Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](C2OC(C)(C)C(C)(C)O2)=[CH:13][C:12]=1[S:27]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2[CH:37]=[CH:38][CH:39]=[CH:40][C:31]1=2)(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].Br[C:43]1[C:48]([C:49]#[N:50])=[CH:47][C:46]([C:51]([F:54])([F:53])[F:52])=[N:45][CH:44]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([C:43]2[CH:44]=[N:45][C:46]([C:51]([F:54])([F:53])[F:52])=[CH:47][C:48]=2[C:49]#[N:50])=[CH:13][C:12]=1[S:27]([N:30]1[CH2:36][CH2:35][CH2:34][CH2:33][C:32]2[CH:37]=[CH:38][CH:39]=[CH:40][C:31]1=2)(=[O:29])=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(C2OC(C)(C)C(C)(C)O2)cc1S(=O)(=O)N1CCCCc2ccccc21
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 100 °C
Yield: 85.5 %

Procedure:
4-[5-Chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-butyric acid tert-butyl ester (60.0 mg, 0.1 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (23 mg, 0.09 mmol), Pd(Ph3P)4 (12 mg, 0.01 mmol) and K2CO3 (56 mg, 0.4 mmol) in a mixture of dioxane (1.5 mL) and water (0.15 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and heated at 100° C. for 16 hrs. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated, washed with brine (2×5 mL), dried over MgSO4, filtered, concentrated and purified by TLC plates eluting with ethyl acetate in hexanes (1/3) to give 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid tert-butyl ester 6-1 as a white foam (50 mg). MS: 593.9 (M+H-tBu)*; tR=6.98 min (method 4). NMR (CDCl3), δ, 8.791 (1H, s), 7.738-8.101 (2H, m), 7.060-7.272 (4H, m), 6.774-6.828 (1H, m), 4.213 (2H, m), 3.780 (2H, m), 2.833 (2H, m), 2.404 (2H, t), 1.912-2.029 (4H, m), 1.591-1.657 (2H, m), 1.448 (9H, s).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:32][C:33]2[NH:34][CH:35]=[CH:36][N:37]=2)[CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13].Cl>O>[NH:28]1[CH:29]=[CH:30][N:31]=[C:27]1[CH2:26][N:25]([CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:19][CH:20]=1)[CH2:32][C:33]1[NH:37][CH:36]=[CH:35][N:34]=1
Reactant: CCCN(CCC)CCCCN(CC(=O)OC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: Cl
Solvent: O
Product: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Yield: 74 %

Procedure:
The compound (533.4 mg) obtained in Example 68-1 was dissolved in water (0.5 ml) and added with concentrated hydrochloric acid (2.5 ml). The whole was refluxed under heating for 30 minutes. After completion of the reaction, the solvent was distilled off, thereby obtaining a hydrochloride (384.1 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH2:24][CH2:25][S:26][CH2:27][CH:28]=3)[S:20][C:19]=2[CH2:29][CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH2:24][CH2:25][S:26][CH2:27][CH:28]=3)[S:20][C:19]=2[CH2:29][CH3:30])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C2=CCSCC2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1sc(C2=CCSCC2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 32 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-{cyclohexyl[5-(3,6-dihydro-2H-thiopyran-4-yl)-2-ethylthiophen-3-yl]methoxy}benzoic acid (234 mg) synthesized in Example 85 (4) and ethyl 3-(methylamino)propanoate (79.8 mg) to give the title compound (89.2 mg, 33%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH3:20])[CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].[CH3:22]I>COCCOCCOC>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH3:20])[CH:19]=[C:13]4[N:12]([CH3:22])[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c3[nH]c4cc(C)nn4c(=O)c3cnc21
Reactant: CI
Agent: [Na]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n3nc(C)cc3n(C)c12
Reaction time: 12 h

