Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:26]([OH:28])=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.O[C@@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: COC(=O)[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a stirred partial solution of 4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-ol (870 mg, 2.36 mmol), methyl (2S)-2-hydroxypropanoate (368 mg, 3.54 mmol) and triphenylphosphine (927 mg, 3.54 mmol) in DCM (20 ml) was added DTAD (814 mg, 3.54 mmol). The mixture was stirred for 1 hour, becoming a clear solution. The solution was extracted with 2N aqueous hydrogen chloride, discarding the organic phase. The aqueous phase was basified with aqueous ammonia and extracted with DCM. The organic phase was washed with brine, dried and evaporated to an oil which crystallised on trituration with ether to give methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (789 mg, 74%); NMR spectrum (300 MHz) 1.70 (d, 3H), 3.78 (s, 3H), 5.51 (q, 1H), 5.76 (s, 2H), 6.95 (d, 1H), 7.16 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.69 (m, 4H), 8.16 (s, 1H), 8.43 (s, 1H), 8.52 (s, 2H), 10.48 (s, 1H); Mass spectrum MH+ 455.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][OH:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-t-butyldimethylsilyloxypyrrolidine (39.96 in dry pyridine (40 ml), acetic anhydride (40 ml) was added, and the resultant mixture was allowed to stand overnight. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium chloride solution, dilute hydrochloric acid, aqueous sodium chloride solution, aqueous sodium bicarbonate solution and aqueous sodium chloride solution in order and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-acetoxymethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=O>ClCCl>[Cl:30][CH2:31][C:32]1[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21

Procedure:
A modification of the method described in Part E of Example 1 was used to treat tert-butyl 2-[(3-aminoquinolin-4-yl)amino]ethylcarbamate (15.65 g, 51.76 mmol) with triethylamine (10.82 mL, 77.64 mmol) followed by chloroacetyl chloride (4.5 mL, 57 mmol). The reaction was carried out in dichloromethane (60 mL). After the reaction mixture was filtered, the filtrate was washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure to provide tert-butyl 2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as an amber-colored solid, which was combined with material from two other runs for use in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1>CCOC(C)=O>[Cl:14][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1ncccc1-c1ccnc(NCCCN2CCOCC2)n1
Temperature: 80 °C

Procedure:
To 2-chloro-4-(2-chloropyridin-3-yl)pyrimidine (100 mg, 0.44 mmol) and potassium carbonate (122 mg, 0.88 mmol) was added DMSO (1.0 mL) and 3-morpholinopropan-1-amine (77 mg, 0.53 mmol). The resulting mixture was heated for 15 hours at 80° C. The cooled reaction was diluted with EtOAc and extracted with water. The organic layer was dried over sodium sulfate, filtered and concentrated to yield the title compound as a yellow oil. MS m/z=334 [M+H]+. Calc'd for C16H20ClN5O: 333.84.
Reaction SMILES: [CH:1]([C:3]1[O:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]([O:11]CC)=O)=O.O.[NH2:15][NH2:16]>CO>[O:8]1[C:3]2[CH:1]=[N:15][NH:16][C:9](=[O:11])[C:4]=2[CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C1=C(C=O)OCCC1
Reactant: NN
Solvent: O
Solvent: CO
Product: O=c1[nH]ncc2c1CCCO2
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
