Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH:12][CH2:13][CH2:14][C:15]12[CH2:22][CH2:21][CH2:20][N:19]1[CH2:18][CH2:17][CH2:16]2>>[N:19]12[CH2:20][CH2:21][CH2:22][C:15]1([CH2:14][CH2:13][N:12]([CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:16][CH2:17][CH2:18]2
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CNCCC12CCCN1CCC2
Product: CN(CCC12CCCN1CCC2)c1ccccc1[N+](=O)[O-]

Procedure:
The procedures described in Example 12 were repeated except that 1-chloro-2-nitrobenzene (1.87 g, 11.9 mmol) and 5-(2-methylaminoethyl)-1-azabicyclo[3.3.0]octane (4.00 g, 28.8 mmol) were employed. In th is case, the desired compound was obtained as a orange liquid (2.95 g, 85.7%).
Reaction SMILES: [CH:1]1([C:6]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([C:14]([O:16]CC)=O)[O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:19]>>[CH:1]1([C:6]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([C:14]([NH2:19])=[O:16])[O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1onc(C2CCCC2)c1[N+](=O)[O-]
Reactant: N
Product: NC(=O)c1onc(C2CCCC2)c1[N+](=O)[O-]
Yield: 62 %

Procedure:
51.59 g (203 mmol) of ethyl 3-cyclopentyl-4-nitro-isoxazole-5-carboxylate (example IV) are stirred, at room temperature for 3 hours, in 600 ml of a 2M solution of ammonia. The solvent is removed in vacuo and the residue is triturated with cyclohexane and dried in vacuo. 31.17 g (62%) of colorless solid are obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[CH3:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28]>C1COCC1>[CH2:11]([O:10][C:3](=[O:9])[C:4]([CH2:13][C:14]1[C:15]([CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[CH:16][CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])=[O:6])[CH3:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1CC(=O)C(=O)OCC
Reaction time: 0.33 h

Procedure:
Sodium hydride (7.5 g) is added to Tetrahydrofuran (125 ml) at ambient temperature under Nitrogen atmosphere and stirred for 10-30 minutes. Diethyl oxalate (20 ml) is added to reaction mixture and at 25-45° C. and stirred the solution for 15 minutes. 2-Methyl-3-nitro-N, N-Di-n-propyl phenyl ethyl amine free base as generated above is added to reaction mixture and stirred slowly under nitrogen atmosphere at 25-30° C. for 36-72 hours. After completion of reaction THF is distilled out from the reaction mixture under vacuum at 35-70° C. and Ethyl acetate (250 ml) is added to reaction mass. Further, 3N HCl (approx. 30 ml) is added to adjust the pH of reaction mass to 7.5-8.0. Organic layer is separated out and dried over sodium sulphate. Ethyl acetate is distilled out to obtain Ethyl-6-(2-di-n-propylaminoethyl)-2-nitrophenylpyruvate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:5][C:6]([CH3:9])=[C:7]([CH3:8])[C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])c(O)c(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(OCc2ccccc2)c(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
2-Chloro-3,4-dimethyl-6-nitrophenol (6.44 g, 31.9 mmol) was dissolved in dry DMF (105 mL) and flushed with argon. Benzyl bromide (4.17 mL,35.1 mmol) and K2CO3 (13.24 g, 95.7 mmol) were added. The reaction mixture was stirred at room temperature for 8 h (protected from light) and filtered. Water (5 mL) was added and the solvent was co-evaporated with xylene (2×150 mL) and CH2Cl2 (100 mL). The residue was mixed with CHCl3 (100 mL), filtered and after evaporation of the solvent 10.8 g of crude product remained. Purification by flash column chromatography (SiO2, CHCl3 -Hexane 1:1) gave the title compound (8.44 g). Mp: 74°-75° C.; 1H NMR (DMSO-d6): δ 7.80 (s, 1 H), 7.48-7.37 (m, 5 H), 5.06 (s, 2 H), 2.37 (s, 3 H), 2.34 (s, 3 H); 13C NMR (DMSO-d6): δ 145.24, 142.22, 142.08, 135.73, 134.73, 129.61, 128.39, 128.37, 128.35, 123.64, 75.74, 19.74, 17.13; MS (EI, 70 eV): m/z (rel.int.) 293/291 (M+, 0.08/0.37), 187/185 (8/24), 91 (100).
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)(=O)[CH3:2].[OH:20][CH2:21]CCO.S(=O)(=O)(O)O>O>[C:14]1([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([O:4][CH2:1][CH2:2][CH2:21][OH:20])=[CH:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCO
Reactant: CC(=O)Oc1cn(-c2ccccc2)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: OCCCOc1cn(-c2ccccc2)c2ccccc12
Temperature: 80 °C

