydrochloric acid, which was combined with previous aqueous layer. While cooling this with ice, pH was made to be 12 or higher with potassium hydroxide and extracted thrice with 100 ml of methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and then solvent was distilled off under reduced pressure to obtain 2.28 g (yield 54%) of 1-(4-chlorophenyl)-3-(3-pyridylmethyl)-2-imidazolidinone as brown crystals.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[C:26]([CH3:33])[CH:25]=1>>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:32]2)=[C:26]([CH3:33])[CH:25]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1cc(Br)ccc1N=C=S
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(Br)ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Bromo-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-bromo -2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-bromo-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([N+:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]=1[CH3:12])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:24][C:25]([Cl:46])([Cl:45])[C:26]1[N:31]=[C:30]([C:32]([Cl:35])([Cl:34])[Cl:33])[N:29]=[C:28]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[N:27]=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[Cl:35][C:32]([Cl:33])([Cl:34])[C:30]1[N:31]=[C:26]([C:25]([Cl:46])([Cl:24])[Cl:45])[N:27]=[C:28]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([CH:12]=[C:4]2[N:3]([CH2:1][CH3:2])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[S:5]2)=[O:40])[N:29]=1
Reactant: CC[n+]1c(C)sc2ccccc21
Reactant: O=C(Cl)c1cccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1C(=CC(=O)c2cccc(-c3nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n3)c2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Ethyl-2-methyl-benzothiazolium-p-toluenesulfonate (5.0 pbw) and 3-(4,6-bis-trichloromethyl-s-triazin-2-yl) benzoylchloride (7.4 pbw) are successively suspended or dissolved, respectively, in 50 pbw of toluene. The mixture is cooled to 15° C. and, at this temperature, 6.0 pbw of triethylamine are added dropwise with the exclusion of moisture. The mixture discolors towards dark brown and is stirred for 3 hours at room temperature. The precipitate that forms is removed by filtration with suction and washed with cold toluene. The residue is digested in 200 pbw of methanol and stirred for about 60 minutes, filtered again and dried. The product is recrystallized from 2-methoxy-ethanol, giving orange-colored crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[F:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:11][C:12]1[N:17]=[CH:16][C:15]([O:10][C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: OCCc1cccc(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: OCCc1cccc(Oc2ccc(F)nc2)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 3-(2-hydroxyethyl)phenol (142.5 mg) in chloroform (5 ml), 279 mg of (6-fluoro-3-pyridinyl)boronic acid, 0.043 ml of triethylamine, 681 mg of copper acetate, and 500 mg of 4A molecular sieve were added, and the reaction solution was stirred at room temperature for 6 days. The reaction solution was filtered through Celite, and the filtrate was diluted with water, extracted with chloroform, and dried over anhydrous magnesium sulfate. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-50:50-75/25)) to afford the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Mg]Br.[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C1COCC1>[C:11]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: O=C1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(C2=CCCC2)c(F)c1
Temperature: 0 °C
Yield: 26.3 %

Procedure:
To a 0.497 M solution of (2,4-difluorophenyl)magnesium bromide (32.4 g, 149 mmol) in THF at 0° C. was carefully added cyclopentanone (13.23 mL, 149 mmol). Upon the end of the addition, the reaction mixture was heated at reflux for 2 h. Ice (10 g) and 6 N aqueous hydrochloric acid were added. The reaction mixture was extracted with ether. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen sulfite, a saturated aqueous solution of sodium bicarbonate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give 1-cyclopentenyl-2,4-difluorobenzene (7.064 g, 39.2 mmol, 26.3% yield) as a colorless oil. LC-MS (M+H)+=181.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.31 (1H, m), 6.75-6.85 (2H, m), 6.26-6.31 (1H, m), 2.68-2.74 (2H, m), 2.51-2.58 (2H, m), 1.93-2.02 (2H, m).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1>[CH2:17]([O:16][C:14](=[O:15])[NH:7][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][CH3:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(N)COC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCC(COC)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 1-methoxymethyl-propylamine (2.50 g, 24.3 mmol, 1.0 eq.) in dioxane (15 mL) was added an aqueous solution of K2CO3 (15 g in 15 mL of H2O) and the mixture was cooled to 0° C. CBZ—Cl (4.16 mL, 1.2 eq.) was then introduced and the resulting mixture was warmed to room temperature and stirred for 3 h, extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (hexanes to 40% EtOAc/hexanes) to give (1-methoxymethyl-propyl)-carbamic acid benzyl ester (4.4 g, 76%) as a white solid.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH2:18][CH2:19][O:20][CH3:21])[N:11]=2)[CH:5]=1.ClC1N=C(C2C=[C:32](C=CC=2)[C:33]([OH:35])=[O:34])C=C(C)N=1>COCCN>[C:4]([O:35][C:33](=[O:34])[CH2:32][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH2:18][CH2:19][O:20][CH3:21])[N:11]=2)[CH:5]=1)=[O:22])([CH3:9])([CH3:5])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)O)c2)nc(Cl)n1
Reactant: COCCNc1nc(C)cc(-c2cccc(C(=O)OC)c2)n1
Agent: COCCN
Product: COCCNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-[2-(2-methoxy-ethylamino)-6-methyl-pyrimidin-4-yl]-benzoic acid methyl ester [prepared by the following procedure: 3-(2-Chloro-6-methyl-pyrimidin-4-yl)-benzoic acid (1.49 g, 6 mmol) was heated in 2-methoxy-ethylamine (5.2 ml) to 80° C. for 2.5 h. The mixture was evaporated in vacuum and the residual oil was stirred in 1N HCl-MeOH (20 ml) for 18 h at 40° C. to give the methyl ester as light yellow solid (1.29 g).] (1.29 g, 4.3 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a light yellow oil (1.44 g).
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][CH:18]=1>>[F:12][C:13]1[CH:18]=[C:17]([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9]2)[CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1(N2CCCC2)CCC1
Reactant: Fc1cccc(I)c1
Product: NC(c1cccc(F)c1)C1(N2CCCC2)CCC1

