Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C@@:10]([CH2:14][OH:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH2:33][C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([CH2:14][O:15][CH2:33][C:34]3[CH:35]=[C:36]([C:44]([F:46])([F:47])[F:45])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=3)([CH2:11]2)[CH:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2C[C@@]2(CO)[C@@H]1c1ccccc1
Reactant: FC(F)(F)c1cc(CI)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC2(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
To Intermediate 19, one enantiomer being (1S,2S)-1-hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.40 g, 1.4 mmol) in THF (10 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5M/toluene, 4.1 mL, 2.1 mmol) dropwise and the mixture was stirred for an additional 5 minutes. 1-Iodomethyl-3,5-bis-trifluoromethyl-benzene (0.69 g, 1.9 mmol) in THF (4 mL) was added and the reaction stirred at −78° C. for 10 minutes, then allowed to warm to room temperature and stirred for 2 hours. Water was added cautiously and the solvent removed at reduced pressure. The residue was partitioned between H2O and EtOAc, the organics were washed with brine and dried over calcium sulfate, filtered and concentrated to an oil. The crude product was purified by flash chromatography by elution with a gradient of hexanes to 20% EtOAc/Hexanes to give the title compound (0.52 g, 73% yield).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])=O)(C)(C)C.[ClH:27]>CCOCC.O>[ClH:27].[F:23][C:20]([F:21])([F:22])[O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:24])[N:11]1[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OC(F)(F)F)cccc3[C@@H]2C1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=C1c2c(OC(F)(F)F)cccc2[C@@H]2CNCCN12
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one (181 mg, 0.5 mmol) in dry ether (5 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 147 mg of a white solid. MS (ESI) 309 (M−Cl).
Reaction SMILES: CON(C)[C:4]([C@@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH3:8])=[O:5].[C:18](=O)=O.CC(C)=O.C[Li].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[C:4](=[O:5])[CH3:18])[CH3:8]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(C)=O
Reaction time: 4 h

Procedure:
A solution of tert-butyl {(1S)-1-[methoxy(methyl)carbamoyl]propyl}carbamate (15.0 g) in tetrahydrofuran (150 mL) was cooled using dry ice/acetone under a nitrogen atmosphere, and 1.0 mol/L-methyllithium/diethyl ether solution (300 mL) was added. The mixture was stirred at the same temperature for 4 hr, saturated aqueous ammonium chloride solution (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentration under reduced pressure to give the title compound as a colorless oil (yield: 12.75 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([CH:22]=[CH2:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]>CCO.C1COCC1.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([CH2:22][CH3:23])[CH:21]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: C=Cc1cc(OC)cc(C(Nc2ccc(C#N)cc2)C(=O)OCC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(OC)c1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Pd-C (10%, 236 mg, 0.22 mmol) was added a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-methoxy-5-vinyl-phenyl)-acetate (1.495 g, 4.44 mmol) obtained in Example 198.3 in EtOH (40 ml) and THF (4 ml) and the mixture was hydrogenated for 1 h. at room temperature. The reaction mixture was filtered, the filtrate was concentrated and the residue was purified by filtration over SiO2 (eluent: AcOEt/hexane 1:1). There were obtained 1.5 g (99%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-methoxy-phenyl)-acetate as a beige solid; MS: 338 ([M]+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:6][N:5]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(Cl)cc2)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Product: CC(=O)N1CCC(Nc2ncc(C(=O)c3ccc(Cl)cc3)c(N)n2)CC1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-chloro-phenyl)-methanone (Example 362) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(4-chloro-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 374.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][NH2:11])=[CH:6][CH:5]=1)=[O:3].[O:14]1[CH:16]([CH2:17][O:18][C:19]2[S:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH3:32])=[O:25])=[CH:22][N:23]=2)[CH2:15]1>C(O)C>[NH2:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][NH:11][CH2:15][CH:16]([OH:14])[CH2:17][O:18][C:19]2[S:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH3:32])=[O:25])=[CH:22][N:23]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CCC(C)CCCNC(=O)c1cnc(OCC2CO2)s1
Reactant: NCCOc1ccc(C(N)=O)cc1
Solvent: CCO
Product: CCC(C)CCCNC(=O)c1cnc(OCC(O)CNCCOc2ccc(C(N)=O)cc2)s1

