Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[C:25](=O)([O-])[O-].[K+].[K+].CI.Cl.CO.CC(C)=O>CO>[CH3:25][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: CI
Product: CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Reaction time: 15 h

Procedure:
To a solution of 250 mg (0.723 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane in 2.9 ml of methanol was added 220 mg (1.59 mmol) of potassium carbonate. To the resulting mixture was added 308 mg (2.17 mmol, 3 equiv) of methyl iodide. Within a short time, most of the solids dissolved. After 15 hours at 21° C., a mass of crystals had separated. Additional methanol was added (2 ml) to dissolve the solid. After 23 hours, an additional 102 mg (0.72 mmol) of methyl iodide was added. After an additional 16 hours, the solution was acidified with concentrated hydrochloric acid and the volatiles were removed on the rotary evaporator. The residue was extracted with methanol, filtered, and the methanol evaporated. The residue was crystallized twice from methanol/acetone yielding 56 mg (0.16 mmol) of a colorless solid, melting point 215-240° (dec.). 13C NMR (D2O, ppm vs TMS): 177.2, 171.1, 57.2, 56.5, 54.1, 52.6, 50.1, 49.9, 43.7. Mass spectrum (FAB): m/e 359 (M-H) and 361 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CC(C)=O>[O:11]=[C:9]([CH3:10])[C:3](=[N:2][O:1][CH2:18][CH2:19][CH3:20])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCON=C(C(C)=O)C(=O)OCC
Yield: 81.2 %

Procedure:
To a suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 15 g.) and potassium carbonate (19.8 g.) in acetone (75 ml.) was added dropwise propyliodide (16.2 g.) with stirring, and the mixture was stirred at ambient temperature for 1.5 hours. The insoluble substance was collected by filtration and washed with acetone. The washings and the filtrate were combined and evaporated to dryness under reduced pressure. To the resultant residue was added water and the aqueous solution was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), oil.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:31])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:32][CH2:33][CH2:34]Br>C(O)C>[CH3:3][O:4][C:5](=[O:31])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:34][CH2:33][Br:32])=[CH:12][CH:13]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccccc1C
Yield: 56.7 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-[(2-(2-methylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.15 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.83 g, 57%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][CH:28]6[CH2:29][CH2:30][CH2:31][O:27]6)[CH:37]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CC3CCCO3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CC4CCCO4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(tetrahydrofuran-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.3 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol) and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. The solid was filtered off. The filtrate was purified with RP-HPLC (pH=10) to afford the desired product (5.8 mg). LCMS (M+H)+: m/z=489.4.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3Cl)CC2)c(OC)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1]/[C:2](=[N:13]\[O:14][C:15]([C@H:17]([CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O)/[CH:3]1[CH2:8][CH2:7][N:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][CH2:4]1.N1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[CH:29]1([CH2:28][CH2:27][CH2:26][C@@H:17]([C:15]2[O:14][N:13]=[C:2]([CH:3]3[CH2:8][CH2:7][N:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][CH2:4]3)[N:1]=2)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)C1CCN(S(C)(=O)=O)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CCN(S(C)(=O)=O)CC2)no1
Yield: 36.2 %

Procedure:
A solution of tert-butyl(3R)-3-{[({(Z)-amino[1-(methylsulfonyl)-4-piperidinyl]methylidene}amino)oxy]carbonyl}-6-cyclohexylhexanoate (preparation 42) (1.50 g, 1.83 mmol) in toluene (100 ml) was treated with pyridine (90 μl, 1.83 mmol) and anhydrous ZnCl2 (150 mg, 1.83 mmol) and heated at reflux for 20 hours. The reaction mixture was diluted with EtOAc and washed with H2O, brine and H2O, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of cyclohexane:EtOAc (90:10) gradually changing to (50:50). The oil was recrystallised from pentane to afford the title compound as a white solid (320 mg, 36%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:31])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>>[CH3:30][S:27]([O-:29])(=[O:28])=[O:26].[CH2:1]([O:17][CH2:18][C:19](=[CH2:31])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][N+:34]1[CH:35]=[CH:36][S:32][CH:33]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: c1cscn1
Reactant: C=C(COCCCCCCCCCCCCCCCC)COCCCCOS(C)(=O)=O
Product: C=C(COCCCCCCCCCCCCCCCC)COCCCC[n+]1ccsc1
Product: CS(=O)(=O)[O-]