Procedure:
The title compound, yellow, oil, MS: m/e=249.2 [(M+H)+], was prepared in accordance with the general method of intermediate K from 1-pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) and 3-fluoro-iodobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[C:29]([Cl:30])=[N:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C>[Cl:31][C:27]1[N:28]=[C:29]([Cl:30])[C:21]2[N:20]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:23](=[O:24])[C:22]=2[CH:26]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1c(C(=O)O)cc(Cl)nc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)nc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
5-Trifluoromethyl-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid chloride (example 2, step 3) (242 mg) was added to a mixture of 3-amino-2,6-dichloroisonicotinic acid (example 1, step 8) (190 mg) in acetonitrile (3 mL). The mixture was stirred for 5 minutes at room temperature and triethylamine (220 μL) was added and stirred for 20 minutes, before a second portion of triethylamine (220 μL) was added. After the mixture was stirred for further 20 minutes at room temperature, methanesulfonyl chloride (70 μL) was added. After stirring for 2 hours at room temperature, the formed precipitate was filtered off, washed carefully with water and MTB-ether and dried in vacuum to afford 350 mg of the title compound of the formula
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.S(=O)=O.[CH2:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]>>[Br:1][C:19]1[CH:20]=[CH:21][C:16]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Cc1ccccc1
Agent: O=S=O
Product: CC(C)Cc1ccc(Br)cc1
Reaction time: 1.08 h
Yield: 2 %

Procedure:
To a mixture of 1.78 g (10 milliMoles) of N-bromosuccinimide in 20 ml of liquid sulfur dioxide at -30° C. is added 1.57 ml (10.0 mMoles) of isobutylbenzene. The mixture is stirred at -30° to -18° for 65 minutes, then worked up as above. Assay gives only 2% p-bromoisobutylbenzene and 88% recovered starting isobutylbenzene, indicating that the reaction with NBS is very slow at this temperature.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:22])[C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1>[NH2:22][C:13]1[C:12]2[N:11]=[C:10]([CH2:23][CH2:24][CH2:25][CH3:26])[N:9]([CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNS(C)(=O)=O
Temperature: 25 °C
Yield: 28.7 %

