Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:58])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:57])[CH2:15][CH2:16][S:17][CH2:18][CH:19]([O:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:40]([O:39][CH:19]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:18][S:17][CH2:16][CH2:15][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:58])=[O:5])=[CH:8][CH:9]=1)=[O:57])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 4-[6,7-bis(palmitoyloxy)-4-thiaheptanoylamino]benzoic acid t-butyl ester as obtained in Example 45 (1.05 g) in chloroform (5 ml)-trifiuoroacetic acid (6 ml) was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was crystallized from methanol-water to yield 4-[6,7-bis(palmitoyloxy)-4-thiaheptanoylamino]benzoic acid (992 mg, yield 100%) as a colorless crystal. A solution of 4-[6,7-bis(palmitoyloxy)-4-thiaheptanoylamino]benzoic acid as obtained above (200 mg), 7-t-butyl ester-glutamyl-glutamic acid di-t-butyl ester as obtained in Reference Example 26 (126 mg), DEPC (63 mg) and triethylamine (78 mg) in dimethylformarnide (6 ml) was stirred at room temperature for 30 minutes. The solvent was concentrated; the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:chloroform=2:1) to yield the title compound (210 mg, yield 68%) as a colorless amorphous substance.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][C:21]1[C:22](Br)=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH:25]=[CH:24]2>C1(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)C=CC=CC=1.COCCOC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:22]1[C:21]([CH3:20])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][CH2:26]2
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Cc1ccc2c(c1Br)C=CC2
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cc1ccc2c(c1-c1ccc3ccccc3c1)C=CC2
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To mixed solution of 2-naphthylboronic acid (5 g, 29 mmol) and DME (100 mL), aqueous solution (30 mL) of cesium carbonate (12 g, 36.8 mmol)(30 mL) and 5-methyl-4-bromoindene (4.3 g, 21 mmol), tetrakis(triphenylphosphino)palladium (0.9 g) were added, and heated under reflux. After 16 hours, reaction solution was poured into 1N HCl-ice water to separate organic layer after stirring. Organic layer was washed with saturated solution of sodium chloride after filtering through Celite, and dried over magnesium sulfate, and solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (Silica-gel: produced by Kanto Chemical Co., Inc., hexane) to obtain the desired 4-(2-naphthyl)-5-methylindene (3.9 g, yield: 74%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=[NH:17])[NH2:16])=[CH:9][CH:8]=1.[OH:23][CH:24]=[C:25]([CH2:30][C:31]1[CH:32]=[N:33][C:34]([O:37][CH3:38])=[N:35][CH:36]=1)[C:26](OC)=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[CH3:38][O:37][C:34]1[N:33]=[CH:32][C:31]([CH2:30][C:25]2[C:24](=[O:23])[N:17]=[C:15]([CH2:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:4]=4)=[CH:12][CH:11]=3)[NH:16][CH:26]=2)=[CH:36][N:35]=1
Reactant: COC(=O)C(=CO)Cc1cnc(OC)nc1
Reactant: N=C(N)CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(Oc4cccc(C(F)(F)F)c4)cc3)nc2=O)cn1
Yield: 64.3 %

Procedure:
The same procedure as E38 from a mixture of 3-(4-(3-(trifluoromethyl) phenoxy)phenyl)propanimidamide (200 mg, 0.580 mmol), methyl 3-hydroxy-2-((2-methoxypyrimidin-5-yl)methyl)acrylate (130 mg, 0.580 mmol) and potassium acetate (171 mg, 1.740 mmol) in toluene (10 mL) to afford the title compound (180 mg, 61.1% yield) as a yellow solid. LCMS: rt=8.88 min, [M+H+]=483.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.[H-].[Na+].O>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: Nc1cnc2ccccc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2nccc(Nc3cnc4ccccc4c3)c2cc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 28.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (88 mg) and 3-aminoquinoline (72 mg) were dissolved in dimethylacetamide (1 ml) to prepare a solution. 60% sodium hydride (46 mg) was added to the solution under ice cooling. The mixture was stirred at 80° C. for 2 hr. Water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (37 mg, yield 28%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[N:13]([C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Yield: 98.9 %