Procedure:
A mixture of 3-acetyloxy-1-phenylindole (24 g), 1,3-dihydroxypropane (240 ml), and conc. sulfuric acid (10 ml) was heated to 80° C. for 2 h. Water was added followed by extraction with ether. The ether phase was dried over magnesium sulfate followed by removal of solvent in vacuo giving 3-(1-phenyl-3-indolyloxy)-1-propanol, sufficiently pure for use in the next step. The title compound was obtained by the method described in EXAMPLE 2 using spiro[isobenzofuran-1(3H),4'-piperidine] and crystallized as the oxalate salt from acetone by addition of oxalic acid. Yield: 2 g, mp: 151°-54° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][C:5]([CH2:8][CH2:9]O)=[CH:6][N:7]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Cl:13][CH2:9][CH2:8][C:5]1[S:4][C:3]([NH2:2])=[N:7][CH:6]=1.[ClH:1]
Reactant: O=S(Cl)Cl
Reactant: Nc1ncc(CCO)s1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Nc1ncc(CCCl)s1
Temperature: 25 °C

Procedure:
To a suspension of 14.73 g of 2-amino-5-thiazoleethanol, monohydrochloride (Example B) in 200 ml of chloroform is added rapidly 50 ml of thionyl chloride. The mixture is refluxed for 30 minutes, cooled to room temperature, filtered through a pad of Celite, concentrated to a brown oily solid, and crystallized from ethanol-diethyl ether to give 5-(2-chloroethyl)-2-thiazolamine as the monohydrochloride salt; mp 145°-147° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16](O)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:36])=O>CN(C=O)C>[CH2:1]([N:8]1[C:16]([Cl:36])([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: C[Si](C)(C)CCOCOc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCOc1ccc(C2(Cl)c3ccccc3C(=O)N2Cc2ccccc2)cc1
Yield: 100 %

Procedure:
2-Benzyl-3-hydroxy-3-[4-(2-trimethylsilanylethoxymethoxy)phenyl]-2,3-dihydroiso-indol-1-one (125 mg, 0.27 mmol) was reacted with thionyl chloride (0.019 mL, 0.27 mmol) and a catalytic amount of DMF (3 drops) as for general procedure G. Removal of the solvent gave 2-benzyl-3-chloro-3-[4-(2 trimethylsilanylethoxymethoxy)phenyl]-2,3-dihydroiso-indol-1-one as a colourless oil (129 mg, 0.27 mmol, 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO[2H]>[NH2:1][C@@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH2:13][OH:14]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [2H]OC
Product: N[C@H](CO)Cc1c[nH]c2ccccc12
Yield: 92 %

Procedure:
The title compound was prepared from (S)-tryptophan according to Method D and was isolated as a solid in 92% yield. δH (MeOD-d3) 7.46 (1H, d, J 7.9 Hz), 7.21 (1H, d, J 8.0 Hz), 6.96 (3H, m), 3.79 (1H, dd, J 11.3 and 3.6 Hz), 3.54 (1H, dd, J 11.3 and 6.2 Hz), 3.05 (1H, m), 2.80 (1H, m), 2.61 (1H, m). Note: exchangeable protons not evident in MeOD.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(Cl)cc1
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 4-chloroaniline to yield 2-[(4-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[CH:21]([CH3:23])[CH3:22])[C:3]([CH3:10])=[CH:4][C:5]([O:7]CC)=[O:6].[OH-].[K+]>C(O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[CH:21]([CH3:23])[CH3:22])[C:3]([CH3:10])=[CH:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C=C(C)C(O)c1ccc(OC)c(OC)c1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(O)C(C)=CC(=O)O)c(C(C)C)c1OC
Temperature: 0 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
Compound 8 (9.00 g, 27.9 mmol) was dissolved in 100 mL of ethanol with 3 g of KOH and refluxed for 1 h. The mixture was poured onto 100 g of ice with 25 ml of 6 M HCL and stirred for 24 h. The white solid was filtered, washed with water, dried and recrystallized from ether/petroleum ether to give 7.38 g (25.1 mmol, 90%) of 9 as white plates: mp 154-155° C.; IR 3411 (OH), 1694 (carbonyl), 1644 (alkene) cm-1 ; 1H NMR δ1.38 (d, J=7.0 Hz, 6H), 2.00 (s, 3H), 3.44 (br s, 1H), 3.85 (s, 6H), 5.41 (s, 1H), 6.33 (s, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.92 (d, J=7.1 Hz, 1H). Anal. (C16H22O5) C,H.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>CS(C)=O>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxyethanol (0.118 mL, 1.50 mmoles) in DMSO (5 mL) was added sodium hydride (Aldrich, 60% dispersion, 0.0720 g, 1.80 mmoles), followed by stirring until H2 evolution ceased (15 minutes). One milliliter of this alkoxide stock solution was added to N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloropyrimidin-4-yl]benzamide (0.147 g, 0.249 mmoles, reference example 1az), followed by heating (60° C.). After two hours, another 0.5 mL of the alkoxide stock solution was added. After two more hours, the reaction was quenched with water (40 mL) and the resulting precipitate collected by filtration. The precipitate was washed with water and CH2Cl2 and dried under vacuum to give the product as a white solid. MS (ion spray) m/z 442 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C[O:12][P:13]1(=O)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([P:13]2(=[O:12])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COP1(=O)Oc2ccccc2-c2ccccc21
Product: Cc1ccc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)cc1
Temperature: 110 °C

