Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21]([CH3:29])=[CH:20][N:19]=2)[CH2:14][C@H:13]1[O:30][CH3:31])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21]([CH3:29])=[CH:20][N:19]=2)[CH2:14][C@H:13]1[O:30][CH3:31]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ncc1C
Agent: [Pd]
Product: CCOC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ncc1C
Yield: 18.5 %

Procedure:
The same operation as in Example (160c) was performed using ethyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-methylpyridine-4-carboxylate obtained in Example (180a) (207 mg, 0.48 mmol) and a 10% palladium-carbon catalyst (200 mg), to obtain 26.1 mg of the title compound as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.CO.C(Cl)Cl>CN(C)C=O.CCOC(C)=O>[CH3:14][O:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([NH:1][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: ClCCN1CCSCC1
Reactant: COCOc1ccc2c(N)noc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: COCOc1ccc2c(NCCN3CCSCC3)noc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 3-amino-6-methoxymethoxy-1,2-benzisoxazole (4.0 g) in N,N-dimethylformamide (DMF) (50 ml) was added sodium hydride (0.74 g) under nitrogen. The reaction was stirred one hour at ambient temperature. A solution of 4-(2-chloroethyl)thiomorpholine (3.6 g) in DMF (25 ml) was added to the reaction and heated to 125° C. for three hours. TLC (5% MeOH/CH2Cl2) revealed the absence of starting material. The reaction was diluted with EtOAc (1 l), washed with brine (4×500 ml), dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 5% acetone/CH2Cl2 afforded the the product (2.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24](C#N)[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:30][C:31]([F:58])([F:57])[O:32]C1C=C(C2N=C(OS(C(F)(F)F)(=O)=O)C=C3C=2N=CC=C3)C=CC=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:32][C:31]([F:58])([F:57])[F:30])[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Reactant: O=S(=O)(Oc1cc2cccnc2c(-c2cccc(OC(F)(F)F)c2)n1)C(F)(F)F
Product: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(OC(F)(F)F)c3)n2)CC1

Procedure:
This compound is prepared in an analogous way to compound 4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester from trifluoromethanesulfonic acid 8-(3-trifluromethoxyphenyl)-[1,7]naphthyridin-6-yl ester. Purification is by chromatography followed by trituration with ether to yield a white solid. MS (AP+) 445
Reaction SMILES: [O:1]([C@H:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:10][C@@H:11]([OH:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH2:35](Br)[C:36]#[CH:37]>>[O:1]([C@H:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:10][C@@H:11]([OH:17])[C@@H:12]([CH2:37][C:36]#[CH:35])[C:13]([O:15][CH3:16])=[O:14])[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3]
Reactant: C#CCBr
Reactant: CCCCCCCCCCCCCCCCC[C@H](C[C@@H](O)CC(=O)OC)O[Si](C)(C)C(C)(C)C
Product: C#CC[C@@H](C(=O)OC)[C@H](O)C[C@@H](CCCCCCCCCCCCCCCCC)O[Si](C)(C)C(C)(C)C

Procedure:
Analogously to Examples Cb) and c), methyl (3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxydocosanoate (Example Ib) was reacted with propargyl bromide to give methyl (2R,3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2-(2-propynyl)docosanoate, IR (cm-1): 3310, 2120, 1740, 1255, the latter was saponified to give (2R,3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2-(2-propinyl)-docosanoic acid, IR (cm-1): 3315, 2120, 1715, 1255, and this acid was cyclized to give (3R,4R)-4-[(R)-2-(t-butyldimethylsiloxy)nonadecyl]-3-(2-propynyl)-2-oxetanone, IR (cm-1): 3315, 2130, 1830, 1255.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]([NH:32][OH:33])=[NH:31])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34].N1C=CC=CC=1.Cl[C:42](OCC(CC)CCCC)=[O:43]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[NH:31][C:42](=[O:43])[O:33][N:32]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34]
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: Cc1cc(F)ccc1-c1nc(NCCC(=N)NO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(F)ccc1-c1nc(NCCc2noc(=O)[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
Under Ar, to a soln of the product of Example 242, 3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-N-hydroxy-propionamidine (100 mg, 0.20 mmol), and pyridine (0.048 mL, 0.6 mmol), was added 2-ethylhexyl chloroformate (0.039 mL, 0.2 mmol). The mixture was stirred at room temperature for 2 h, then diluted with H2O and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was diluted with xylene (10 mL) and heated to reflux for 18 h to give the crude material, which was purified by preparative hplc to give the desired product 28 mg (28%). LC-MS: 495.0 (MH+, m/z), 1.96 (Rt, min).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11]>C(O)(=O)C.CN(C)C=O>[Cl:4][C:14]1[CH:13]=[C:9]([CH:8]=[C:7]([F:6])[C:15]=1[OH:16])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (4.7 mL) is added to a solution of 3-fluoro-4-hydroxy-benzoic acid (2.97 g) in acetic acid (20 mL) stirred at 50° C. in N,N-dimethylformamide (3 mL) at room temperature. The resulting solution is stirred for 2 h, prior to the addition of another portion of sulfuryl chloride (1.0 mL). The solution is stirred at 60° C. for another 1.5 h and then cooled to ambient temperature. The solution is poured into ice-cold water and the precipitate formed is separated by filtration, washed with ice-cold water, and dried at 50° C. to afford the title compound as a beige solid.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:24](O)(=[O:27])[CH2:25][CH3:26].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:24](=[O:27])[CH2:25][CH3:26])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4N)ccc21
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Temperature: 25 °C
Yield: 101.8 %

