Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][NH2:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(CC)CC)C>C(OCC)(=O)C.O.O1CCCC1.C1(C)C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][NH:28][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CCNC(=O)Cc2ccc(Cl)cc2)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A mixture of 5.00 g (29.3 mmol) of (4-chlorophenyl)acetic acid, 5.23 g (43.9 mmol) of thionyl chloride and 50 ml of toluene was stirred at 50° C. for 30 minutes and then 80° C. for 2.5 hours, cooled and concentrated under reduced pressure. The residue was added to a mixture of 5.18 g (28.5 mmol) 2-(3,4-dimethoxyphenyl)ethylamine, 3.46 g (34.2 mmol) of triethylamine and 50 ml tetrahydrofuran at 0° C. and kept at 0° C. for 30 minutes and at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture and precipitated solid was collected with filtration. The obtained solid was dried to give 5.75 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(4-chlorophenyl) acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:31][CH3:32].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:14]([S:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:27][CH2:26]3)=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: COc1cc(C(C)(C)c2cnc(SCC3CCNCC3)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)c2cnc(SCC3CCN(S(C)(=O)=O)CC3)n2-c2ccc(F)cc2)ccc1Cl
Yield: 74.6 %

Procedure:
To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)piperidine (0.154 g, 0.33 mmol) and triethylamine (0.089 mL, 0.65 mmol) in DCM (2 mL) was added mesyl chloride (0.027 mL, 0.34 mmol). After 2 h the reaction was concentrated in vacuo and purified by column chromatography, using Hex:EtOAc as eluents, to afford the title compound (0.136 g) as a white solid. MS (EI) m/z 552 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14](I)[C:13]([NH2:17])=[N:12][CH:11]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.[Cu]I.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>[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:13]([NH2:17])=[N:12][CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N)c(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Trimethylsilyl acetylene (10.5 mL, 79.1 mmol) was added to a solution of 6-amino-5-iodo-nicotinic acid methyl ester (11 g, 39.6 mmol), copper (I) iodide (754 mg, 4.0 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 g, 2.0 mmol) and diisopropylethylamine (21 mL, 118.7 mmol) in N,N-dimethyl formamide (80 mL) at 0° C. After addition, the reaction mixture was allowed to warm up to 25° C. and stirred for 2 h. The mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (QingDao silica gel, 200-300 mesh, 5% dichloromethane/hexanes to 60% dichloromethane/hexanes) to afford 6-amino-5-trimethylsilanylethynyl-nicotinic acid methyl ester (7.1 g, 72%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.28 (s, 9H), 3.88 (s, 3H), 5.58 (br. s., 2H), 8.14 (d, J=2.2 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:18][OH:19])[CH:7]=[C:8]([O:15][CH2:16][CH3:17])[C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:2]>C1(C)C=CC=CC=1.O=[Mn]=O>[CH2:16]([O:15][C:8]1[CH:7]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH:18]=[O:19])[CH3:17]
Reactant: CCOc1cc(CO)cc(OCC)c1-n1cccc1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Yield: 89.1 %

Procedure:
To a solution of 3,5-diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester (1.51 g, 4.98 mmol, 1.0 equiv) in toluene (5 mL) was added slowly over a time period of 15 min under slight cooling to 20° C. a solution of diisobutylaluminium hydride (8.9 mL, 12.45 mmol, 2.5 equiv; 20% solution in toluene). After 1 h the excess hydride was quenched by cautious addition of water (10 mL) and a 28% solution of NaOH (2 mL). The mixture was stirred for 30 min and the organic phase filtered over Hyflo Super Cel. The aqueous layer was extracted with toluene (2×50 mL), the combined organic phases washed with a sat. solution of NaCl (2×50 mL) and concentrated by evaporation under reduced pressure to afford 1.30 g (100%) of (3,5-diethoxy-4-pyrrol-1-yl-phenyl)-methanol. The crude alcohol (1.30 g, 4.98 mmol, 1.0 equiv) was dissolved in toluene (20 mL) and activated MnO2 (7.79 g, 89.5 mmol, 18.0 equiv) was added. The reaction mixture was heated to reflux for 7 h, after which time the reaction mixture was filtered through Hyflo Super Cel and concentrated yielding 1.15 g (89% yield) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.17 (t, J=7.0 Hz, 6H), 4.02 (q, J=7.0 Hz, 4H), 6.08-6.09 (m, 2H), 6.75-6.76 (m, 2H), 7.25 (s, 2H), 9.89 (s, 1H). MS (ISP): 260.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[C:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[O:10]1[CH2:11][CH2:12][C:7](=[C:5]([CH3:6])[CH2:4][OH:3])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(C)=C1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(CO)=C1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 121.1 %

