Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]#N)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:15][O:16][CH2:17][CH2:18][CH2:19][Mg]Br.BrCCC[O:26]C.[Mg].Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:13][C:19](=[O:26])[CH2:18][CH2:17][O:16][CH3:15])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCCC[Mg]Br
Reactant: COCCCBr
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: COCCC(=O)CC1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (15 g) in ether (50 ml) was added dropwise to a stirred solution of 3-methoxypropylmagnesium bromide [prepared in the usual manner from 1-bromo-3-methoxypropane (15.3 g) and magnesium (2.4 g)] in ether (55 ml), then the mixture was stirred at reflux temperature for 2.5 hours, cooled to ambient temperature, and added to a mixture of crushed ice (100 g) and concentrated hydrochloric acid (80 ml). The resulting mixture was heated at 95° C. with occasional stirring for 1.5 hours, then it was allowed to stand at ambient temperature for 48 hours. The product was extracted into ether (3×100 ml), and the combined extracts were washed with water (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml) and water (100 ml), dried (MgSO4), and the solvent was removed in vacua. The residue was distilled to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutanone as a pale yellow oil (16.4 g), b.p. 138-147° C./0.5 mbar.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>C(#N)C.C(OCC)(=O)C>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: O=Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cnc(N2CCOCC2)s1
Reaction time: 23.5 h
Yield: 66.4 %

Procedure:
2-Chlorothiazole-5-carbaldehyde (200 mg, 1.36 mmol) was dissolved in acetonitrile (4 mL). To this, potassium carbonate (376 mg, 2.72 mmol) and morpholine (0.237 mL, 2.72 mmol) were added at room temperature and the mixture was stirred at the same temperature for 23.5 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=15/1) to give 2-morpholinothiazole-5-carbaldehyde (179 mg, yield: 66%).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14]/[C:15](=[N:36]\O)/[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>O1CCOCC1.CN(C=O)C>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([NH:25][S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]3[N:36]=[C:11]([C:9]4[N:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][CH:8]=4)[O:13][N:14]=3)=[CH:21][CH:20]=2)(=[O:24])=[O:23])[CH:31]=[CH:30][CH:29]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc(/C(N)=N/O)cc2)c1
Reactant: CC(=O)Nc1cccc(C(=O)O)n1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc(-c3noc(-c4cccc(NC(C)=O)n4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1-Carbonyldiimidazole (9.78 g) dissolved in dioxane (100 ml) is added dropwise to 6-acetylaminopyridine-2-carboxylic acid (10.86 g) in a mixture of dioxane (100 ml) and DMF (60 ml) and the mixture is stirred at room temperature for 3 h. N-{3-[({4-[(Z)-Amino(hydroxyimino)methyl]phenyl}sulfonyl)amino]phenyl}acetamide is then added as a solid and the reaction mixture is stirred at room temperature for 16 h. Subsequently, the reaction mixture is stirred at 100° C. for 4 h and then poured onto ice/water. The product is left to stand for 10 min, collected by filtration, washed with water (three times) and dried in a vacuum oven. 25.55 g (90% of theory) of product are obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:16]/[C:15]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Reactant: O=CC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)cc1

Procedure:
A solution of 17 g (96 mmol) of (E)-4-(4-methoxyphenyl)but-3-en-2-one and 8.9 g (96 mmol) of glyoxylic acid monohydrate in 25 ml of glacial acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether/hexane yielded (E,E)-6-(4-methoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 138°-139°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28].O>ClCCl>[CH2:27]([O:26][C:25]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1)=[O:29])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Piperidinyl)-3,4-dihydrocarbostyril (500 mg) and triethylamine (0.6 ml) are dissolved in dichloromethane (10 ml) and thereto is added dropwise ethyl chlorocarbonate (0.31 ml) gradually. The mixture is stirred at room temperature for 2 hours and poured into water. The mixture is extracted with chloroform, dried with sodium carbonate and purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:1). The resultant is recrystallized from ethanol/n-hexane to give 1-(1-ethoxycarbonyl-4-piperidinyl)-3,4-dihydrocarbostyril (0.1 g) as white powder, m.p. 82°-83° C.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=4)[N:9]=[CH:8][C:7]=3[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Cl:27]N1C(=O)CCC1=O>CN(C)C=O>[Cl:27][C:6]1[C:7]2[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=3)=[CH:11][C:12]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(ccn3C3CC3)cn2)cc1
Solvent: CN(C)C=O
Product: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(cn2)c(Cl)cn3C2CC2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
In a 100 mL round bottom flask was added (R)—N-(1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (200 mg, 0.57 mmol) in N,N-dimethylformamide (2.8 mL) to give a light yellow solution. This was followed by addition of N-chlorosuccinimide (76 mg, 0.57 mmol) at room temperature and the mixture was heated to 60° C. After 4 h, another 0.1 eq of N-chlorosuccinimide was added and the mixture was heated for another hour. The mixture was directly loaded onto a silica gel column, eluting with 20-70% EtOAc in hexanes for purification. Product-containing fractions were combined and a pinkish solid was formed upon evaporation of solvents. The solid was collected and washed with 5 ml EtOAc to give the title compound (23, 71 mg, 32%) as a light pink product. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 2H) 1.10 (dd, J=7.07, 4.55 Hz, 2H) 1.43 (s, 3H) 3.42-3.54 (m, 3H) 4.72 (br. s., 1H) 5.00 (s, 1H) 7.56-7.62 (m, 3H) 8.02 (d, J=8.59 Hz, 2H) 8.52 (d, J=0.76 Hz, 1H) 8.56-8.60 (m, 1H) 10.64 (s, 1H); ESI-MS: m/z 386 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.Cl[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[Si:10]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1