Procedure:
1-Hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane (from Preparation 7) (2.5 g) was heated with thiazole (2 ml) at 60° C. for 4 days. Excess thiazole was removed in vacuo.
Reaction SMILES: C(OC([NH:8][C:9]1[NH:37][CH2:36][C:35]2[CH:38]=[C:39]([Cl:40])[C:32](=[C:33]([Cl:41])[CH:34]=2)[NH:31][C:30](=[O:42])[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][CH2:25][CH:24]=[CH:23][CH2:22][O:21][C:20]2[CH:50]=[CH:51][C:17](=[CH:18][CH:19]=2)[C:16]2[C:12](=[C:13]([CH3:52])[S:14][N:15]=2)[C:11](=[O:53])[N:10]=1)=O)(C)(C)C.[H][H]>CO.[Pd]>[NH2:8][C:9]1[NH:37][CH2:36][C:35]2[CH:34]=[C:33]([Cl:41])[C:32](=[C:39]([Cl:40])[CH:38]=2)[NH:31][C:30](=[O:42])[CH2:29][NH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:17](=[CH:51][CH:50]=2)[C:16]2[C:12](=[C:13]([CH3:52])[S:14][N:15]=2)[C:11](=[O:53])[N:10]=1
Reactant: [H][H]
Reactant: Cc1snc2c1C(=O)N=C(NC(=O)OC(C)(C)C)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(C(=O)OC(C)(C)C)CCCC=CCOc1ccc-2cc1
Agent: [Pd]
Solvent: CO
Product: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCCCCCCOc1ccc-2cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The intermediate (20 mg) from Example 4, Step 4(C) was dissolved in methanol (4 mL), followed by the addition of 10-20 mg of 5% Pd/C. Hydrogen was introduced with a balloon and the reaction mixture was stirred at room temperature for 30 min. (longer reaction time for reaction at larger scale). The reaction mixture was filtered through Celite to remove the catalyst. Solvent was evaporated in vacuo to give a crude product, which was subjected to the protocol described in Example 1, Step 1(D) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH:6]=1.[CH2:7]([C:9](CC)([O:11][CH:12]=[C:13]([C:17]([O-:19])=O)[C:14]([O-])=O)C)C.C([OH:24])C>>[O:19]=[C:17]1[C:13]([C:12]([O:11][CH2:9][CH3:7])=[O:24])=[CH:14][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[N:1]1
Reactant: CCC(C)(CC)OC=C(C(=O)[O-])C(=O)[O-]
Reactant: CCO
Reactant: NC1=CCCN1
Product: CCOC(=O)c1cn2c(nc1=O)CCC2
Temperature: -10 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
50.5 g of 2-amino-pyrroline are dissolved in 600 ml. of ethanol and the solution is cooled to -10° C., and added dropwise under stirring at -10° C. to a solution of 127.8 g. of diethyl-ethoxy-methylene-malonate in 200 ml. of ethanol within 3 hours. The reaction mixture is then stirred for a further 1 hour at 0° C. and allowed to stand for 24 hours. The ethanol is distilled off at reduced pressure and the residual yellow oil, containing a mixture of ethyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate and ethyl 2-oxo-2,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidino-3-carboxylate at a ratio of 4:1 is dissolved under boiling in 400 ml. benzene. The benzene solution is allowed to crystallize under cooling. The precipitated crystals are filtered. 22 g. (17%) of ethyl 2-oxo-2,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are obtained, melting at 193° C. after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH2:21][CH3:22])[C:11](=O)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][NH:31][NH2:32])=[CH:28][CH:27]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>CC(O)C>[CH2:1]([O:8][N:9]=[C:10]([CH2:21][CH3:22])[C:11](=[N:32][NH:31][CH2:30][C:29]1[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=NOCc1ccccc1)C(=O)C(=O)N1CCOCC1
Reactant: COc1ccc(CNN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCC(=NOCc1ccccc1)C(=NNCc1ccc(OC)cc1)C(=O)N1CCOCC1
Yield: 82.2 %

