Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]([CH2:24][C:25]([N:27]([N:29]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)[CH3:28])=[O:26])[CH2:9][C:10]([NH:12][CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH3:16])=[O:11])[CH:7]=1.Cl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]([CH2:24][C:25]([N:27]([N:29]2[CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:37]2)[CH3:28])=[O:26])[CH2:9][C:10]([NH:12][CH2:13][CH2:14][NH:15][CH3:16])=[O:11])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N(CC(=O)NCCN(C)C(=O)OC(C)(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNCCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
The compound (294 mg, 0.54 mmol) obtained in step A was dissolved in dichloromethane (5.5 ml), 4N hydrochloric acid-ethyl acetate solution (1.35 ml) was added, and the mixture was stirred at room temperature for 8 hr. The aqueous layer was alkalified by addition of saturated aqueous sodium hydrogen carbonate, and the organic layer was extracted with dichloromethane, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (NH silica gel use, methanol-dichloromethane) to give the title compound (179 mg, yield 75%) as a pale-yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][OH:14])=[CH2:12])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][O:14][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH2:12])=[CH:15][CH:16]=1
Reactant: C=C(CO)CCOCc1ccc(OC)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(CCOCc1ccc(OC)cc1)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine 4-(p-methoxybenzyloxy)-2-hydroxymethylbut-1-ene (0.77 g, 3.46 mmol) with pyridine (3 mL) and add dropwise benzoyl chloride (603 μL, 5.2 mmol). Stir the mixture at room temperature for 20 hours. Dilute the reaction mixture with diethyl ether (100 mL) and washed 3X with saturated sodium bicarbonate solution, dry over MgSO4 and concentrate in vacuo. Chromatograph on silica gel eluting with 1/9 ethyl acetate/hexane to give the title compound as an oil. Rf =0.28, silica gel, 1/9 ethyl acetate/hexane.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([OH:10])=[O:9].[CH2:17](O)[CH3:18]>>[F:6][C@@H:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([O:10][CH2:17][CH3:18])=[O:9]
Reactant: CCCCCC[C@H](F)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCCCCC[C@H](F)C(=O)OCC
Yield: 87 %

Procedure:
Partial Resolution of of Ethyl 2-fluorooctanoate by Enzyme Catalysed Hydrolysis.-Ethyl 2-fluorooctanoate 65 (71.6 g, 0.377 mol) was added to 0.063 M phosphate buffer (pH 7.0) (280 ml) and deionised water (280 ml) in a beaker fitted with a pH electrode, magnetic stirrer bar and a cooling bath. Pseudomonas lipase (Amano PS) (22 mg) was added and the mixture was stirred at ca. 5° C. The pH was maintained at ca. 7 by adding 1.0 M sodium hydroxide solution via a syringe pump. Hydrolysis continued until 151 ml of the hydroxide solution had been added (40% conversion). The mixture was extracted with ether (3 times) and the combined organic solutions were washed with brine, dried (K2CO3) and evaporated to give partially resolved (R)-ester. The aqueous layer was acidified to pH 2.7 with conc. hydrochloric acid and extracted with ether. The organic solutions were dried and evaporated to give partially resolved (S)-(-)-2-fluorooctanoic acid. Concentrated sulphuric acid (2 ml) was added to (S)-2-fluorooctanoic acid (24.0 g, 0.15 mol) in ethanol (200 ml) and the solution was heated under reflux for 4 h. Most of the ethanol was distilled off at atmospheric pressure; dichloromethane was added and the solution was washed with sat. sodium bicarbonate solution until neutral, brine, dried (MgSO4) and evaporated. The yellow liquid was distilled to give partially resolved ethyl (S)-(-)-2-fluorooctanoate 66 (25.13 g, 87%) b.p. 68° C. at 0.45 mm Hg.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[F:51][C:52]1([F:58])CCNCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][C:52]([F:58])([F:51])[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CCC(F)(F)CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4,4-difluoropiperidine hydrochloride and isolated as light-yellow gum (10.9 mg, 55%). MS(m/e): 421.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:8]([C:9]2[C:20]([CH3:21])=[N:19][C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:7][C:5]([NH2:6])=[C:4]([F:22])[CH:3]=1.C([O-])(O)=O.[Na+].Cl[C:29]([O:31][C:32]([CH3:34])=[CH2:33])=[O:30]>CCOC(C)=O>[Br:1][C:2]1[C:8]([C:9]2[C:20]([CH3:21])=[N:19][C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:7][C:5]([NH:6][C:29](=[O:30])[O:31][C:32]([CH3:34])=[CH2:33])=[C:4]([F:22])[CH:3]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: CSc1ncc2cc(-c3cc(N)c(F)cc3Br)c(C)nc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(Br)cc1F
Yield: 100 %