Procedure:
Methanesulfonyl chloride (1.27 g, 11.1 mmol) was slowly added to a solution of 1-(2-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 10.6 mmol) in pyridine (60 mL). The reaction was maintained at ambient temperature overnight and then it was concentrated to dryness. The residue was combined with warm dichloroethane and water and then filtered to provide an off white solid. The dichloroethane layer was concentrated to provide an off white solid. The two solids were combined and then recrystallized from N,N-dimethylformamide to provide 1.1 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as a white solid, m.p. 210.0–211 .0° C. Analysis: Calculated for C17H23N5O2S: % C, 56.49; % H, 6.41; % N, 19.37. Found: % C, 56.45; % H, 6.49; % N, 19.50.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]1[CH:9]=[C:8]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:17]([CH2:30][CH3:31])[CH:16]=2)=O)[CH:7]=[C:6]([CH3:33])[N:5]=1)[CH3:2].C(N(CC)C1C=C(C2OC(C3C=C(C)C(O)=C(CC)C=3)=NN=2)C=C(C)N=1)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:72])=CC=1>C1COCC1.CC(=O)OCC>[CH2:23]([O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:14]2[S:72][C:10]([C:8]3[CH:7]=[C:6]([CH3:33])[N:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:34][CH3:35])[CH:9]=3)=[N:12][N:13]=2)=[CH:16][C:17]=1[CH2:30][CH3:31])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1cc(C(=O)NNC(=O)c2cc(C)nc(N(CC)CC)c2)cc(C)c1OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: CCc1cc(-c2nnc(-c3cc(C)nc(N(CC)CC)c3)o2)cc(C)c1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(-c2nnc(-c3cc(C)nc(N(CC)CC)c3)s2)cc(C)c1OCc1ccccc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N′-(2-diethylamino-6-methyl-pyridine-4-carbonyl)-hydrazide (1.29 g, 2.72 mmol, intermediate from Example 81 step a)) in THF (15 mL), Lawesson reagent (1.21 g, 2.99 mmol) is added. The mixture is stirred at 110° C. for 15 min under microwave irradiation (300 W, external cooling). The mixture is cooled to rt, diluted with EA (100 mL) and washed with sat. aq. Na2CO3-solution (3×50 mL) followed by brine (1×50 mL). The org. extract is dried over MgSO4, filtered, concentrated and dried to give crude {4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]thiadiazol-2-yl]-6-methyl-pyridin-2-yl}-diethyl-amine (2.43 g) as a yellow oil; LC-MS: tR=1.01 min, [M+1]+=473.20.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][CH:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:6].[Cl-].[NH4+]>CCOCC>[CH3:6][CH:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH3:1])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:4]
Reactant: C[Mg]Br
Reactant: CC(C)N1CCCc2cc(C=O)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1ccc2c(c1)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.9 ml (15 mmol) of a 3.0M ethereal solution of methylmagnesium bromide was diluted with 15 ml of ether. An ethereal solution of 2.0 g (10 mmol) of 1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde was dropped into the dilution prepared above at room temperature. The obtained mixture was stirred at room temperature for one hour, followed by the addition of an aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum to give 2.1 g of the title compound as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][C:20]1=[O:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][N:19]([NH:18][C:15](=[O:17])[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[C:20](=[O:35])[CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-piperidinylacetic acid (440 mg), 1-amino-4-benzyloxycarbonyl-2-piperazinone (541 mg), triethylamine (273 mg) and HOBt (333 mg) in DMF (30 ml) was combined with WSC (518 mg) and stirred at room temperature for 15 hours. The reaction mixture was concentrated to obtain a residue, which was partitioned between ethyl acetate and water, and the organic phase was washed with water, aqueous sodium bicarbonate, an aqueous solution of citric acid and brine, dried and concentrated to obtain N-(4-benzyloxycarbonyl-2-oxo-1-piperazinyl)-2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetamide (840 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH:18]=[CH:17][C:16]4[CH:25]=[CH:26][CH:27]=[CH:28][C:15]3=4)[C:11](=[O:29])[NH:10][C:9]2=[O:30])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH:25]1[C:16]2[CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]([C:12]3[C:11](=[O:29])[NH:10][C:9](=[O:30])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])[N:7]=4)[CH:13]=3)[C:15]=2[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CN
Reactant: O=c1[nH]c(=O)n(-c2ccnc(Cl)n2)cc1C1c2ccccc2C=Cc2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)CNc1nccc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Temperature: 90 °C

Procedure:
A mixture of the product from example 6 step (i) (1 g), glycine methyl ester hydrochloride (0.339 g) and N,N-diisopropylethylamine (1.13 ml) in 1-methyl-2-pyrrolidinone (20 ml) was heated at 90° C. for 7 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was dissolved in methanol/chloroform and the product precipitated by the addition of 50% ethyl acetate in isohexane. Yield 0.96 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12]CC.CN(C)CCN(C)C.ICC.[NH4+].[Cl-]>C1COCC1>[CH2:11]([C:3]1[C:2](=[O:10])[N:1]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2)[CH3:12]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1=c2ccccc2=NC1=O
Temperature: 25 °C
Yield: 2.9 %

Procedure:
A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) under N2 was cooled to −25° C. and treated drop wise with n-butyl lithium (2.5M in hexanes, 240 ml, 0.6 mol). To the resulting solution was added N,N,N′,N′-tetramethylethylenediamine (90.4 ml, 0.6 mol). After 30 min. iodoethane (48 ml, 0.6 mol) was added and the reaction mixture was allowed to warm to RT and stirred over night. The reaction mixture was poured into aqueous NH4Cl solution, extracted with EtOAc (2×) and the combined organic layers were washed with dil. HCl, water, brine, dried (MgSO4) and concentrated. The residual oil was triturated with hexane to afford the crude product (24.5 g, 51%). A sample (3 g) was recrystallized from EtOAc/hexane to obtain the title compound (1.4 g), mp. 100-101° C.; 1H-NMR (DMSO-d6) δ0.76 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H), 3.38 (t, 3H, J=5.7 Hz), 6.8 (dt, 11H, J=7.69, 0.45 Hz), 6.93 (dt, 1H, J=7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS (ESI) m/z 270 [M+H].