Procedure:
1.0 g (3.3 mmol) of 4-(3-benzyloxyimino-2-oxovaleryl)morpholine was dissolved in 20 ml of 2-propanol and 1.24 g (6.6 mmol) of 4-methoxybenzylhydrazine hydrochloride, 1.08 g (13.2 mmol) of sodium acetate and 1 ml of acetic acid were added and the mixture was refluxed for 15 hours. After distilling the solvent off under reduced pressure, 20 ml of water was added and the mixture was extracted three times with 30 ml of diethylether. After washing with 1N aqueous hydrochloric acid, water, a saturated aqueous sodium bicarbonate, water and then a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 1.19 g (yield: 83%) of 4-(3-benzyloxyimino-2-(4-methoxybenzylhydrazono)valeryl)morpholine as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[N:7]=[C:6]([CH3:8])[O:5][N:4]=1)=[CH2:2].[N:9]1([C:20](=[O:21])[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12])[CH3:10]>CN(C)C=O>[CH3:8][C:6]1[O:5][N:4]=[C:3]([CH2:1][CH2:2][N:18]2[C:19]3[C:20](=[O:21])[N:9]([CH3:10])[C:11](=[O:12])[N:13]([CH3:14])[C:15]=3[N:16]=[CH:17]2)[N:7]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: C=Cc1noc(C)n1
Solvent: CN(C)C=O
Product: Cc1nc(CCn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 72 %

Procedure:
2.2 g. of 3-vinyl-5-methyl-1,2,4-oxadiazole, 30 cm3 dimethylformamide and 0.2 cm3Triton-B catalyst are boiled with 3.6 g. of theophylline for 1 hour. The solvent is distilled off and the residue is crystallized from ethanol. 4.2 g. (72% yield) of 7-[2-(5-methyl-1,2,4-oxadiazol-3-yl)-ethan-1-yl]-theophylline are obtained. m.p.: 112°-114° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[CH:16]1[O:20][N:19]=[C:18]([C:21](=O)[CH2:22]Cl)[CH2:17]1)(=[O:4])=[O:3].[C:25]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)(=[S:27])[NH2:26].O>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][C:7]=1[CH:16]1[O:20][N:19]=[C:18]([C:21]2[N:26]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[S:27][CH:22]=2)[CH2:17]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1cc(C(F)(F)F)ccc1C1CC(C(=O)CCl)=NO1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccc(C(F)(F)F)cc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of 2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-(trifluoromethyl)phenyl methanesulphonate (200 mg) and tert-butyl 4-carbamothioylpiperidine-1-carboxylate (108 mg) in tetrahydrofuran (2 ml) at room temperature was added tetrabutylammonium bromide. The reaction mixture was stirred at room temperature for 12 hours. Then water was added thereto, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave tert-butyl 4-[4-(5-{2-[(methylsulphonyl)oxy]-4-(trifluoromethyl)phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (168 mg, 56%).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Cl:5][CH:6]([C:11]1([O:19][CH2:18][CH2:17][O:16]1)[C:12]([F:15])([F:14])[F:13])C(F)(F)F.S(=O)(=O)(O)O.[CH2:25]([OH:27])[CH3:26]>>[Cl:5][CH:6]([C:11]1([O:16][CH2:17][CH2:18][O:19]1)[C:12]([F:13])([F:14])[F:15])[CH2:1][C:2]([O:27][CH2:25][CH3:26])=[O:3]
Reactant: CCO
Reactant: CC[O-]
Reactant: FC(F)(F)C(Cl)C1(C(F)(F)F)OCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC(Cl)C1(C(F)(F)F)OCCO1

Procedure:
80 g of a 20% strength solution of sodium ethylate in ethanol were added to 30 g of 2-chloro-1,1,1,4,4,4-hexafluoro-3,3-ethylenedioxybutane in 30 ml of ethanol and the mixture was stirred under reflux for 10 hours. 100 ml of 50% strength sulfuric acid were then metered in and the mixture was stirred under reflux for 6 hour. It was poured onto ice and extracted with methylene chloride. After drying over sodium sulfate and removal of the solvent and subsequent distillation in vacuo, 24 g of ethyl 2-chloro-4,4,4-trifluoro-3,3-ethylenedioxybutanecarboxylate of boiling point 108° C./20 mbar were obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C@H:15]2[C@@H:20]([OH:21])[CH2:19][CH2:18][CH2:17][NH:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>C(Cl)Cl.[OH-].[Na+]>[C:1]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:20]([OH:21])[C@@H:15]1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc([C@@H]2NCCC[C@@H]2O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc([C@H]2[C@@H](O)CCCN2C(C)=O)cc1OC
Reaction time: 0.5 h