Procedure:
To a stirred brown solution of (rac)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (intermediate A-2) (92.2 mg, 0.30 mmol) and propionic acid (24.4 mg, 0.33 mmol) in CH2Cl2 (1.5 mL) at 0° C. under Argon was added EDCI (63.3 mg, 0.33 mmol). Stirring was continued over night and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was poured into aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and with aq. sat. NaCl solution; the combined organic phases were dried over Na2SO4, filtered and evaporated to afford the title compound (111 mg, quantitative) as light yellow foam. MS: 364.2 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[N:35]O)[NH2:34])=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:35]=[C:33]([C:30]4[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=4)[N:34]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(Cl)cc4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 4-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 61 mg (64% of theory)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1cc2nc(-c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)cn2cc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc(OCCO)cc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
571 mg (corresponding to 1.24 mmol) of 6-bromo-2-[4′-(2″-t-butyldimethylsiloxyethoxy)phenyl]-7-methylimidazo[1,2-a]pyridine was dissolved in 3.0 mL of tetrahydrofuran, and 1.24 mL of a 1.0 mol/L solution in tetrahydrofuran of tetrabutylammoniumfluoride was added thereto. After the reaction mixture was stirred at room temperature for 20 minutes, an aqueous ammonium chloride solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was washed with water and ethyl acetate, to obtain 320 mg (corresponding to 0.922 mmol) of 6-bromo-2-[4′-(2″-hydroxyethoxy)phenyl]-7-methylimidazo[1,2-a]pyridine (FIG. 9, Step 5).
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:6]1(=[O:7])[NH:2][C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 198.7 %

Procedure:
(S)-3-Hydroxypiperidine hydrochloride was dissolved in distilled water (2.5 ml), sodium hydrogencarbonate (889 mg) was added to the solution, a solution (2.5 ml) of 4-nitrobenzyl chloroformate (836 mg) in acetone was slowly was added to the mixture at room temperature, and the resulting mixture was stirred for 2 hours. Ethyl acetate and distilled water were added to the reaction mixture, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=1:2) to obtain a protected compound (971 mg). (2) The compound obtained in (1) mentioned above (971 mg) was dissolved in tetrahydrofuran, N-hydroxyphthalimide (848 mg) and triphenylphosphine (1.36 g) were added to the solution. Diisopropyl azodicarboxylate (1.02 ml) was added to the reaction mixture under ice cooling, and then the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=1:2) to obtain a phthalimide compound (1.52 g). (3) The compound obtained in (2) mentioned above (1.52 g) was dissolved in ethanol (10 ml) and chloroform (10 ml), hydrazine monohydrate (638 μl) was added to the solution under reflux by heating, and the resulting mixture was stirred for 1.5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=1:2), then a 4 mol/L solution of hydrochloric acid in dioxane (866 μl) was added to the purified residue, and the resulting mixture was concentrated under reduced pressure to obtain the title compound (825 mg).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][CH2:22][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:29]([NH:33][C:17]([C:14]1[CH:15]=[C:16]2[C:11]3=[C:12]([CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][CH2:22][N:10]3[CH2:9][CH2:8][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1)=[O:19])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN
Reactant: O=C(O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCNC(=O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxylic acid (14), (189 mg, 0.512 mmol) in dicloromethane (10 mL) were added butyl amine (0.027 mL, 0.512 mmol), EDCI (196 mg, 1.02 mmol), followed DMAP (4-(Dimethylamino)pyridine) (70 mg, 1.02 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The reaction was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 25 to 30% EtOAc:Hexane to give N-butyl-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxamide (481), (113 mg 52%). 1H NMR (300 MHz, CDCl3) ppm 1H NMR (300 MHz, Solvent) ppm 0.87 (t, J=6.0 Hz, 3H) 1.17-1.38 (m, 2H) 1.36-1.52 (m, 2H) 2.03-2.17 (m, 2H) 2.18-2.36 (m, 2H) 3.06-3.37 (m, 6H) 4.21 (t, J=5.27 Hz, 2H) 5.61-5.75 (m, 1H) 7.03-7.16 (m, 4H) 7.17-7.37 (m, 8H).
Reaction SMILES: Cl[CH:2]([CH3:5])[CH:3]=[CH2:4].[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])(=[O:8])[CH3:7]>>[CH3:5][CH:2]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6](=[O:8])[CH3:7])[CH:3]=[CH2:4]
Reactant: CC(=O)Nc1ccccc1O
Reactant: C=CC(C)Cl
Product: C=CC(C)Oc1ccccc1NC(C)=O
Yield: 40.2 %