Procedure:
2-Amino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic-acid tert-butyl ester (7.96 g, 15.4 mmol) and hydrazine hydrate (3.85 g, 77.0 mmol) in ethanol (250 ml) was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the solid residue was extracted with diethyl ether (3×200 ml). The fractions were combined and the solvent removed in vacuo to give 5.9 g (100%) of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.C1C=C(C2C=CC=C([OH:36])C=2)C(O)=CC=1>O1CCOCC1>[OH:1][C:2]1([OH:36])[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH2:3]1
Reactant: Oc1cccc(-c2ccccc2O)c1
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=Cc1ccccc1)C1=CCC(O)(O)C=C1
Temperature: 19 °C
Reaction time: 1.17 h

Procedure:
Trimellitic anhydride chloride (10.53 grams, 0.05 mole) and anhydrous 1,4-dioxane (400 milliliters) are added to a reactor and maintained under a nitrogen atmosphere with stirring to provide a solution. The resultant solution is cooled in an ice bath to 12° C., then a solution of 4,4'-dihydroxy-alpha-methylstilbene (5.66 grams, 0.05 hydroxyl equivalent), anhydrous 1,4-dioxane (50 milliliters) and pyridine (0.05 mole, 3.96 grams) is added dropwise to the reactor from a pressure equalizing addition funnel at a rate so as to maintain the temperature at 10°-12° C. The 4,4'-dihydroxy-alpha-methylstilbene used contains 98.8 area percent of the diphenol and 1.2 area percent of a single dimeric component as determined by high pressure liquid chromatographic analysis (uv detector set at 254 nm). After 70 minutes, addition of the solution is completed. After and additional 11 minutes, the ice bath cooling the reactor exterior is removed and the product slurry is allowed to warm to 19° C. over the next 236 minutes. The product slurry is filtered under a nitrogen atmosphere through a bed of diatomaceous earth with washing of the filter cake using anhydrous 1,4-dioxane (250 milliliters). The clear filtrate is concentrated to approximately 100 milliliters total volume via removal of 1,4-dioxane by rotary evaporation at 90° C. under vaccuum. The resultant slurry of crystalline product is held under a nitrogen atmosphere for 24 hours followed by filtration to recover the solid product. After drying in a vacuum oven at 100° C. and 1 mm Hg the product is recovered at a constant weight of 9.3 grams of light yellow colored powder. During the drying process, a minor amount of pyridine hydrochloride sublimed out of the product. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product demonstrated the presence of anhydride carbonyl group absorbances (1868 and 1782 (with 1815 as a shoulder) cm-1) and the ester carbonyl group absorbance (1742 cm-1). Proton magnetic resonance spectroscopy additionally confirms the product structure.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6](=[O:8])[O:5][C:3]1=O.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6](=[O:8])[N:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:3]1=[O:5]
Reactant: CC1(c2ccccc2)CC(=O)OC1=O
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1(c2ccccc2)CC(=O)N(c2ccncc2)C1=O
Reaction time: 7 h

Procedure:
The starting material is prepared as follows: The mixture of 68.6 g of 2-methyl-2-phenylsuccinic anhydride, 34 g of 4-aminopyridine and 675 ml of xylene is refluxed on a water separator while stirring for 7 hours. It is cooled to 40°, filtered, cooled to 0° and filtered again. The second residue is recrystallized from isopropanol-hexane, to yield the 3-methyl-3-phenyl-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 90°-92°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.Cl>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([N:8]2[C:20](=[O:21])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:22])[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N2C(=O)c3ccccc3C2=O)cc(C(C)(C)C)c1O
Yield: 77.5 %