Procedure:
A solution of 20 g 4-pyridylcarbinol, 28.9 g of chloro-tert-butyl-dimethylsilane and 14.4 g imidazole in 200 ml dimethylformamide is stirred 3 hours at room temperature. Product is isolated by extraction into ethyl acetate/hexane (1:1) and washing extract 4 times with 400 ml of water. The solution is filtered through silica gel and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxymethyl)pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:37]C)=[C:6]([C:8]([CH3:36])([CH3:35])[CH2:9][C:10]([C:31]([F:34])([F:33])[F:32])([OH:30])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:18]3)[CH:7]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:37])=[C:6]([C:8]([CH3:35])([CH3:36])[CH2:9][C:10]([C:31]([F:32])([F:34])[F:33])([OH:30])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(CN3CCOCC3)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CC(O)(CNc1cccc2nc(CN3CCOCC3)ccc12)C(F)(F)F)c1cc(F)ccc1O

Procedure:
Analogously to Example 38, 80 mg (0.15 mmol) of 4-(5-fluoro-2-methoxyphenyl)-1-(2-(morpholin-4-ylmethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol is mixed with 3.0 ml (3.0 mmol) of a 1 M boron tribromide solution in dichloromethane. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%) as well as ethyl acetate-methanol (0–20%), 53 mg (68% of theory) of the product is obtained.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C(N(CC)CC)C.ClC1([C:17]([OH:33])([CH2:26][N:27]2[C:31]([SH:32])=[N:30][CH:29]=[N:28]2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])CC1>ClCCl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH:17]([OH:33])[CH2:26][N:27]1[C:31]([S:32][C:2]([O:4][CH3:5])=[O:3])=[N:30][CH:29]=[N:28]1
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Sc1ncnn1CC(O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At temperatures between 0 and 5° C., first a solution of 1.28 ml (6 mmol) of methyl chloroformate in 10 ml of absolute dichloromethane and then 0.84 ml (6 mmol) of triethylamine are added dropwise with stirring to a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol and 10 ml of absolute dichloromethane. After the addition, the reaction mixture is stirred at room temperature for a further 2 hours and then diluted with dichloromethane and washed with ice-cold aqueous sodium carbonate solution. The organic phase is dried over sodium sulphate and subsequently concentrated under reduced pressure. The 1.7 g of crude product that remain are chromatographed over silica gel using a mixture of petroleum ether/ethyl acetate=1:1. Concentration of the eluate gives 0.7 g (35% of theory) of 2-(]-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-methoxycarbonylthio-1,2,4-triazol-1-yl)-propan-2-ol in the form of an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16](O)=[O:17].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[C:25]([O:24][C:22]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16](=[O:17])[NH:13][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][N:10]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1nccc(-c2ccccc2)n1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nccc(-c2ccccc2)n1