Procedure:
The compound (557 mg, 40%) was prepared from 3-chloro-1-butene (747 ml, 7.42 mmol) and 2-acetamidophenol (1.02 g, 6.75 mmol) analogously to that described in Example 8 i).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].CN(CCN(C)C)C.CN([CH:30]=[O:31])C>C1COCC1>[OH:18][CH:11]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:30](=[O:31])[N:10]1[C:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(NC(=O)c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2ccccc2C1O
Yield: 96.7 %

Procedure:
In a similar manner to Step 2 of Example 16. N-(1-methyl-1-phenylethyl)benzamide (5.00 g, 20.9 mmol) was dissolved in THF (200 mL), and the solution was treated with TMEDA (10.0 mL, 66.9 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 66.0 mL, 66.9 mmol) and DMF (3.60 mL, 46.0 mmol), followed by purification by slurry using diisopropylether to obtain 3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (5.40 g, yield 97%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:12](=O)[CH3:13])=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1.C(O)C>[OH:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:12](=[N:16][OH:17])[CH3:13])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)c1ccc(O)c2c1OCCO2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(O)c2c1OCCO2
Yield: 57.4 %

Procedure:
A solution of 19.4 g (0.1 mole) of 5-hydroxyl 8-acetyl-1,4-benzodioxane (VIIi) and 10.4 g (0.15 mole) of hydroxylamine hydrochloride in 50 ml of pyridine and 50 ml of ethanol was brought to reflux for 7 hours. Then, the solvents were evaporated and the residue crystallized in water. 12 g of product were obtained.
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1[O:11][N:10]=[CH:9][C:8]=1[C:12]([OH:14])=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]23[NH:40][CH2:39][CH2:38][N:23]2[C:24](=[O:37])[C:25]2[N:26]([C:28]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=2)[CH2:27]3)=[CH:18][CH:17]=1.C(#N)C>ClCCl.N1C=CC=CC=1.C([O-])(O)=O.[Na+].O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]23[N:40]([C:12]([C:8]4[CH:9]=[N:10][O:11][C:7]=4[CH3:6])=[O:14])[CH2:39][CH2:38][N:23]2[C:24](=[O:37])[C:25]2[N:26]([C:28]([C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=2)[CH2:27]3)=[CH:18][CH:17]=1
Reactant: Cc1oncc1C(=O)O
Reactant: O=C1c2ccc(-c3ccncc3)n2CC2(c3ccc(Cl)cc3)NCCN12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1oncc1C(=O)N1CCN2C(=O)c3ccc(-c4ccncc4)n3CC12c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.6 %

Procedure:
To generate the acid chloride oxalyl chloride (100 μL, 1.2 mmol) and a drop of DMF were added to a suspension of 5-methyl-1,2-oxazole-4-carboxylic acid (76 mg, 0.60 mmol) in dichloromethane (0.5 mL) at 0° C. The suspension was allowed to stir for a further 15 min at 0° C., followed by 2 h at room temperature. The resulting solution was concentrated in vacuo to give a dark oil that was twice suspended in n-hexanes (2×1 mL) and concentrated in vacuo. To a chilled (ice bath) suspension of the acid chloride (generated as above; 0.60 mmol) in pyridine (0.5 mL) and CH2Cl2 (0.5 mL) was added crude 10a-(4-chlorophenyl)-8-(pyridin-4-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.14 mmol) in pyridine (0.5 mL). The dark reaction mixture was warmed to room temperature and stirred for a further 16 h. LCMS analysis confirmed completion of the reaction. The reaction mixture was diluted with a saturated solution of NaHCO3 (25 mL) and extracted with CH2Cl2 containing 20% of propan-2-ol (3×25 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to yield a crude brown solid, which was purified using flash chromatography (Biotage SP4, 12 g cartridge, 0-10% MeOH gradient in CH2Cl2) and reverse phase chromatography (Biotage SP4.12 g cartridge, C18 phase, 20-40% acetonitrile gradient in water) to give 10a-(4-chlorophenyl)-1-[(5-methyl-1,2-oxazol-4-yl)carbonyl]-8-(pyridin-4-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (32) as a white solid (7 mg, yield 12%).
Reaction SMILES: C([N:8]1[C@H:12]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[CH2:11][CH2:10][C@@H:9]1[C:22]1([OH:25])[CH2:24][CH2:23]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[F:19][C:17]1[CH:18]=[C:13]([C@H:12]2[NH:8][C@@H:9]([C:22]3([OH:25])[CH2:23][CH2:24]3)[CH2:10][CH2:11]2)[CH:14]=[C:15]([F:21])[C:16]=1[F:20]
Reactant: OC1([C@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N2Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: OC1([C@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N2)CC1
Reaction time: 3 h
Yield: 99 %