Procedure:
A mixture of 8.8 g (40 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline and 5.9 g (40 mmol) of phthalic anhydride in 100 ml of tetrahydrofuran was refluxed for 24 hours. Concentrated hydrochloric acid (0.5 ml) was added and the mixture was refluxed for an additional seventeen hours and concentrated in vacuo. The resulting solid (13.2 g) was washed successively with water and hexane and then recrystallized from acetone-hexane to yield 10.9 g (31 mmol, 77%) of N-(3,5-di-tert-butyl-4-hydroxyphenyl)phthalimide, mp 196°-201° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]([C:32]([OH:34])=O)[CH:29]=[N:30][CH:31]=1.CCN(C(C)C)C(C)C.[CH3:44][C@@H:45]1[NH:50][CH2:49][CH2:48][N:47]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:46]1>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]([C:32]([N:50]2[CH2:49][CH2:48][N:47]([S:51]([C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:58][CH:59]=3)(=[O:52])=[O:53])[CH2:46][C@@H:45]2[CH3:44])=[O:34])[CH:29]=[N:30][CH:31]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (458 mg, 1.21 mmol) was added to a solution of 5-bromo-3-pyridinecarboxylic acid (supplied by Aldrich) (203 mg, 1.01 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.438 ml, 2.51 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (372 mg, 1.21 mmol) was added and stirring was continued for 1.5 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave an dark brown gum.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:38]1([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:45]([O:47][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Cc1ccccc1
Reactant: O=C(O)CCCCNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Yield: 70.2 %

Procedure:
The target compound was prepared as a colorless solid substance in an amount 5.94 g at a yield of 70.2% in the same manner as in Example 1 except that 5.0 g (19.9 mmol) of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 50 ml of THF and 3.55 g (21.9 mmol) of CDI was added; 7.83 ml (59.7 mmol) of diisopropylamine and 30 ml of THF were added and 37 ml (59.7 mmol) of 1.63N BA solution was added dropwise; 11.5 g (59.7 mmol) of t-butyl phenylacetate instead of methyl phenylacetate was dissolved in 30 ml of THF; and 50 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 40 g of 4N hydrochloric acid was added, and 140 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: C[O:2][C:3]1[C:4](=O)[CH:5]([C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]([CH3:10])([CH3:9])[CH2:7][CH:8]=1.[CH3:19][NH:20][NH2:21]>C(O)(=O)C.O>[CH3:19][N:20]1[C:4]2[C:3](=[O:2])[CH2:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]=2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:21]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)C1C(=O)C(OC)=CCC1(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(C)c2c1C(C)(C)CCC2=O
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A solution of ethyl (3-methoxy-6,6-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate from the previous step (40.2 mmol theoretically) in acetic acid (65 mL) was treated dropwise with a solution of methyl hydrazine (2.14 mL, 40.2 mmol) in acetic acid (20 mL) and allowed to stand at room temperature overnight. The mixture was then diluted with water (800 mL) and extracted with ethyl acetate (500 mL×2). The organic extracts were washed with brine, dried on Na2SO4 and evaporated to dryness. The crude material was chromatographed on silica gel eluted with dichloromethane/ethyl acetate 100:5 to obtain the pure title compound (4.8 g, 47.7% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]1.S(=O)(=O)(O)O.[CH3:14]O>>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:14])=[O:7])[CH2:2]1
Reactant: CO
Reactant: O=C(O)C1CCOC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCOC1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of tetrahydro-3-furancarboxylic acid (10.00 g, 86.0 mmol) in MeOH (172 mL) was added sulfuric acid (13.8 mL, 258 mmol). The reaction was heated to reflux for 18 h. The reaction was then cooled to rt and concentrated. The residue was partitioned between water (500 mL) and DCM (200 mL). The phases were separated and the aqueous fraction was extracted with DCM (200 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated to afford methyl tetrahydro-3-furancarboxylate (10.1 g, 78 mmol, 90% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.99 (t, J=8.4 Hz, 1H), 3.86-3.95 (m, 2H), 3.76-3.86 (m, 1H), 3.71 (s, 3H), 3.01-3.18 (m, 1H), 2.03-2.32 (m, 2H).
Reaction SMILES: Cl/[C:2](/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]/[O-].[K+].S(=O)(=O)(O)O.O.[CH:17]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[CH:30]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]>CCOCC>[CH:17]([N:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]3[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:35]=[C:31]3[CH:30]=2)[CH2:24][CH2:25]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCN(CCOc2ccnc(N)c2)CC1
Reactant: CCOC(=O)/C(Cl)=C\[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cnc2cc(OCCN3CCN(C(C)C)CC3)ccn12
Temperature: 65 °C
Yield: 59.4 %