Procedure:
To a cooled (0° C.) solution of 4.2 g (24.39 mmol) of 2-(tetrahydropyran-4-ylidene)propionic acid ethyl ester obtained in the above 1) in ether (50 mL) was added 1.20 g (31.7 mmol) of lithium aluminum hydride under an atmosphere of argon, and stirred for 1 hour at 0° C., followed by stirring for 2 hours at room temperature. After the reaction mixture was diluted with ether, excess reagent was carefully quenched with ethanol and aqueous ammonium chloride solution. After drying of the reaction mixture with anhydrous magnesium sulfate and subsequent evaporation of the solvent, 4.2 g (yield 100%) of 2-(tetrahydropyran-4-ylidene)propan-1-ol was obtained as colorless liquid. Its physical property is shown below.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][S:6][C@H:5]2[CH2:8][C@:9]([NH:16]C(=O)OC(C)(C)C)([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:11])[N:4]12)#[N:2].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C1(SC)C=CC=CC=1>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:16][C@@:9]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:11])[N:4]2[C@@H:5]([S:6][CH2:7][C@H:3]2[C:1]#[N:2])[CH2:8]1
Reactant: CC(C)C[C@@]1(NC(=O)OC(C)(C)C)C[C@@H]2SC[C@@H](C#N)N2C1=O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@]1(N)C[C@@H]2SC[C@@H](C#N)N2C1=O

Procedure:
53 mg of tert-butyl (3R,6R,7aS)-(3-cyano-6-isobutyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl)-carbamate were reacted with 3 ml of trifluoroacetic acid and 600 μl of thioanisole at 0° C. for 30 min. The solvents were then removed in vacuo, and the residue was stirred in diethyl ether, filtered off with suction and dried.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C=O)C.[Cl:15]N1C(=O)CCC1=O>C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: CCc1cccnc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-3-ethylpyridine (Wonda Science, CAS[42753-67-3]; 12.2 g, 0.1 mol) is dissolved by stirring in 500 ml of ethyl acetate with 10 ml DMF. A thermometer is placed in the solution to monitor temperature. N-Chlorosuccinimide (13.3 g, 0.1 mol) is added in several portions to keep the solution at room temperature. The solution becomes dark in color and is stirred at room temperature overnight. The supernatant is decanted from the dark solids that formed and transferred to a separatory funnel. The organic solution is washed with 500 ml saturated aqueous sodium bisulfite and then 500 ml brine. The organic layer is dried with MgSO4 and concentrated on a rotovap. The dark brown crude product is chromatographed on 500 g of flash silica-gel eluting with 35% EtOAc/Hexanes. Concentration of the appropriate fractions on a rotovap gives a light-tan oil. The oil is dissolved in hexanes and decolorized with activated carbon. The solvent is cooled to −20° C. and the solid which forms is isolated by filtration to give the product as a flaky off-white solid. (MP 67-68° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][C:12]([O:15][C:16](=[O:26])[N:17]([CH2:19][CH2:20][CH:21]([OH:25])[CH2:22][CH2:23][CH3:24])[CH3:18])([CH3:14])[CH3:13]>>[CH3:13][C:12]([O:15][C:16](=[O:26])[N:17]([CH2:19][CH2:20][CH:21]([O:25][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH2:22][CH2:23][CH3:24])[CH3:18])([CH3:11])[CH3:14]
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)cc1F
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using 4-chloro-2-fluorobenzonitrile and (3-hydroxyhexyl)methylcarbamic acid 1,1-dimethylethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][Br:23])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: BrCCOCCOCCOCCBr
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOCCBr
Yield: 59.3 %