Procedure:
8.05 g. of 3-ethyl-3,11-dihydro-9-methyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one (0.03 mol.) are refluxed with stirring in 100 ml. of diethyleneglycol dimethylether together with 0.9 g. of sodium (0.04 mol.) for 2 hours. After this time, 14.2 g. of methyl iodide (0.1 mol.) are added and heating is continued for 12 hours. The solvent is removed in vacuo and the residue crystallized with methanol, filtered and washed with water to obtain 3-ethyl-3,11-dihydro-9,11-dimethyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]-pyrimidin-6-one, yield 5.2 g. (61%), m.p. 306°-307° (methanol).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:24]>CN(C=O)C.O.C(OCC)(=O)C>[O:24]=[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
Part A: To a mixture of tert-butyl piperazine-1-carboxylate (1.863 g, 10.00 mmol) and cesium carbonate (6.52 g, 20.00 mmol) in 50 mL of DMF at 25° C. was added 2-(bromoacetyl)pyridine hydrobromide (2.81 g, 10.00 mmol) in portions over five minutes. The reaction mixture then was stirred at 25° C. for 3 h. The resulting mixture was diluted with water and ethyl acetate. The phases were separated, and the organic phase was washed with water (×3) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 10-50% ethyl acetate/chloroform) provided 1.61 g (53%) of tert-butyl 4-(2-oxo-2-(pyridin-2-yl)ethyl)piperazine-1-carboxylate as a crystalline solid; 1H NMR (500 MHz, CDCl3) δ 8.63 (d, 1H, J=4.5 Hz), 8.05 (m, 1H), 7.85 (t, 1H, J=9 Hz), 7.49 (m, 1H), 4.30 (s, 2H), 3.62 (m, 4H), 2.75 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>O1CCOCC1.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>[CH3:22][O:21][C:4]1[CH:3]=[C:2]([C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CNc1nc(Nc2ccc(Br)cc2OC)ncc1C(F)(F)F
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(-c3cnn(C)c3)cc2OC)ncc1C(F)(F)F
Yield: 24.8 %

Procedure:
A mixture of N2-(4-bromo-2-methoxyphenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (0.365 g, 1 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), K2CO3 (0.415 g, 3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.415 g, 2 mmol) in dioxane (10 mL) and water (1.25 mL) was degassed under a stream of nitrogen for 10 min. The reaction tube was sealed and the mixture irradiated in the microwave at 100° C. for 20 min. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL) and the product extracted into ethyl acetate (2×20 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) afforded a residue that was triturated with diethyl ether yielding N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine as an off-white solid (94 mg, 25%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=379 at 3.11 min. 1H NMR (400 MHz, CDCl): δ 8.49 (d, J=8.4, 1H); 8.17 (s, 1H); 7.76-7.68 (m, 2H); 7.58 (s, 1H); 7.10 (dd, J=8.4, 1.9, 1H); 6.98 (d, J=1.9, 1H); 5.20 (s, 1H); 3.95 (s, 6H); 3.12 (d, J=4.7, 3H).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)=[O:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: NC1CCCCC1
Product: CN(C(=O)Oc1ccc(C(=O)NC2CCCCC2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and cyclohexylamine. The crude product was used without further purification (79%, off-white crystals). HPLC-MS: m/z=353.2 (M+1); Rt: 3.98 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]([CH2:12][C:13]#[CH:14])[C:10]2[CH:15]=[CH:16][C:17](=[O:24])[C:18]([O:20][CH2:21][C:22]#[CH:23])=[CH:19][C:9]=2[C:8](=[O:25])[CH:7]=1)=[O:5])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]([CH2:12][CH2:13][CH3:14])[C:10]2[CH:15]=[CH:16][C:17](=[O:24])[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[CH:19][C:9]=2[C:8](=[O:25])[CH:7]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: C#CCOc1cc2c(=O)cc(C(=O)OCC)n(CC#C)c2ccc1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCOc1cc2c(=O)cc(C(=O)OCC)n(CCC)c2ccc1=O

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-1-(2-propynyl)-6-(2-propynyloxy)-1H-cyclohepta[b]pyridine-2-carboxylic acid ethyl ester (20 g, described in Example 20), 5% palladium on charcoal (2.0 g) and acetic acid (400 ml) is stirred rapidly under an atmosphere of hydrogen until 5.7 liters of hydrogen are absorbed. The mixture is filtered and the filtrate is evaporated. The residue is subjected to chromatography on silica gel using acetone-hexane (1:1). The eluates are evaporated to give a residue of the title compound.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[CH2:32][CH2:31]3)=[C:20]([NH:25][CH2:26][CH:27]([F:29])[F:28])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:29][CH:27]([F:28])[CH2:26][NH:25][C:20]1[N:21]=[C:22]2[CH2:23][CH2:24][NH:15][CH2:16][C:17]2=[N:18][C:19]=1[N:30]1[CH2:31][CH2:32][CH:33]([O:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])[CH2:34][CH2:35]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CCNC4)CC2)c(F)c1
Reaction time: 2 h