Procedure:
This example illustrates further methods according to the invention of preparing further compounds of formula I of the invention. In this example 1 g. of β-(4-aminocarbonylphenoxy)-ethylamine (Cox et al, J. Med. Chem., v. 16, No. 11 (1973)) is added to a solution containing 0.4 g. of 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20° C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of the 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue which is then further purified by thin-layer chromatography on silica gel yielding 1-[β-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[S:4][N:3]=1.[Li+].C[Si]([N-:26][Si](C)(C)C)(C)C>C1COCC1.O.[NH4+].[Cl-].CCOC(C)=O>[NH2:26][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[S:4][N:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nc(Br)ns2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(N)ns2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(3-bromo-1,2,4-thiadiazol-5-yl)phenylcarbamate (3.22 g, 9.04 mmol) in THF (35 mL) at 0° C. was added LiHMDS (1 M in PhMe, 23 mL, 23.0 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. Water (20 mL) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water, saturated NH4Cl, and EtOAc. The aqueous phase was extracted with EtOAc (2×), and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. The concentrate was dissolved in 10% MeOH in DCM (200 mL), filtered through a pad of silica (2 cm), and diluted with hexanes (150 mL). The precipitate that formed was collected by filtration, washed with hexanes, and dried under high vacuum to give tert-butyl 4-(3-amino-1,2,4-thiadiazol-5-yl)phenylcarbamate.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[N:11]=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:22][C:13]1[N:12]=[N:11][C:10]([O:1][CH2:2][C:3]2([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]2)=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=1
Reactant: OCC1(CO)CCC1
Reactant: Cc1cc(-c2ccccc2)c(Cl)nn1
Product: Cc1cc(-c2ccccc2)c(OCC2(CO)CCC2)nn1

Procedure:
The title compound was prepared using the same experimental procedure as in example 25a from [1-(hydroxymethyl)cyclobutyl]methanol and 3-chloro-6-methyl-4-phenylpyridazine. 1H NMR (300 MHz, CDCl3) δ 7.58-7.25 (m, 6H), 4.64 (s, 2H), 3.59 (d, J=6 Hz, 2H), 3.05 (t, J=7 Hz, 1H), 2.63 (s, 3H), 2.00-1.73 (m, 6H). GC-MS m/z 285 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:10]2([CH3:21])[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[O:13][C:12]([NH2:20])=[N:11]2)[C:5]([O:8]C)=[N:6][CH:7]=1.Cl.O1CCOCC1>O>[NH2:1][C:2]1[CH:3]=[C:4]([C@:10]2([CH3:21])[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[O:13][C:12]([NH2:20])=[N:11]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(N)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(N)c[nH]c2=O)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 100 °C

Procedure:
(4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (14b, 0.650 g, 2.224 mmol, as described in Example 146, method U, Step 2), hydrogen chloride, 4.0 N solution in 1,4-dioxane (1.0 mL, 28.8 mmol) and water 0.5 mL were combined in a microwave tube. The vials was sealed and heated at 100° C. for 3 h. The mixture was concentrated to dryness and carried to the next step without purification. MS m/z=291.0 [M+H]+. Calculated for C11H13F3N4O2: 290.2
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:16]=[CH:15][C:10]2[S:11][CH:12]=[C:13]([CH3:14])[C:9]=2[CH:8]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CCCCCC.C(OCC)C>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]2[S:11][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([CH3:14])[C:9]=2[CH:8]=1
Reactant: Cc1csc2ccc(Cl)cc12
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1sc2ccc(Cl)cc2c1C
Temperature: 0 °C
Yield: 65.4 %

Procedure:
n-Butyllithium in hexane (2.6 M, 2.3 ml) was added to a solution of 5-chloro-3-methylbenzo(b)thiophene (1,0 g, 6 mmol) in ethyl ether (20 ml) stirred at 0° C. under argon. The mixture was stirred for 30 minutes and transferred slowly under argon pressure to a stirred solution of ethyl chloroformate (0.63 g, 6 mmol) in ethyl ether (20 ml). The mixture was stirred at 0° C. for 30 minutes and at 25° C. for 1.5 hours. The mixture was treated with water and the organic phase was dried, concentrated and triturated with hexane to give 1.0 g (67%) of ethyl 5-chloro-3-methylbenzo(b)thiophene-2-carboxylate: mp 92.5-94° C.
Reaction SMILES: C([B:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])C(C)C.C(O)(=O)C(C)(C)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)C>>[NH:21]([B:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: CC(C)CB(CC(C)C)CC(C)C
Agent: CC(C)(C)C(=O)O
Agent: CC(C)C
Product: CC(C)CB(CC(C)C)Nc1ccccc1
Reaction time: 3 h