Procedure:
30.8 g (0.2 mol) of 4-methylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 46 g (0.2 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]-oxaphosphorin 6-oxide were added dropwise over the course of 1 hour while stirring. The temperature was then slowly increased to 110° C. When the reaction was complete, the residue slowly crystallized out at room temperature. 60 g (90% of theory) of the abovementioned compound, which, after recrystallization from toluene, had a melting point of 124 to 125% C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].O[C@H:25]1[CH2:30]C(=O)O[C@H](COC(=O)C2C=CC=CC=2)[CH2:26]1.COC(=O)C[C@H]1C[C@@H](COC(=O)C2C=CC=CC=2)OC(C)(C)O1>>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:25]([CH3:30])([CH3:26])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1C[C@H](O)C[C@@H](COC(=O)c2ccccc2)O1
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Agent: COC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1

Procedure:
93.1%; (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester: 3.4%; (2S,4R)-4-hydroxy-6-oxo-2-[(benzoyloxy)methyl]tetrahydro-2H-pyran: 0.1%; 2-[(4R,6S)-2,2-dimethyl-6-benzoyloxymethyl-1,3-dioxan-4-yl]acetic methyl ester: 0.1%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].CCOC(C)=O>>[ClH:25].[ClH:25].[CH:19]1([CH:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)CC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CC(C1CCCCC1)N1CCNCC1

Procedure:
A solution of the product from Step II (406 mg, 1.21 mmol) in 1N HCl/EtOAc (25 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and solid washed twice with Et2O to afford the title compound as a white solid. MS m/z 239.3 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:4][CH:5]=[N:6][C:7]=1[SH:8].[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[S:8][C:7]3[N:6]=[CH:5][N:4]=[C:3]([N:9]4[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]4)[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(S)c2N)CC1
Reactant: O=C(O)c1ccc(F)cc1
Product: Fc1ccc(-c2nc3c(N4CCNCC4)ncnc3s2)cc1
Yield: 74 %

Procedure:
This compound was synthesized from tert-butyl 4-(5-amino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using 4-fluorobenzoic acid, yielding the title compound in 74% yield.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[O:7][C@@H:6]1[C@H:22]([OH:51])[CH:23]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[NH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:45])[C@H:30]([C@@H:42]([OH:44])[CH3:43])[NH:31]C(=O)OCC1C=CC=CC=1)(=[O:3])[CH3:2]>[Pd].CO>[NH2:31][C@@H:30]([C@@H:42]([OH:44])[CH3:43])[C:29]([NH:28][CH2:27][CH2:26][CH2:25][NH:24][CH:23]([C@H:22]([C@@H:6]1[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[O:7]1)[OH:51])[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:45]
Reactant: CCOC(=O)C(NCCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)O)[C@@H](O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(NCCCNC(=O)[C@@H](N)[C@H](C)O)[C@@H](O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 94.4 %