Procedure:
Treat a mixture of 4-bromo-2-fluoro-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)aniline (0.20 g, 0.527 mmol) in EtOAc (10 mL) and saturated. NaHCO3 (10 ml) with isopropenyl chloroformate (0.064 ml, 0.580 mmol) and stir the biphasic mixture vigorously at RT for 4 h. Separate the layers, extract the aqueous layer with additional EtOAc (1×), wash the combined organics with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound (assume 100% yield). MS (m/z): 463.0.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[NH:8][CH2:7]2)[O:5][CH2:4]1.[Cl:19][CH2:20][CH2:21][CH2:22]Cl>CN(C=O)C>[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[N:8]([CH2:22][CH2:21][CH2:20][Cl:19])[CH2:7]2)[O:5][CH2:4]1
Reactant: ClCCCCl
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2C2(CN1CCCCl)OCCO2
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a suspension of 2.20 g (50 mmol) of 60% sodium hydride in 100 ml of DMF, a solution of 12.06 g (50 mmol) of 3,4-dihydro-2H-1,2-benzothiazin-4-one 1,1-dioxide ethylene acetal in 50 ml of DMF was added under ice cooling and stirring. The reaction mixture was stirred for 30 minutes at 0° C. and then for further one hour at room temperature. Under ice cooling, a solution of 16.95 g (150 mmol) of 1,3-dichloropropane in 50 ml of DMF was added to the reaction mixture, followed by stirring for 17 hours at room temperature. The post-treatment and purification were conducted as in Example 10, whereby 13.41 g of the title compound were obtained (yield: 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[NH:6]1)=[O:4].CCN(CC)CC.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:6]1[S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])=[O:4]
Reactant: COC(=O)[C@H]1CC[C@@H](c2cccc(F)c2)N1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@@H](c2cccc(F)c2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 75.4 %

Procedure:
(2R,5S)-5-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester (0.33 g, 1.5 mmol) was dissolved in 1,2-dichloroethane (2 mL) and Et3N (1.0 mL, 7.4 mmol, 5 eq) was added followed by 4-chlorobenzenesulfonyl chloride (0.78 g, 3.7 mmol, 2.5 eq). The mixture was heated at 100° C. for 16 hr. Solvent was removed under vacuum and the residue was dissolved in EtOAc (10 mL), washed with 10% NaHCO3 and brine, dried (Na2SO4) and concentrated under vacuum. Chromatography on silica gel (5–10% EtOAc/hexanes) yielded 0.45 g (75%) of pure (2R,5S)-1-(4-chloro-benzenesulfonyl)-5-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester as yellowish solid. 1H NMR (CDCl3, 300 MHz) δ 7.67 (2H, d), 7.42 (2H, d), 7.24 (3H, m), 6.98 (1H, m), 4.95 (1H, t), 4.82 (1H, q), 3.94 (3H, s), 2.45–2.25 (3H, m), 2.05 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[OH:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41](=[S:43])[NH2:42]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:43][C:41]([C:40]([CH3:45])([CH3:44])[CH2:39][OH:38])=[N:42][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(CO)C(N)=S
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Product: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described for Intermediate 9 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (750 mg, 1.7 mmol), NBS (317 mg, 1.782 mmol), and 3-hydroxy-2,2-dimethylpropanethioamide (248 mg, 1.86 mmol), the title compound was obtained as an yellow foam (460 mg, 45%). A portion of the sample was crystallized from ethyl acetate hexanes. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H) 8.54 (d, J=5.31 Hz, 1H) 7.64-7.74 (m, 1H) 7.41-7.50 (m, 2H) 7.31-7.36 (m, 1H) 7.24 (t, J=8.97 Hz, 2H) 6.87 (d, J=5.31 Hz, 1H) 5.2-5.4 (br s, 1H) 3.54 (s, 2H) 1.36 (s, 6H). MS (ESI): 555.0 [M+H]+.
Reaction SMILES: [K].[NH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[Br:8][C:9]([CH2:11]Br)=[CH2:10]>C1(C)C=CC=CC=1.O>[Br:8][C:9](=[CH2:10])[CH2:11][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7]
Reactant: O=C1CCCN1
Reactant: C=C(Br)CBr
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(Br)CN1CCCC1=O
Temperature: 0 °C
Yield: 64 %