Procedure:
20% palladium hydroxide on carbon (100 mg, 50% water contain) was added to an ethanol (7 mL) solution of 1-[(2R,5S)-1-benzyl-5-(3,4,5-trifluorophenyl)pyrrolidine-2-yl]cyclopropanol (600 mg). Under a hydrogen atmosphere, stirring was continued for 3 hours. The resultant was filtered on celite, and by removing the solvent under a vacuum, the title compound (440 mg) was obtained. The physical property values are as follows.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:36]=[CH:35][S:34][CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[S:34]1[CH:35]=[CH:36][C:32]([CH2:31][NH:30][C:26]2[N:25]=[C:24]([C:23]3[C:18]4[C:19](=[N:20][C:15]([NH:14][CH:11]5[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]5)=[N:16][CH:17]=4)[NH:21][N:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:33]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)n4)nn(COCC[Si](C)(C)C)c3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)n4)n[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of {4-[3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (415 mg, 0.638 mmol) in dichloromethane (5 mL) was added CF3COOH (5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. A saturated aqueous solution of NaHCO3 was added to the residue, and then extracted with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by prep-HPLC, concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give N-(3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-cyclohexane-1,4-diamine; hydrochloride. (Yield 27 mg).
Reaction SMILES: [F:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:43][C:44]1[CH:45]=[CH:46][C:47]([Cl:66])=[C:48]([C:50]2[N:51]=[C:52]3[N:57]=[CH:56][C:55]([NH:58][C:59](=[O:64])[O:60][CH:61]([CH3:63])[CH3:62])=[CH:54][N:53]3[CH:65]=2)[CH:49]=1>CN(C=O)C>[Cl:66][C:47]1[CH:46]=[CH:45][C:44]([NH:43][C:7]([C:5]2[O:6][C:2]([F:1])=[CH:3][CH:4]=2)=[O:9])=[CH:49][C:48]=1[C:50]1[N:51]=[C:52]2[N:57]=[CH:56][C:55]([NH:58][C:59](=[O:64])[O:60][CH:61]([CH3:62])[CH3:63])=[CH:54][N:53]2[CH:65]=1
Reactant: CC(C)OC(=O)Nc1cnc2nc(-c3cc(N)ccc3Cl)cn2c1
Reactant: O=C(O)c1ccc(F)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)cn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 40 mL vial isopropyl (2-(5-amino-2-chlorophenyl)imidazo[1,2-a]pyrimidin-6-yl)carbamate (I-9) (30 mg, 0.09 mmol) was dissolved in DMF (Volume: 0.3 mL). 5-fluorofuran-2-carboxylic acid (11 mg, 0.09 mmol) was then added to the reaction mixture followed by HATU (65.98 mg, 0.17 mmol) and (iPr)2NEt (0.043 mL, 0.26 mmol). The reaction was stirred at rt for 8 hrs. The reaction was monitored was LCMS which indicated the reaction was complete with a new peak of desired mass was observed (M+H=468.1). The reaction mixture was quenched with water and extracted with ethyl acetate (3×5 mL). Combined all organics, dried over sodium sulfate and concentrated under reduce pressure. The crude reaction purified by reverse phase HPLC yeild 2-(2-chloro-5-(5-fluorofuran-2-carboxamido)phenyl)imidazo[1,2-a]pyrimidin-6-yl)carbamate (1). The TFA salt was neutralized to a free base by a HCO3 column. 1H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 10.01 (s, 1H), 9.31 (s, 1H), 8.69 (s, 1H), 8.61 (d, J=2.7, 1H), 8.51 (d, J=2.7, 1H), 7.87 (dd, J=2.7, 8.8, 1H), 7.53 (d, J=8.7, 1H), 7.47 (t, J=3.6, 1H), 6.11 (dd, J=3.7, 7.1, 1H), 5.03-4.85 (m, 1H), 1.29 (d, J=6.2, 6H). M/Z=(458.1M+1). RT=1.64 min.