Procedure:
Potassium (E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (Preparation E; 41.32 g, 219.0 mmol) was suspended (through vigorous magnetic stirring) in anhydrous ether (365 mL) and 6N sulfuric acid (18.25 mL, 109.5 mmol) was added. Water (100 mL) was added to aid in phase separation. When the pH of the bottom (aqueous) phase, dropped below 3, the ether layer was separated. The aqueous phase was further extracted with ether (400 mL). The combined ether phases were dried over sodium sulfate and magnesium sulfate for 10 minutes. The solution was filtered and concentrated under reduced pressure, with the temperature of the water bath not exceeding 20° C. A residual oil was obtained, which crystallized upon drying under high vacuum overnight. This residue was dissolved in absolute EtOH (360 mL). 4-(2-(4-Isopropylpiperazin-1-yl)ethoxy)pyridin-2-amine (Preparation G; 28.95 g, 109.5 mmol) was added, and the mixture was heated under nitrogen at 65° C. for 18 hours. After allowing the mixture to cool, the resulting suspension was evaporated to dryness. The resulting solids were shaken with THF and collected by filtration, then dried under vacuum. This material (HCl salt) was mixed with water (400 mL) and ethanol (200 mL). Sodium bicarbonate (20 g) was added and the mixture was stirred for 16 hours (some effervescence occurred). The suspension was evaporated to dryness under vacuum. The solids were shaken in EtOAc/THF and filtered. These solids were washed with a large volume of ethyl acetate and THF. The organic solution was further dried with sodium sulfate and magnesium sulfate, filtered and evaporated under vacuum to give an amber gum. This material was triturated with 2:1 ether-hexanes, and the resulting solids were collected by filtration to afford ethyl 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (23.46 g, 59% yield) as beige solids.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:9]=[CH:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][N:28]=1)CCC>C1(C)C=CC=CC=1.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>[N:13]1([CH2:12][CH2:11][N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[C:3]3[CH:10]=[N:9]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1ncnc2c1cnn2CCN1CCCCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1coc(-c2ncnc3c2cnn3CCN2CCCCC2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A mixture of 4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.188 mmol), 2-(tri-n-butylstannyl)oxazole (0.059 ml, 0.282 mmol) in toluene (3 mL) was introduced in a microwave vial. It was degassed by argon for 30 minutes followed by the addition of Pd(Ph3P)4 (22 mg, 19 mmol) after which the mixture was degassed for 10 additional minutes. The mixture was stirred at 100° C. for 30 min under microwave irradiation (150 W). The solvent was removed and the crude thus obtained was purified by flash chromatography to provide 2-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxazole as a cream-colored solid (37 mg, 0.12 mmol, 66%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:20][O:21][N:22]=[C:23]1[C:27]2([CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[CH2:26][NH:25][CH2:24]1>C(#N)C>[C:34]([O:33][C:31]([N:29]1[CH2:30][C:27]2([C:23](=[N:22][O:21][CH3:20])[CH2:24][N:25]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:26]2)[CH2:28]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: CC#N
Product: CON=C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CN(C(=O)OC(C)(C)C)C2
Yield: 46.4 %

Procedure:
1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and 840 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10 ml of acetonitrile and the resulting mixture was refluxed for 3 hours. Then the precipitated solid was filtered and dried to give 340 mg of the titled compound(yield: 46.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:25][N:26]=[C:27]=[O:28]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:27](=[O:28])[NH:26][CH3:25])=[CH:9][CH:8]=1
Reactant: CN=C=O
Reactant: OCc1ccc(OCc2cccc(F)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)OCc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
In a sealed glass tube, a solution of 1.0 g of [4-(3-fluoro-benzyloxy)-phenyl]-methanol [Example 25b)], 0.03 ml of triethylamine and 0.245 g of methyl isocyanate in 40 ml of dichloromethane was heated at 40° C. for 3 d. At that time a transformation rate of 50% was reached, determined by NMR. For the working-up, the reaction mixture was cooled and evaporated. The residue was dissolved in 2 ml of pyridine and 1 ml of acetic acid anhydride and the solution stirred at room temperature for 3 h. Thereafter, the mixture was evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a 2:1-mixture of heptane and ethyl acetate as the eluent. There were obtained 580 mg (47% of theory) of methyl-carbamic acid 4-(3-fluoro-benzyloxy)-benzyl ester as a white solid; MS: m/e=289 (M)+.