Procedure:
Acetyl chloride (9.75 g, 125 mmoles) is added dropwise to a cooled (0° to 10° C) and stirred solution of cis-2-(3,4-dimethoxyphenyl)-3-piperidinol (25.0 g, 105 mmoles, described in Example 4) in methylene chloride (200 ml) and 8N sodium hydroxide (100 ml). The mixture is stirred for 30 minutes and the organic phase is separated. The aqueous phase is extracted with methylene chloride. The organic extracts are washed with dilute hydrochloric acid, aqueous sodium carbonate, brine, dried (MgSO4) and evaporated. The residue is subjected to chromatography on silica gel using methanol-ether 1:3 and the eluates are evaporated to give cis-1-acetyl-2-(3,4-dimethoxyphenyl)-3-piperidinol; nmr (CDCl3) δ 2.12 (s, 3H), 3.86 (s, 6H) and 7.0 (m, 3H).
Reaction SMILES: Br[C:2]1[N:3]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@H:12]1[CH3:17])[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][C@H:19]1[CH3:24])[N:5]=2.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C@@H:19]1[CH2:20][O:21][CH2:22][CH2:23][N:18]1[C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[N:3]2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(Br)n(C3CCCCO3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(-c3ccccn3)n(C3CCCCO3)c2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
8-Bromo-2,6-bis-((R)-3-methyl-morpholin-4-yl)-9-(tetrahydro-pyran-2-yl)-9H-purine (40 mg, 83 μmol) was dissolved in 2 mL of toluene under argon in a microwave vial, and 2-(tributylstannyl)-pyridine (36 mg, 83 μmol) and Pd(PPh3)4 (4.8 mg, 4.2 μmol) were added. The microwave vial was capped, and the reaction mixture was stirred for 3 hours at 120° C. The vial was cooled to room temperature and opened. The mixture was diluted with EtOAc (20 mL) and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (12 g SiO2, heptane/TBME in a gradient from 4/1 to 2/3) to give the product as a solid (35 mg, 88%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[CH3:41])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:18]>>[CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:39]2[CH:38]=[C:16]([CH:15]=[CH:14][C:40]=2[CH3:41])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=2)=[O:18])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(NC(C)C)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:67-68° C.; 1H NMR (300 MHz, CDCl3) δ: 8.97 (1 H, s), 8.06 (1 H, s), 7.98-8.01 (1 H, d, J=9.0 Hz), 7.97 (1 H, s), 7.83-7.85 (1 H, d, J=6.0 Hz), 7.58-7.60 (1 H, d, J=6.0 Hz), 7.30-7.32 (2 H, m), 6.61-6.64 (1 H, d, J=9.0 Hz), 5.05 (1 H, s), 4.02-4.05 (1 H, m), 3.70 (2 H, s), 2.79-2.99 (8 H, brs), 2.66 (3 H, s), 2.52 (3 H, s), 1.29 (6 H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H34F3N6O: 551.2741. found: 551.2734.
Reaction SMILES: C(OC(N[CH:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][CH:11]([OH:39])[CH:12]([NH:20][C:21](=[O:38])[C@H:22]([CH2:34][C:35](=[O:37])[NH2:36])[NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.CO.C([NH2:51])(C)C.C(Cl)(Cl)Cl>>[NH2:51][CH:10]([CH:11]([OH:39])[CH:12]([NH:20][C:21](=[O:38])[C@H:22]([CH2:34][C:35](=[O:37])[NH2:36])[NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)NC(CC(O)C(Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)c1ccccc1
Reactant: CC(C)N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Yield: 95 %

Procedure:
Using the procedure of Example 11 with the resultant compound of Example 66 gave, after silica gel chromatography using methanol/isopropylamine/chloroform, the desired compound (RF 0.3; 2.5% methanol/2% isopropylamine/chloroform) in 95% yield. Mass spectrum (M+H)+ =519.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]([CH3:23])[C:15]1[C:20]([CH:21]=O)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]([CH3:23])[C:15]1[C:20]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: CN(C)c1ncccc1C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CN(C)c1ncccc1C=C1N=C(c2cccs2)OC1=O
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 2-(dimethylamino)-3-pyridinecarboxaldehyde (50 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 29 mg of the above-captioned compound.