Procedure:
A mixture of 3.08 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 16.0 g of 1,11-dibromo-3,6,9-trioxaundecane and 2.8 g of anhydrous potassium carbonate in 75 ml of anhydrous acetone was stirred at reflux for 5 days. During this period, 1.0 g portions of potassium carbonate were added after 18 hours and after 25 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil (20 g) which was chromatographed on 200 g of silica gel using 10% ethyl acetatetoluene to give 3.24 g (59% yield) of 4-[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14]O>>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Product: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-Methyl-3-nitro benzoic acid (12.5 g, 69 mmol) was dissolved in anhydrous methanol (500 mL) in a 1 L flask. HCl gas was then bubbled through the solution until saturation (3 h). The HCl source was then removed, and the reaction was stirred at room temperature overnight. The reaction was then concentrated to dryness and dried over phosphorus pentoxide overnight to yield 13.34 g (99%) of product which was 99% pure by QC HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.[OH-].[Na+]>Cl>[F:9][C:5]1[C:6]([NH2:8])=[CH:7][C:2]2[C:3](=[CH:10][C:11](=[O:13])[N:1]=2)[CH:4]=1
Reactant: Nc1cc(N)c(CC(=O)O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(cc1F)=CC(=O)N=2
Temperature: 25 °C
Yield: 83.4 %

Procedure:
(2,4-Diamino-5-fluoro-phenyl)-acetic acid 3c (7.12 g, 38.7 mmol) was dissolved in hydrochloric acid (100 ml, 1 mol/L) under stirring at room temperature. The solution was heated to reflux for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was cooled down to room temperature, neutralized with sodium hydroxide solution (100 ml, 1 mol/L) in an ice-water bath, extracted with ethyl acetate (125 ml×4). The combined organic extracts were washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-fluoro-6-amino-indol-2-one 3d (5.3 g, yield 82.8%) as a yellow solid.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([O-:11])=O)[CH3:5].[K+].[CH3:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][C@H:21](C(O)=O)[CH2:20][C@@H:19]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[O:17]>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([C@H:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH3:14])=[O:17])[C@@H:19]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[CH2:20]1)=[O:11])[CH3:5]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COC(=O)N1CC[C@H](C(=O)O)C[C@@H]1Cc1ccc(C(F)(F)F)cc1
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: [Cl-]
Agent: [K+]
Product: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
Magnesium chloride (7.39 g, 77.58 mmol) and potassium 3-ethoxy-3-oxopropanoate (13.20 g, 77.58 mmol) were suspended in methyl THF (100 mL) under nitrogen and the resulting suspension heated to 50° C. while stirring with an oversized stirring bar for 4 h, then cooled to room temperature (flask 1). In a separate flask was added to cis-1-(methoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (14.1 g, 40.83 mmol) (reference compound 46) in methyl THF (100 mL) di(1H-imidazol-1-yl)methanone (10 g, 61.67 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 4 h 30 min (flask 2). Then, the contents of flask 2 is transferred into flask 1 by transfer needle, washed with methyl THF (40 mL). The resulting suspension was stirred at room temperature for 19 h 30 min. Additional magnesium chloride (3.7 g, 38.86 mmol) and potassium 3-ethoxy-3-oxopropanoate (6.6 g, 38.78 mmol) in methyl THF (50 mL) were sonicated at 50° C. for 2 h 30 min, then added to the reaction mixture. Stirred at room temperature for 21 h. The reaction mixture was partitioned between 2 M HCl (ca. 150 mL) and MTBE. The phases were separated. The organic phase was washed with brine and satd NaHCO3, then dried over MgSO4 and evaporated. Crude cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (14.9 g, 88%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.21-1.30 (m, 3H), 1.63-2.04 (m, 4H), 2.67-2.86 (m, 2H), 2.93-3.09 (m, 2H), 3.46 (s, 2H), 3.60 (s, 3H), 3.85-3.98 (m, 1H), 4.11-4.26 (m, 3H), 7.30 (d, 2H), 7.53 (d, 2H). MS m/z 416 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]([CH3:36])=[CH:19][CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32](O)=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:17][C:18]([CH3:36])=[CH:19][CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: CC(C)=CCn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CC(C)=CCn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
137 mg of compound 12 was obtained in a similar manner to those described in the Examples 1 and 2 using 332 mg of ethyl 4-(2-aminophenoxy)butyrate and 200 mg of 3-[1-(3-methyl-2-butenyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([C:29]1[C:30]2[N:31]([CH:36]=[CH:37][N:38]=2)[C:32]([Br:35])=[CH:33][N:34]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:10]([C:20](C)(C)[O:21][SiH2]C(C)(C)C)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6](=[O:39])[N:7]([C:29]1[C:30]2[N:31]([CH:36]=[CH:37][N:38]=2)[C:32]([Br:35])=[CH:33][N:34]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[C:10]([CH2:20][OH:21])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)c(C(C)(C)O[SiH2]C(C)(C)C)c1)c1ncc(Br)n2ccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)c(CO)c1)c1ncc(Br)n2ccnc12