Procedure:
4-Phenyl-pyrimidin-2-ylamine (200 mg, 1 mmol), Boc-L-Pro-OH (327 mg, 1.3 mmol) and TFFH (Fluoro-N,N,N′-tetramethylformamidinium hexafluorophosphate; 463 mg, 1.3 mmol) were stirred as a solution in DCM (10 mL) containing triethyl amine (300 mL, 2 mmol). Purification by silica gel chromatography gave the title compound. m/z 369.1 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[CH3:2].[C:33]([O:40]CC)(=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35].[H-].[Na+].Cl.[NH2:46]O>C1(C)C=CC=CC=1.C(O)C.C(O)(=O)C>[CH2:37]([O:36][C:34]([C:33]1[O:40][N:46]=[C:1]([C:4]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)=[CH:22][C:5]=2[O:6][CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1)=[O:35])[CH3:38]
Reactant: NO
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)=O)c1ccccc1C
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1-c1cc(C(=O)OCC)on1)c1ccccc1C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
A solution of ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (2.91 g) and diethyl oxalate (2.82 g) in dry toluene are stirred at room temperature whilst adding sodium hydride (0.28 g, 60% dispersion in mineral oil) portionwise. The reaction mixture is heated at reflux for 5 hours then left at room temperature for 18 hours. Evaporation gives an orange oil which is dissolved in ethanol (100 mL) and treated with glacial acetic acid (1.5 mL). Hydroxylamine hydrochloride (0.49 g) is added and the mixture heated at reflux for 5 hours. The reaction mixture is partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase is extracted with three times ethyl acetate (50 mL). The combined organic phases are washed with brine (50 mL), with water (50 mL), dried over magnesium sulphate and evaporated. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give ethyl (RS)-4-[2-(5-ethoxycarbonylisoxazol-3-yl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (2.56 g) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[C:14]#[N:15].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:7]1[C:2]([Cl:1])=[C:3]([C:14]#[N:15])[C:4](=[O:13])[N:5]([CH:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)C(C)n1ccc(Cl)c(C#N)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(C)n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 93.7 %

Procedure:
To a solution of 4-chloro-1-(3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (305 mg) in N,N-dimethylformamide (3.0 mL) was added N-bromosuccinimide (296 mg) at room temperature. The reaction mixture was heated at 50° C. for 4 hr, and cooled to room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (386 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:25][CH2:24][C@H:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22]2)[CH3:10])[C:5]([C:35]#[N:36])=[C:4]([CH3:37])[N:3]=1.C(O)(C(F)(F)F)=O.[Cl:45]CCl>>[ClH:45].[NH2:1][C:2]1[N:3]=[C:4]([CH3:37])[C:5]([C:35]#[N:36])=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][CH3:27])[CH2:22]2)[CH3:10])[N:7]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CC[C@H](N(C)C(=O)OC(C)(C)C)C2)c1C#N
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CCN(c2cc3c(ccn3C)nc2[C@H](C)Nc2nc(N)nc(C)c2C#N)C1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a 25 mL pear flask was added tert-butyl ((S)-1-(5-((S)-1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidin-3-yl)(methyl)carbamate (61 mg, 0.121 mmol) in dichloromethane (0.8 mL) to give a solution. To this solution was added TFA (0.27 mL), and the mixture was stirred at room temperature for 18 hours. All the volatiles were removed in vacuo, and the residue was re-suspended in toluene and concentrated to remove residual TFA. The residue was then diluted in ACN and water (total of about 90 mL), followed by the addition of 2 N HCl (4 mL). The mixture was then lyophilized to give an HCl salt of the title compound as a yellow-green solid (41 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66 (d, J=6.82 Hz, 2H), 2.17 (td, J=12.69, 7.20 Hz, 1H), 2.31-2.45 (m, 3H), 2.61 (s, 2H), 3.20-3.39 (m, 2H), 3.46 (br s, 1H), 3.57 (br s, 1H), 3.95 (s, 3H), 5.91 (t, J=6.95 Hz, 1H), 6.79 (br s, 1H), 7.68 (br s, 1H), 8.03 (br s, 1H), 8.48 (br s, 1H), 8.77 (br s, 1H), 9.32-9.50 (m, 1H), 9.60-9.82 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C21H27N9, 406. found 406.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=1.[C:23](OCC)(=O)C>CN(C=O)C>[F:20][C:19]([F:22])([F:21])[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:23])=[O:7])[N:3]=[CH:2]2)[CH:18]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: COC(=O)c1c[nH]cn1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(C(F)(F)F)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 1H-imidazole-4-carboxylate (417 mg, 3.3 mmol) in DMF (10 mL) was added sodium hydride (130 mg, 3.3 mmol). After being stir for 1 h at room temperature, 2-chloro-4-(trifluoromethyl)pyridine (500 mg, 2.8 mmol) was added. The mixture was stirred at 80° C. overnight. After being cooled to room temperature, ethyl acetate was added. The solution was washed with brine several times, dried (MgSO4) and concentrated. Chromatography on silica gel eluting with EtOAc/hexanes (1:1) afforded the title compound (120 mg). MS (M+H) 272.1.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:21][C:6]2[NH:7][C:8]([C:10]3[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=3)[C:15](O)=[O:16])=[N:9][C:5]=2[CH2:4]1.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][CH:3]1[CH2:4][C:5]2[NH:9][C:8]([C:10]3[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=3)[C:15]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:16])=[N:7][C:6]=2[CH2:21]1
Reactant: COC1Cc2nc(-c3cc(C(=O)O)c(C)cc3C)[nH]c2C1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1Cc2nc(-c3cc(C(=O)N4CCC(c5ccc(C#N)cc5)CC4)c(C)cc3C)[nH]c2C1
Reaction time: 8 h
Yield: 11.5 %