To a stirred 0° C. mixture of ethyl 6-formyl-3,4-dihydro-2H-pyran-5-carboxylate (1.705 g, 9.26 mmol) in methanol (80 mL) was added very quickly 35% hydrazine hydrate (0.311 g, 9.72 mmol). After 20 minutes, the solvent was removed under reduced pressure, and the residue was treated with acetic acid (70 mL) and water (7 mL) and stirred at 110° C. for 20 minutes. The solvents were removed in vacuo. The crude residue was eluted by silica gel chromatography with a 0 to 25% gradient of methanol/dichloromethane to afford the title compound (1.384 g) as a light yellow solid in better than 90% purity. MS (ESI) [m/e, (M+H)+]=153.2. 1H NMR (400 MHz, chloroform-d) δ ppm 10.56 (br s, 1H), 7.53 (s, 1H), 4.17-4.35 (m, 2H), 2.57 (t, J=6.57 Hz, 2H), 1.99-2.08 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][N:15]3[C:14]2=[O:23])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]#[N:33]>C(#N)C>[C:32]([CH2:31][N:6]1[C:5]2[CH:11]=[C:12]([N:13]3[C:14](=[O:23])[N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][N:16]4[C:21]3=[O:22])[C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])#[N:33]
Reactant: N#CCCl
Reactant: O=C1COc2cc(F)c(-n3c(=O)n4n(c3=O)CCCC4)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1C(=O)COc2cc(F)c(-n3c(=O)n4n(c3=O)CCCC4)cc21
Yield: 70.8 %

Procedure:
A mixture composed of 2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-hexahydro-1H-(1,2,4)-triazolo (1,2-a)-pyridazine-1,3-dione (2.04 g), potassium carbonate (1.06 g), chloroacetonitrile (0.96 g) and acetonitrile (30 ml) is refluxed for 3 hours. The reaction mixture is made free from acetonitrile by evaporation in vacuo and mixed with water. The resultant solid is collected by filtration and washed with a small amount of ethanol to obtain an end product 2-[4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-hexahydro-1H-(1,2,4)-triazolo (1,2-a)-pyridazine-1,3-dione (1.62 g),
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].C[Si](Cl)(C)C.CC1(C)[O:20][C:19](=O)[CH2:18][C:17](=[O:22])[O:16]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:19](=[O:20])[CH2:18][C:17]([OH:22])=[O:16]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccccc1F
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: O=C(O)CC(=O)Nc1ccccc1F
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a suspension of 2-fluorobenzeneamine (1 mL, 7.80 mmol) in DCM (78 mL) was added TMSCl (0.99 mL, 7.80 mmol) at RT [Rigo, B.; Fasseur, D.; Cauliez, P. and Couturier, D. Tetrahedron Lett.; 30; 23; 1989; 3073-3076.]. The reaction mixture was stirred for 30 min then 2,2-dimethyl-1,3-dioxane-4,6-dione (1.12 g, 7.80 mmol) was added and the combined mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was dissolved in NaHCO3 solution, which was washed with EtOAc. The organic phase was discarded and the aqueous phase was acidified with conc. HCl to pH˜3, extracted with EtOAc; extract was dried (anhydrous Na2SO4) and concentrated. The residue was purified by flash chromatography (eluent CHCl3/MeOH/AcOH 8:1:0.1) to afford the acid 29 (0.4 g, 26% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 12.67 (s, broad, 1H), 9.95 (s, 1H), 7.95 (m, 1H), 7.25 (m, 1H), 7.12 (m, 1H), 3.43 (s, 2H). MS (m/z): 198.0 (M+H).
Reaction SMILES: [C-:1]#[C-:2].[Na+].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH3:20].N>>[CH:20]#[C:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]/[CH:9]=[CH:8]\[CH2:7][CH2:6][CH2:1][CH3:2]
Reactant: [C-]#[C-]
Reactant: CCCC/C=C\CCCCCCCCCBr
Agent: N
Agent: [Na+]
Product: C#CCCCCCCCCC/C=C\CCCC
Reaction time: 3 h

Procedure:
The reaction mixture containing sodium acetylide is then admixed with 1-bromo-Z-10-pentadecene in an amount of 0.8 to 1.2 moles per mole of the sodium acetylide and the reaction is effected at a temperature in the range from -20° to +20° C., usually, for 1 to 5 hours. After completion of the reaction, the reaction mixture is freed from ammonia and washed with water or diluted hydrochloric acid followed by isolation of the pro-duct by a conventional procedure including the methods of solvent extraction, distillation, column chromatography and the like to give the desired Z-12-heptadecen-1-yne in a good yield which is usually in the range from 65 to 85% based on the amount of the sodium metal.