Procedure:
To a suspension of 5.0 g (40.6 mmol) of pyrrolidinone potassium salt prepared from Example 1 in 40 mL of toluene, solution of 5.24 mL (2 equiv.) of 2,3-dibromopropene in 10 mL of toluene was added dropwise for 1 hour in water bath and the reaction mixture was reacted at 60˜70° C. for 2 hours. Upon completion of the reaction, the mixture was cooled to 0° C. and filtered to remove solid. It was then concentrated under reduced pressure and purified by separation with silica gel column chromatography (ethyl acetate/n-hexane (1:1)) to obtain 5.30 g (64% yield) of 1-(2-bromoallyl)-pyrrolidin-2-one. To degassed solution of 1.0 g (4.90 mmol) of 1-(2-bromoallyl)-pyrrolidin-2-one prepared in the above in 50 mL of ethanol/benzene (1:1), 5 mol% (172 mg) of ditriphenylphosphine palladium dichloride, degassed solution of 7.35 mL of 2N sodium carbonate and 3-pyridyl-tributyltin, dimethyl borate, trimethyl borate lithium salt, boronic acid propanediol ring ester (2 equiv.), etc. were added. The mixture was reacted for 15 minutes at room temperature, followed by heating at reflux for 18 hours. After concentrating under reduced pressure, it was extracted with ethyl acetate for three times and washed with brine for two times. The concentrated solution was purified by separation with silica gel column chromatography (ethyl acetate followed by methylene chloride/methanol (20:1)) to obtain 810 mg (82% yield) of 1-(2-pyridin-3-yl-allyl)-pyrrolidin-2-one. Ozones were added to solution of 100 mg (0.494 mmol) of 1-(2-pyridin-3-yl-allyl)-pyrrolidin-2-one at −78° C. to obtain 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one, which was the same as synthesized in Example 20.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)=[CH:29][CH:28]=2)O1>>[N:33]1([C:30]2[CH:31]=[CH:32][C:27]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]4[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:4][CH:3]=3)=[CH:28][CH:29]=2)[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: CC1(C)OB(c2ccc(-n3ccnc3)cc2)OC1(C)C
Product: COc1nn(-c2ccccc2)c2cc(-c3ccc(-n4ccnc4)cc3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 58 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole as the building block.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1>S(=O)(=O)(O)O.O>[C:5]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([Cl:8])=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
To a mixture of 50 ml of acetic anhydride and two drops of sulfuric acid was added 34.5 grams of 4-chloro-2-nitroaniline in several portions. At the end of addition, the solution was heated at 50° C. for one hour and then allowed to cool. 300 ml of cold water was added to the solution to induce precipitation of crystals, which were removed by filtration and washed with water. There were obtained the crystals of 2-acetylamino-5-chloronitrobenzene in a yield of 41.8 grams.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][CH2:21][O-:22].[Na+]>C(O)C>[CH2:21]([O:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:20]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1Cl)OCO3
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3

Procedure:
To a mixture containing 126 g of ethyl 4-chloro-6,7-methylenedioxyquinoline-3-carboxylate and 200 ml of absolute ethanol was added dropwise an ethanolic sodium ethylate solution prepared from 34 g of sodium ethylate and 250 ml of ethanol with stirring. The resulting mixture was refluxed for 1.5 hours and the ethanol was removed under reduced pressure. The residue was poured into ice-water, the insoluble solid was filtered, washed with water and dried to provide 126 g of almost pure ethyl 4-ethoxy-6,7-methylenedioxyquinoline-3-caboxylate, m.p. 84°-86°C. Recrystallization from petroleum ether gave colorless needles, m.p. 85°-85.5°C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8](Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>O.C(O)C(C)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][CH2:3]1
Reactant: CCCCCCCCCCCl
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)CO
Product: CCCCCCCCCCN1CCN(C)CC1
Temperature: 150 °C
Yield: 74.9 %

Procedure:
100 g (1 mole) of 1-methyl-piperazine and 176.5 g (1 mole) of decyl chloride were heated under reflux, at an external temperature of 150° C, until the reaction mixture had ceased boiling. After cooling, the solid product was extracted by shaking with a mixture with 40 g (1 mole) of sodium hydroxide in 500 ml of water and 500 ml of isobutanol. The organic phase was separated off and concentrated, and the residue was extracted with petroleum ether. After evaporating the petroleum ether solution, 180 g (75% of theory) of 1-methyl-4-decyl-piperazine were obtained in a form which was pure according to thin layer chromatography.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:16][CH:13]1[CH2:14][CH2:15][N:11]([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:12]1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: OC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCC(O)C2)cn1
Reaction time: 16 h
Yield: 73.4 %