Procedure:
Into around-bottom flask, was placed a solution of 5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoic acid (compound 461.7, 60 mg, 0.17 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 46 mg, 0.20 mmol, 1.00 equiv), 4-dimethylaminopyridine (52 mg, 0.43 mmol, 2.00 equiv), and EDC.HCl (80 mg, 0.42 mmol, 2.00 equiv) were added and the mixture was stiffed overnight at room temperature. The resulting solution was diluted with ethyl acetate (30 mL) and washed with brine (3×10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue (40 mg) was purified by preparative-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (15.0% CH3CN up to 55.0% in 7 min, up to 100.0% in 1 min, down to 15.0% in 1 min); Detector, Waters 2489 254 & 220 nm. The fractions containing pure product were combined and lyophilized to obtain the title compound as a white solid (8.9 mg, 11%). m/z (ES+) 455 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[S:5][CH:6]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[C:25](O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[CH3:1][C:2]1[N:3]=[C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][CH2:12][NH:8]2)[S:5][CH:6]=1.[CH3:11][C:7]1[N:8]=[C:25]([C@H:20]2[CH2:21][CH2:22][CH2:23][CH2:24][N:19]2[C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[S:5][CH:4]=1
Reactant: Cc1csc([C@H]2CCCN2)n1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Product: Cc1csc([C@H]2CCCCN2)n1
Product: Cc1csc([C@H]2CCCCN2C(=O)OC(C)(C)C)n1

Procedure:
(R)-4-methyl-2-(piperidin-2-yl)thiazole was prepared following the same procedure as in the preparation of (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole starting from the commercially available (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Aldrich) to obtain (R)-tert-butyl 2-(4-methylthiazol-2-yl)piperidine-1-carboxylate which was deprotected using standard TFA conditions to obtain the desired product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1>C(Cl)(Cl)Cl.O1CCCC1.[O-2].[O-2].[Mn+4]>[O:12]=[C:9]1[NH:8][C:7]2[CH:13]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=2[S:11][CH2:10]1
Reactant: O=C1CSc2ccc(CO)cc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Yield: 72.2 %

Procedure:
A stirred solution of the alcohol (b) (3.5 g) in chloroform (150 ml) and tetrahydrofuran (300 ml) was treated with manganese dioxide (7.8 g) for 18 hours and was filtered and evaporated to give a white solid (2.5 g).
Reaction SMILES: [NH3:1].[F:2][C:3]([F:13])([F:12])[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.C(O)CCC>CO.[Pd]>[F:2][C:3]([F:13])([F:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:1])[CH2:7][CH2:6]1
Reactant: O=C1CCN(CC(F)(F)F)CC1
Reactant: N
Agent: [Pd]
Solvent: CO
Solvent: CCCCO
Product: NC1CCN(CC(F)(F)F)CC1
Reaction time: 18 h

Procedure:
A 25% aqueous solution of ammonia (170 mL), 10% Pd/C (7.4 g), and a solution of the above 1-(2,2,2-trifluoroethyl)piperidin-4-one/butanol mixture (72.5 g, 0.344 mol, 86:14 weight ratio) in methanol (420 mL) were placed into a 2 L glass autoclave purged with argon. The reaction mixture was hydrogenated in a Parr apparatus at a hydrogen pressure of 40 psi for 18 h. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to 150 mL. Potash (46 g) and ether (200 mL) were added, and the mixture was vigorously stirred for 20 min. The organic layer was separated, and the aqueous one was extracted with ether (100 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to afford a mixture (74.4 g) of 1-(2,2,2-trifluoroethyl)piperidin-4-amine and 1-(2,2,2-trifluoroethyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]piperidin-4-amine in 72:28 weight ratio (containing butanol). This mixture was fractionated at 7-8 mmHg on a 15 cm Vigreaux column (a fraction with bp 75-95° C. was collected) to afford 1-(2,2,2-trifluoroethyl)piperidin-4-amine (38.5 g) as a colorless liquid.