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[NH:6]1[CH:10]=[N:9][CH:8]=[N:7]1>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CCOCCl
Solvent: Cc1ccccc1
Product: CCOCn1cncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of chloromethyl ethyl ether (23.5 g) in toluene (300 ml ), was added dropwise, over an hour, to a solution of 1,2,4-triazole (50 g) in toluene (50 ml), and the reaction stirred at room temperature for 18 hours. On cooling, the reaction mixture was evaporated to dryness in vacuo, the residue triturated with dichloromethane, and the resulting suspension filtered. The filtrate was evaporated in vacuo and purified by column chromatography over silica gel (5/95 methanol/dichloromethane) to afford the title compound as a colorless oil, 23.9 g.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].O.S(=O)(=O)(O)O.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]2>C(Cl)(Cl)Cl>[F:11][C:12]1[CH:21]=[CH:20][C:19]2[NH:1][C:18](=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1
Reactant: O=C1CCCc2cc(F)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCCc2cc(F)ccc2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
Sodium azide 1.1 g (16.92 mmol) was added to a mixture of 6.0 mL of chloroform and 1.1 mL of water at 0° C. Concentrated sulfuric acid (0.44 mL) was added dropwise and the mixture stirred at 0° C. for two hours then filtered. The chloroform layer containing hydrazoic acid was added to a solution of 1.3 g (7.92 mmol) of 6-fluoro-1-tetralone (prepared by the method of Allinger and Jones, J. Org. Chem., 27, 70-76 (1962)) in 4.8 mL of chloroform. Additional sulfuric acid (2.16 mL) was added dropwise with stirring while maintaining the temperature below 40° C. The mixture was stirred at 40° C. for two hours then at room temperature for 16 hours. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was added to ice; the resulting precipitate was extracted with methylene chloride (5×). The combined extracts were washed with brine, dried over magnesium sulfate and filtered through a silica plug. Solvents were removed under vacuum to afford 162 mg (0.92 mmol,11%) of the product. 1H NMR (300 MHz, CDCl3): 2.21 (m,2H), 2.32 (t,7 Hz,2H), 2.77 (t,7 Hz,2H), 6.93 (m,3H), 7.8 (br s,1H). FAB-MS: calculated for C10H10FNO 179; found 180 (M+H,100%).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]([CH2:7][CH2:8][CH2:9][C:10](OC)=[O:11])[C:4](=[O:14])[CH:3]=1.Cl.C(O)(=[O:18])C>>[Cl:1][C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9](=[C:10]=[O:11])[OH:18])[C:4](=[O:14])[CH:3]=1
Reactant: CC(=O)O
Reactant: COC(=O)CCCn1sc(Cl)cc1=O
Agent: Cl
Product: O=C=C(O)CCn1sc(Cl)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The methyl ester of the isothiazolones were hydrolyzed to the free acids. 5-Chloro-2-(3-methoxycarbonylpropyl)-3-isothiazolone (4.0 g) was taken up in 6 ml of acetic acid. To this stirred solution at room temperature was added 6M aqueous HCl (7 ml). This solution was then stirred at room temperature for 24 hours, during which time a white precipitate formed. The solution was filtered and the filtrate further concentrated to yield more of the same precipitate (5-chloro-2-(3-hydroxy-carbonylpropyl)-3-isothiazolone). The combined yield was 2.95 g (m.p. 158°-161° C.).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][S:39][CH3:40])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:40][S:39][CH2:38][C:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[O:37][N:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CSCc1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1 g; compound B50) is reacted with 5-(chloromethyl)-3-[(methylsulfanyl)methyl]-1,2,4-oxadiazole (410 mg; compound D11) in the presence of potassium carbonate (320 mg) in DMF (20 ml). The reaction mixture is stirred at 100° C. for 1 h. Ice cold water is added and the mixture is extracted with DCM 4 times. The combined organic layers are dried (sodium sulfate) and concentrated in vacuo. The residue is purified by flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 1/0 to 1/1 (v/v)] to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[Zn][C:10]1[O:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:14]=1>CCOC(C)=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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:10]1[O:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:14]=1
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1ccc([Zn]Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccccn2)o1