Procedure:
A solution of (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-morpholin-4-yl-phenyl]-carbamic acid tert-butyl ester (0.164 g, 0.265 mmol) in 1M tetrabutylammonium fluoride in THF (0.29 mL, 0.29 mmol) is stirred at room temperature overnight. The solvent is removed under vacuum and the residue is purified by silica gel column chromatography eluting with ethyl acetate. The title compound is isolated (0.126 g, 94%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH2:41]1COCC1.CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:36][N:35]([CH2:34][C:32]1[CH:33]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]2)[CH:29]=[C:30]([F:37])[CH:31]=1)[CH3:41]
Reactant: C1CCOC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Agent: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN(C)C)c4)cc23)CC1
Yield: 80.2 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2M dimethylamine in THF (210 ul, 0.42 mmol) for methanamine to afford 33.7 mg of the title compound (80.2%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C1(C)C(C)=CC=CC=1>[CH3:7][C:4]1[S:3][C:2]2=[N:1][CH:18]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:10])[N:6]2[CH:5]=1
Reactant: Cc1cnc(N)s1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cnc2sc(C)cn2c1=O
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 2-amino-5-methyl thiazole (1.14 g) and diethyl ethoxymethylenemalonate (2.16 g) is heated at 135° C. in xylene (20 mL) for 2 h allowing for removal of the ethanol product. After the solvent is removed, the mixture is suspended in diphenyl ether (10 mL). The mixture is then heated to reflux with removal of ethanol for 30 min. The reaction mixture is cooled to rt and hexanes (20 mL) is added. The resulting precipitate is filtered, washed with diethyl ether (2×10 mL) and dried to afford 2.1 g (86%) of the title compound as a tan solid. Physical characteristics: 1H NMR (DMSO) δ 8.61, 8.05, 4.25, 2.48, 1.28; MS (ESI+) m/z 239 (M+H)+.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C1COCC1.B.[Na].OC1C=CC(C=O)=CC=1>C(OCC)(=O)C.O>[C:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[CH:11][CH:12]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Oc1ccc(C=O)cc1
Agent: B
Agent: O=Cc1ccc(O)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C(=O)Oc1ccc(CO)cc1

Procedure:
To the entire amount of the compound obtained in (3-1), 300 ml of THF and 100 ml of water were added and stirred. To this solution, sodium boron hydride was added little by little under ice cooling. Every each addition, disappearance of starting materials was confirmed by TLC. After the starting materials disappeared, water and ethyl acetate were added to the reaction solution and the reaction solution was extracted by liquid separation. The organic phase was dried over magnesium sulfate, concentrated and then subjected to silica gel column chromatography to produce the objective compound. The objective compound was obtained as a slightly brown oily product. Yield: 40.1 g (41.7%) (through two steps from 4-hydroxybenzaldehyde).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)=[C:17]([NH:20][C:21](=[O:33])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][C@@H:29]([CH3:31])[O:28][C:27](=[O:32])[CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[OH-:40].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)=[C:17]([NH:20][C:21](=[O:33])[CH:22]=[CH:23][CH2:24][N:25]([CH2:26][C:27]([OH:28])=[O:32])[CH2:30][C@H:29]([OH:40])[CH3:31])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H]1CN(CC=CC(=O)Nc2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc2OCC2CC2)CC(=O)O1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CC(=O)O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
100 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline is mixed with 1.63 ml of water and 0.37 ml of 1N hydrochloric acid. The reaction mixture is stirred for three hours at 60° C. and then left to stand overnight at ambient temperature. For working up, 0.37 ml 1N sodium hydroxide solution is added and the mixture is cooled in an ice bath, whereupon a light-colored precipitate is deposited. This is suction filtered, washed with cold water, and dried. Yield: 60 mg (58% of theory); mass spectrum (ESI−): m/z=556, 558 [M−H]−.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11]1
Reactant: COC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)CC1CC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)N1CCC(CO)CC1CC(C)(C)C

Procedure:
The compound was prepared as described in Reference Compound 4, Step 4 starting from methyl 4-((tert-butyldimethylsilyloxy)methyl)-2-neopentylpiperidine-1-carboxylate and TBAF (34.2 mL, 34.2 mmol, 1 M in THF). The residue was purified by automated flash column chromatography on a Biotage® KP-SIL 340 g column. A gradient from 30% to 100% EtOAc in heptane was used as eluent, which resulted in the title compound.