Procedure:
A mixture is prepared from 18.4 g. (0.1 moles) of triisobutylborane and 0.5 g. pivalic acid and heated to 70° C. Within 3 hours, 9.4 g. (0.1 moles) of aniline are added dropwise and then heating is continued for 2.5 hours to a maximum of 80° C. 1890 Nl (84.4 Mmoles) of isobutane are evolved. After having collected a small amount of first runnings of b.p. up to 28° C./0.1 mm. Hg, 18.4 g. (84.8%) of colorlos anilinodi-isobutyl borane of b.p. 49°-51° C./0.1 mm. Hg and 1.1 g. of residue are obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1ccc2cc[nH]c2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-3-fluoro-1-nitrobenzene (13 g) in anhydrous THF (80 mL) was added 1 M vinylmagnesium bromide in THF (178 mL) dropwise at −78° C. slowly. Then the mixture was allowed to warm to RT and stirred for 2 hours. TLC indicated the reaction was complete. The reaction mixture was poured into saturated NH4Cl solution, the organic phase was separated by extraction with EtOAc (3×200 mL). Purification by column chromatography afforded of 7-bromo-6-fluoro-1H-indole (D140) (3 g) as a brown oil.
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12]COC)[C:6]=2[CH2:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:3]1.C[Si]([C:26]#[N:27])(C)C.B(F)(F)F.CCOCC.O>C(Cl)Cl>[C:26]([CH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=2[CH2:5][CH:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:3]1)#[N:27]
Reactant: COCOc1cccc2c1CC(c1ccccc1)OC2O
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: N#CC1OC(c2ccccc2)Cc2c(O)cccc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of 9.07 g (31.7 mmol) of 3,4-dihydro -1-hydroxy-5-methoxymethoxy-3-phenyl-1H-2-benzopyran, from Step 2 above, in 150 mL of methylene chloride at -78° C. was treated, sequentially, with trimethylsilyl cyanide (8.5 mL, 64 mmol) and boron trifluoride etherate (6 mL, 49 mmol). After being stirred for 1.5 h at -78° C., and for 4 h at ambient temperature, 100 mL of water was added and stirring was continued for 1 h. The reaction mixture was then extracted with 2×300 mL of ethyl acetate and the combined organic extract was washed with 200 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with 10% ethyl acetate in hexane to give 7.33 g (92% yield) of the title compound as a 4:1 mixture of the trans and cis isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH2:22]O)=[C:12]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:35])(=O)=O>ClCCl>[Cl:35][CH2:22][C:11]1[O:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:13][C:12]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: COc1ccc(-c2nc(COC3CCCCO3)c(CO)o2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc(COC3CCCCO3)c(CCl)o2)cc1
Temperature: 25 °C

Procedure:
2.0 g [2-(4-Methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-5-yl]-methanol were dissolved in 30 ml dichloromethane and cooled in an ice bath. 0.88 ml triethylamine were added, followed by the addition of 0.49 ml methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 2.5 g of 5-chloromethyl-2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole as an oil which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9](OCC)=[O:10])[N:4]=[CH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:4]=[CH:3]1
Reactant: CCOC(=O)CCc1cn(C)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc(CCCO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To an ice-cooled solution of ethyl 3-(1-methyl-1H-imidazol-4-yl)propionate (2.63 g) in tetrahydrofuran (26 ml) was added lithium aluminum hydride (0.55 g) by small-portions under nitrogen atmosphere. After the mixture was stirred for 0.5 hour, water and 15% aqueous sodium hydroxide solution were added successively to the mixture. The resulting precipitates were filtrated off through Celite pad and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using dichloromethane-methanol (100:1) as eluent to give 3-(1-methyl-1H-imidazol-4-yl)-1-propanol (940 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:25])[C:23]=1F)[C:19]#[N:20]>CN(C)C=O>[CH3:7][N:8]1[C:12]([O:13][C:23]2[C:16]([F:15])=[CH:17][C:18]([C:19]#[N:20])=[CH:21][C:22]=2[F:25])=[CH:11][C:10]([CH3:14])=[N:9]1
Reactant: CC1=NN(C)C(=O)C1
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c(F)cc(C#N)cc2F)n(C)n1
Temperature: 75 °C
Yield: 92.3 %