Procedure:
Ethyl (5S)-12-[(R)-[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (86 mg, 0.119 mmole, obtained from Example 31) was hydrogenated using 10% palladium on carbon in methanol (2 ml) under atmospheric pressure. The catalyst was removed and the volatiles were removed in vacuo to provide ethyl (3R)-2-[(3-{[(2S,3S)-2-amino-3-hydroxybutanoyl]amino}propyl)amino]-3-[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (66 mg, 94%) as a white amorphous solid.
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[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=5)[CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[NH2:34][CH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: NCCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(N)CC4)ncc23)n1)c1cccc(Cl)c1

Procedure:
To a solution of crude [4-(3-{2-[3-tert-butoxycarbonylamino-1-(3-chloro-phenyl)-propylamino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (21 mg, 0.03 mmol) in methanol (40 mL) was bubbled in HCl (gas) for 3 hours at room temperature. The mixture was then concentrated by evaporation to afford N-(3-{2-[3-amino-1-(3-chloro-phenyl)-propylamino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-cyclohexane-1,4-diamine; hydrochloride. (Yield 20 mg, 93.0%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](=[O:25])[CH3:24])[CH:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH:12][C:17]3[N:22]=[CH:21][N:20]=[C:19]([C:23](=[O:25])[CH3:24])[CH:18]=3)[CH:10]=[C:5]2[CH:4]=1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: CC(=O)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 8 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 32 mg, 0.149 mmol), 1-(6-chloro-4-pyrimidinyl)ethanone (Intermediate 18, 34.9 mg, 0.223 mmol) and DIPEA (0.052 mL, 0.297 mmol) were added together in N-methyl-2-pyrrolidone (1 mL) and the resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (4 mg);
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[C:7](=[O:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[OH-].[Na+].[BH4-].[Na+]>C(O)C>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(C)CC(O)C(C)C(C)(CC)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a 2-liter, 3-necked flask equipped with a stirrer, condenser, thermometer and nitrogen inlet were placed 197.3 g. (1.0 moles) of 2,6-diethyl-2,3,6-trimethylpiperidin-4-one, 500 ml of 2N sodium hydroxide and 500 ml of absolute ethanol. To the stirred reaction mixture, maintained under nitrogen, was added portionwise 18.92 m (0.5 moles) of sodium borohydride over a 11/2 hour period. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was decanted into a 4-liter separatory funnel and 2 liters of water were added. The aqueous layer was separated and the organic layer diluted with 500 ml of ether. The ether solution was washed with 2×1 l water. The first aqueous layer was extracted with 2×50 ml of ether, then the combined ether extracts were washed with 500 ml of water. The ether layers were combined, dried over 4A molecular sieves and evaporated under reduced pressure, giving 187.4 g of the desired 2,6-diethyl-2,3,6-trimethylpiperidin-4-ol which was purified further by vacuum distillation, b.p. 111°-115°/6 mm.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CN(C=O)C.[Br:23][C:24]1[CH:29]=[C:28](Cl)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1>CCOCC>[Br:23][C:24]1[CH:29]=[C:28]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(Br)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
N-Boc-4-piperidinemethanol (860 mg, 4.0 mmol) was added to a suspension of 60% sodium hydride (160 mg, 4.0 mmol) in DMF (40 mmol) at room temperature. After 20 minutes, 2-bromo-4-chloro-5-nitropyridine (949 mg, 4.0 mmol) was added in one portion, and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with ether and washed with water. The aqueous phase was extracted with ether. The combined organic phases were washed with water and brine, then dried (Na2SO4) and concentrated. Silica column chromatography, eluting with 20% ethyl acetate-hexane, gave tert-butyl 4-((2-bromo-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (789 mg, 62%) as a viscous, pale yellow oil which solidified on standing.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:21]=2)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH3:2].ClC(Cl)(Cl)C([N:36]=C=O)=O>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:21]=2)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:36])[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine (1.64 g, 3.90 mmol) in anhydrous dichloromethane (50 mL) was cooled to 6° C., and a solution of trichloroacetyl isocyanate (0.51 mL, 4.29 mmol) in dichloromethane (5 mL) was added dropwise. The solution was stirred for 30 minutes, and then the solvent was removed under reduced pressure. The residue was treated with sodium methoxide in methanol (10 mL of a 25% w/w solution) and methanol (40 mL). The resulting mixture was stirred for 18 hours at room temperature. A precipitate was present and was isolated by filtration, washed with methanol and diethyl ether, and dried under high vacuum at 80° C. for 18 hours to provide 0.999 g of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a white solid, mp 190.0-191.0° C.