Procedure:
A solution of 6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (152 mg, 0.241 mmol) and Pd(OH)2 on carbon (33.9 mg, 0.048 mmol) in THF (2.41 mL) was purged with and placed under hydrogen (balloon) atmosphere at room temperature for 2 h. The mixture was then filtered through Celite™ and concentrated to give the title compound as a TFA salt (115 mg, 0.213 mmol).
Reaction SMILES: [C:1]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:32]=[CH:33][N:34]=4)[N:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26](O)=[O:27])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH4+].CC[N:38]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>O1CCOCC1.ClCCl>[C:1]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:32]=[CH:33][N:34]=4)[N:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([NH2:38])=[O:27])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C1CCN(c2cccc(Nc3cc(-c4cccc(C(=O)O)c4)nn4ccnc34)n2)C1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C1CCN(c2cccc(Nc3cc(-c4cccc(C(N)=O)c4)nn4ccnc34)n2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
A mixture of 3-(8-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (25 mg, 0.106 mmol), 0.5 M ammonium in dioxane solution (2 mL), EDCI (43 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol), Et3N (23 mg, 0.22 mmol) and dichloromethane (2 mL) was stirred at room temperature for 16 h. The solution was concentrated in vacuo and purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give 3-(8-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (6 mg, 24%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.79 (s, 1H), 8.91 (s, 1H), 8.47 (s, 1H), 8.31 (s, 1H), 8.16-8.02 (m, 3H), 7.79 (s, 1H), 7.63 (t, 1H, J=7.6 Hz), 7.52-7.47 (m, 2H), 6.72 (d, 1H, J=7.8 Hz), 6.11 (d, 1H, J=8.4 Hz), 3.72-3.66 (m, 1H), 3.52-3.40 (m, 2H), 3.12 (t, 1H, J=10.0 Hz), 2.13-1.94 (m, 2H), 1.78-1.74 (m, 1H), 0.86 (s, 9H). LC-MS: [M+H]+, 456, tR=1.72 min, HPLC: 99.11% at 214 nm, 99.64% at 254 nm, tR=4.22 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]1>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Product: CCOC(=O)C1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 75.4 %

Procedure:
Using 4-bromobenzotrifluoride (3.15 g, 13.99 mmol) and ethyl isonipecotate (2.2 g, 13.99 mmol), ethyl 1-(4-trifluoromethylphenyl)piperidine-4-carboxylate (3.18 g, yield 74%) as a pale brown crystalline powder was prepared in the same manner as described in Reference Example 21.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[O:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:29]3[CH2:28][CH2:27][N:26]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:31][CH2:30]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CCN(C3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (165 mg, 0.59 mmol), 1-(tetrahydropyran-4-yl)piperazine (110 mg, 0.65 mmol) and molecular sieves (4 Å, powdered, 750 mg) in DCE (10 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 95:5 to 90:10) to afford 2-Chloro-9-methyl-6-morpholin-4-yl-8-[4-(tetrahydropyran-4-yl)piperazin-1-ylmethyl]-9H-purine as a white solid (250 mg, 98%). 1H NMR (CDCl3, 400MHz) δ 4.27 (m, 4 H), 4.01 (dd, J=11.5, 4.2 Hz, 2 H), 3.81 (m, 7 H), 3.69 (s, 2 H), 3.36 (dd, J=12.5, 10.9 Hz, 2 H), 2.55 (m, 8 H), 2.40 (m, 1 H), 1.75 (d, J=12.5 Hz, 2 H) and 1.56 (m, 2 H)
Reaction SMILES: [ClH:1].C([CH2:9][NH:10][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[C:18]([CH3:24])[CH:19]=[C:20]([CH3:23])[N:21]=2)[CH:16]=[CH:15][C:14]1=[O:25])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[ClH:1].[CH3:9][NH:10][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[C:18]([CH3:24])[CH:19]=[C:20]([CH3:23])[N:21]=2)[CH:16]=[CH:15][C:14]1=[O:25]
Reactant: [H][H]
Reactant: Cc1cc(C)c2ccc(=O)n(CCNCCc3ccccc3)c2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCCn1c(=O)ccc2c(C)cc(C)nc21