Procedure:
A mixture of 5-chloropicolinonitrile (2 g, 14.4 mmol), pyrrolidin-3-ol hydrochloride (2 g, 25.9 mmol) and K2CO3 (4 g, 28.9 mmol) in DMF (15 mL) was stirred at 140□ for 16 h. The organic solvent was removed under vacuum and the residue was taken into DCM (200 mL). Solid was removed by filtration and the filtrate was concentrated to give crude product (2.0 g yield 73%) as a yellow solid. [LCMS: RtA=1.19 min, m/z 190.2 [M+H]+].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=[S:13])[NH2:12])[CH:8]=[C:7]([C:14]([F:17])([F:16])[F:15])[N:6]=1)([CH3:3])[CH3:2].CI.[CH3:20]C(C)=O.CCCCCC>CC(C)=O>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]([S:13][CH3:20])=[NH:12])[CH:8]=[C:7]([C:14]([F:16])([F:17])[F:15])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(C)Oc1cc(C(N)=S)cc(C(F)(F)F)n1
Solvent: CI
Solvent: CCCCCC
Product: CSC(=N)c1cc(OC(C)C)nc(C(F)(F)F)c1

Procedure:
In a 100 mL capacity 3-neck round-bottomed flask attached with nitrogen bubbler & magnetic stirrer 2-isopropoxy-6-(trifluoromethyl)pyridine-4-carbothioamide (7.5 g), CH3I (10.18 g), dissolved in 75 ml acetone at RT. Reflux it for 2 h. The completion of the reaction was confirmed by TLC with 20% acetone-hexane as mobile phase. The reaction mixture was distilled & crude 2-isopropoxy-6-(trifluoromethyl)pyridine-4-carbimidothioate forwarded to next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][C:26]([NH:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:27][CH:28]=1.[ClH:38].O1CCOCC1>CC(N(C)C)=O>[ClH:19].[ClH:38].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][C:23]3[CH:24]=[N:25][C:26]([NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:27][CH:28]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1cnc(NC(=O)c2ccccc2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cnc(NC(=O)c4ccccc4)nc3)ncnc2cc1OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (760 mg, 2.53 mmol) and N-(5-amino-pyrimidin-2-yl)-benzamide (542 mg, 2.53 mmol) in DMA was added 4N HCl in dioxane (822 μl, 3.29 mmol) and the reaction heated at 50° C. for 4 hours under nitrogen. The reaction was cooled and filtered. The precipitate was washed with Et2O and dried under reduced pressure to provide the title compound as a light tan brown solid (706 mg).
Reaction SMILES: [CH2:1]([N:3](C(=O)C)[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:7]([F:17])=[CH:6][C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2].[OH-].[K+]>CO>[CH2:1]([NH:3][C:4]1[C:5]([N+:18]([O-:20])=[O:19])=[CH:6][C:7]([F:17])=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:9]=1)[CH3:2]
Reactant: CCN(C(C)=O)c1cc(N2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCNc1cc(N2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of N-ethyl-4'-fluoro-5'-(4-methyl-1-piperazinyl)-2'-nitroacetanilide (20 g, 61 mmol) in methanol (160 ml) is treated with an aqueous potassium hydroxide solution (34.6 g, 616 mmol). The solution is heated to 80° for 3 hours and thereafter cooled to room temperature. The crystals obtained are filtered off and washed with water. There are obtained 13.7 g (78.7%) of 1-(5-(ethylamino)-2-fluoro-4-nitrophenyl)-4-methylpiperazine with a m.p. of 149°-150°.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[S:4][N:3]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])[S:4][N:3]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1nsc(NC(=O)OCC(Cl)(Cl)Cl)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nsc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)n1
Temperature: 70 °C
Reaction time: 15 h
Yield: 36.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3-methyl-1,2,4-thiadiazol-5-yl)carbamate (260 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (116 mg, 36.8%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@H:25]5[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]5)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CC[C@H](Nc2nc3ccc(Cn4cnc5cc(F)cnc54)cc3s2)CC1
Temperature: 110 °C

Procedure:
To a stirred suspension of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (119 g, 0.3 mmol) from Step 4 of Example 162 and trans-4-aminocyclohexanol (119 mg, 1.0 mmol) in anhydrous DMA (1 mL) was added DIEA (180 μL, 1.0 mmol). The mixture was heated in a sealed tube at 110° C. for 15 h. The mixture was cooled to rt and was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford trans-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 37%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.41 (s, 1H), 8.06 (dd, J=2.6, 9.3 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 5.48 (s, 2H), 4.55 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 1.93-2.03 (m, 2H), 1.78-1.87 (m, 2H), 1.19-1.30 (m, 4H); LCMS (ESI) m/z 398 (M+H)+.