Temperature: 70 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 2-bromopyridine (1.4 mL, 15 mmol) and bromo[5-(ethoxycarbonyl)-2-furyl]zinc (0.5 M in THF, 30 mL) was degassed. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (0.9 g, 0.8 mmol). The reaction mixture was allowed to stir at 70° C. overnight and then to cool to rt. The mixture was diluted with EtOAc and washed with aq. Sat. NaHCO3. A precipitate formed and was filtered. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give ethyl 5-pyridin-2-yl-2-furoate (2.02 g, 62%). LCMS: (FA) ES+ 218.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=O.C(=O)(O)[O-].[Na+]>CCO>[CH3:7][C:4]1[S:3][C:2]2=[N:1][C:10]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[CH:9][N:6]2[CH:5]=1
Reactant: Cc1cnc(N)s1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cn2cc(-c3ccc([N+](=O)[O-])cc3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
A mixture of 2-amino-5-methylthiazole (0.24 g, 2.11 mmol) and 2-bromo-4′-nitroacetophenone (0.5 g, 2.05 mmol) in EtOH (20 ml) was heated under reflux for 16 h. The reaction mixture was allowed to cool and sodium bicarbonate (200 mg, 2.38 mmol) was added and heating was continued for 1 h. On cooling to room temperature, the solvent was removed under reduced pressure and the residue dissolved in DCM (75 ml) and washed with water (30 ml), brine (30 ml) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by flash chromatography (50:1 DCM/MeOH) to give the title compound (0.143 g, 26%) as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1.N1C=CC=CC=1>C(Cl)Cl>[C:4]([CH:3]([N:2]([CH3:1])[C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: O=C1CCC(=O)O1
Reactant: CNC(C#N)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)CCC(=O)O)C(C#N)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of the compound obtained in Step A (9 mmol), succinic anhydride (7.5 mmol) and pyridine (1 ml) in methylene chloride (30 ml) is stirred overnight. After conventional treatment, the title compound is obtained in pure form.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:7]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:7]=[C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)[CH:3]=[N:4][CH:5]=2)[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(Br)c2)c(F)c1
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: CCO
Solvent: COCCOC
Product: CSc1cccc(-c2cncc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1
Temperature: 88 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
5-(3-Bromo-pyridin-5-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 4 of Preparation 10, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (12.7 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (600.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 20.0 mg of the titled compound as a white liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:17]=[C:18]=S.[Cl:20][C:21]1[C:22]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:39])([F:38])[F:37])[CH2:31]2)=[CH:23][C:24]([NH:28][CH3:29])=[C:25]([CH:27]=1)[NH2:26].C(Cl)CCl>CC#N>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:17][C:18]1[N:28]([CH3:29])[C:24]2[CH:23]=[C:22]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:38])([F:39])[F:37])[CH2:31]3)[C:21]([Cl:20])=[CH:27][C:25]=2[N:26]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1N
Solvent: CC#N
Solvent: ClCCCl
Product: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (938 mg, 3.1 mmol) was added to 5-chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1-yl)aniline (920 mg, 3.0 mmol) in MeCN (20 mL). The mixture was stirred for 4 h at rt, then EDC (582 μL, 3.3 mmol) was added and it was stirred overnight. The reaction mixture was purified by chromatography to give the sub-title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=1)[CH3:9]>>[CH3:9][N:8]([CH2:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)[CH3:7]
Reactant: CCOC(=O)c1csc(CN(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)Cc1nc(CO)cs1
Temperature: 7.5 °C
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
To a mixture of lithium aluminum hydride (4.5 g, 119 mmol) in ice cold tetrahydrofuran (100 mL) was added ethyl 2-dimethylaminomethylthiazole-4-carboxylate (8.5 g, 39.7 mmol in 40 mL of tetrahydrofuran) dropwise over 40 min maintaining an internal temperature of 5-10° C. The mixture was stirred at this temperature range for 90 min. The reaction was carefully quenched with saturated aqueous ammonium chloride (30 mL). The resulting gray slurry was stirred 15 min and filtered through celite. The pad was well washed with ethyl acetate. The filtrate was washed with brine and dried over sodium sulfate. Concentration of this organic solution gave 4.2 g (62%) of 2-dimethylaminomethyl-4-hydroxymethylthiazole as an amber oil which had NMR δ 7.12 (s, 1H), 4.71 (s, 2H), 3.73 (s, 2H), 2.50 (br s, 1H), 2.32 (s, 6H). The material was used without further purification.