Procedure:
1(2-Benzylmethylaminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one hydrochloride (8.56 g., 0.024 mole) is dissolved in 80 ml. of ethanol, 5% palladium on carbon (0.8 g.) catalyst is added and the mixture is hydrogenated at a pressure of 45 lbs. per sq. inch until hydrogen is no longer taken up. The mixture is filtered concentrated under reduced pressure and the residue is crystallized from isopropanol. 1-(2-Methylaminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one hydrochloride having a melting point of 106°-109° C. is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16]Br)=[CH:11][C:10]=1[NH:26][CH:27]=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1CCCC1=O>[CH2:29]([NH:36][CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([NH:26][CH:27]=[O:28])[CH:11]=1)[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a 500 mL three-necked round-bottomed flask was added N-{2-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl]phenyl}formamide (100 g, 215 mmol) and N-methyl-2-pyrrolidone (300 mL). Benzylamine (69.4 mL, 648 mol) was added and the reaction mixture was flushed with nitrogen. The reaction mixture was then heated to 90° C. and stirred for about 8 hours. The reaction mixture was then cooled to room temperature and water (1.5 L) and ethyl acetate (1.5 L) were added. The layers were separated and the organic layer was washed with water (500 mL), a 1:1 mixture of water and saturated brine (500 mL total), and then again with water (500 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide crude N-{5-[(R)-2-benzylamino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-benzyloxyphenyl}formamide (100 g, 90% yield, 75-80% purity) as an orange-brown thick oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[N:16]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]#[N:16])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: N#CCBr
Product: N#CCN1CCN(c2ccncc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-4-yl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=202.2: 1HNMR(DMSO-d6) 8.15 (d, 2H), 6.80 (d, 2H), 3.80 (s, 1H), 3.35 (t, 4H), 2.50 (t, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]#[N:18])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2)#[N:18]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)CNC2
Temperature: 40 °C
Yield: 94.5 %

Procedure:
A mixture of 2-(tert-butyloxycarbonyl)-5-cyano-2,3-dihydro-1H-isoindole (7.6 g) and trifluoroacetic acid (20 ml) in dichloromethane (200 ml) was heated at 40° C. for 0.5 h, then cooled and evaporated in vacuo and the residue partitioned between dichloromethane and 2M sodium hydroxide. The aqueous phase was re-extracted with dichloromethane and the combined organics dried and evaporated to give the title compound as a pink solid (4.24 g, 94%).
Reaction SMILES: C([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=[CH:22][C:9]1=2)C1C=CC=CC=1.[BH4-].[Na+]>C(O)C>[OH:24][CH2:23][C:20]1[CH:21]=[CH:22][C:9]2[NH:8][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]=2[CH:19]=1
Reactant: O=Cc1ccc2c(c1)CCc1ccccc1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc2c(c1)CCc1ccccc1N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
5-Benzyl-2-formyl-10,11-dihydro-5H-dibenz[b,f]-azepine (3.29 g) was dissolved in 200 ml of ethanol, and 0.5 g of sodium borohydride was added to the solution, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was diluted with dichloromethane. The mixture was washed with 1N aqueous hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was dissolved in 300 ml of ethanol. To the solution was added 300 mg of 10% palladium carbon and the mixture was stirred in a stream of hydrogen for 4 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (2/1)] to give 1.0 g (42%) of the product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([OH:24])=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:22]([C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:24])[CH2:28][CH2:27]1
Reactant: CN1CCNCC1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Product: CN1CCN(C(=O)C2(c3ccc(OCCCN4CCCC4)cc3)CCCCC2)CC1
Yield: 8 %

Procedure:
The title compound (10 mg, 8%) was prepared using 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarboxylic acid and 1-methylpiperazine similarly to the procedure used for example 149. 1H NMR (400 MHz, CD3OD) δ 1.32 (m, 1H), 1.64-1.69 (m, 7H), 1.81-1.85 (m, 4H), 1.98-2.03 (m, 2H), 2.05-2.13 (m, 4H), 2.15 (s, 3H), 2.25-2.28 (m, 2H), 2.59-2.62 (m, 4H), 2.69 (t, 2H), 3.33-3.42 (m, 4H), 4.01 (t, 2H), 6.90 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 414.3107 [MH]+.