Procedure:
Potassium carbonate (1.38 g, 10 mmol) was added to a solution of 2,4-dihydro-2,5-dimethyl-3H-pyrazol-3-one (0.70 g, 6.3 mmol) in N,N-dimethylformamide (15 mL). 3,4,5-Trifluorobenzonitrile (0.94 g, 6.0 mmol) was added, and the reaction mixture was heated at 75° C. under a nitrogen atmosphere for 16 h, then allowed to cool. The reaction mixture was partitioned between water (60 mL) and ethyl acetate (30 mL). The organic phase was washed with water (2×30 mL) and brine (30 mL), dried over MgSO4, and concentrated to give the title compound as a yellow oil (1.38 g).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:11][CH2:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1cnccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1cnccn1
Reaction time: 1 h
Yield: 223.9 %

Procedure:
To a solution of 2-(2′-hydroxyethyl)pyrazine (0.91 g) in 30 mL dichloromethane at 0° C. was added carbon tetrabromide (2.65 g) followed by triphenylphosphine (2.1 g) portionwise. The solution became very dark. After stirring for 1 h the reaction mixture was adsorbed onto HMN diatomaceous earth and purified by silica gel chromatography eluting with 0-5% MeOH/dichloromethane to give a cream solid (3.07 g) that was purified further by silica gel chromatography eluting with 0-50% EtOAc/pentane to give the sub-titled compound (0.47 g, 34%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]([C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: COC(=O)C1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2nccnc2Cl)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dichloropyrazine (1.45 g, 9.73 mmol) and methyl tetrahydro-2H-pyran-4-carboxylate (2.60 mL, 19.47 mmol) in Toluene (19.47 mL) at room temperature was added LiHMDS (19.47 mL, 19.47 mmol, 1M solution) dropwise. After overnight room temperature stirring, reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. Purification by Biotage (0-10% MeOH/DCM) produced product.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([C:20]([O:22]C)=O)[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH:24]1([N:30]2[CH2:2][CH2:3][C:4]3([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:11])[CH2:8][CH2:9]3)[C:20]2=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)C1(CCCl)CCN(C(=O)OCc2ccccc2)CC1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CCN(C1CCCCC1)C2=O
Temperature: 120 °C
Yield: 48.6 %

Procedure:
A mixture of 1-benzyl 4-methyl 4-(2-chloroethyl)piperidine-1,4-dicarboxylate (0.5 g, 0.001 mol), cyclohexanamine (0.18 mL, 0.0016 mol), sodium iodide (0.22 g, 0.0015 mol) and potassium carbonate (0.61 g, 0.0044 mol) in DMF (5.0 mL) was stirred and heated at 120° C. for overnight. Then the reaction mixture was diluted with brine, and extracted with ethyl acetate (3X). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by combiflash (ethyl acetate in hexanes: 40%) to give 180 mg of benzyl 2-cyclohexyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]2[N:21]=[CH:22][CH:23]=[C:4]2[N:3]=1.[CH:24]([O:27][C:28]1[CH:34]=[C:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:32]([CH3:41])=[CH:31][C:29]=1[NH2:30])([CH3:26])[CH3:25].Cl>C(O)(C)C.O1CCOCC1>[CH:24]([O:27][C:28]1[CH:34]=[C:33]([CH:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]2)[C:32]([CH3:41])=[CH:31][C:29]=1[NH:30][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]2[N:21]=[CH:22][CH:23]=[C:4]2[N:3]=1)([CH3:26])[CH3:25]
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCNCC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)nc2ccnn12
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccccc3S(=O)(=O)C(C)C)n3nccc3n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-N-(2-(isopropylsulfonyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.1 mmol) and 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (0.1 mmol) in 2 mL of isopropanol, was added 25 uL of HCl in dioxane (2 N). The suspension was stirred at 150° C. for 3 hours. After work-up and prep-HPLC, product was obtained. 1H NMR (CDCl3, 400 MHz) δ 7.88-7.95 (m, 3H), 7.73-7.75 (d, 1H), 7.61-7.64 (m, 1H), 7.23-7.26 (m, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 6.17-6.18 (d, 1H), 6.09 (s, 1H), 4.46-4.54 (m. 1H), 3.30-3.34 (m, 2H), 3.12-3.21 (m, 1H), 2.79-2.83 (m, 3H), 2.27 (s, 3H), 1.77-1.79 (m, 4H), 1.15-1.28 (m, 12H); MS (ES+): 563.28 (M+1)+.