Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:24]([CH2:31][CH3:32])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([N:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)=[N:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:31]([N:24]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:4]1[C:5]([CH3:23])=[C:6]([CH:22]=[C:2]([C:41]2[CH:46]=[N:45][C:44]([N:47]3[CH2:48][CH2:49][NH:50][CH2:51][CH2:52]3)=[CH:43][CH:42]=2)[CH:3]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:32]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: [Na+]
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(N3CCNCC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
A solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.5 g, 0.99 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.43 g, 1.48 mmol), and tetrakis (0.114 g, 0.09 mmol) in dioxane (7 mL) was purged with argon for 10 min. To this, aq. Na2CO3 (0.377 g, 3.5 mmol, 2 mL) was added and again degassed for 10 min. Reaction mixture was heated at 100° C. for 16 h. On completion, it was concentrated to obtain crude material which was column purified to afford the title compound (0.35 g, 60.13%).
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.Br[CH2:23][CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:23][CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.5 g, 1.35 mmol, intermediate 8) in DMF (5 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.45 g, 2.03 mmol, intermediate 3), potassium carbonate (0.37 g, 2.7 mmol). The mixture was stirred at 50° C. for 3 h; then it was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was washed with ethanol and dried under vacuum to give 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.5 g, 72.2%) as a white solid. LCMS retention time 1.732 min, LCMS MH+-THP 429.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[O:11])=[CH:4][CH:3]=1.CC(C)=[O:14].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:14])=[O:11])=[CH:6][CH:7]=1
Reactant: O=CCCc1ccc(O)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
0.79 g (5.19 mmoles) of 3-(4-hydroxyphenyl)-1-propanal were dissolved in acetone (20 ml) and Jones reagent (chromic anhydride in sulphuric acid) (8 ml) was added to it drop by drop until the yellow-brown colour persisted. The solution was stirred for one hour at 0° C. The excess reagent was destroyed with methanol and the solution was filtered and evaporated at reduced pressure. The residue was extracted in ethyl acetate, dried over anhydrous sodium sulphate and concentrated, diving an impure residue (0.6470 g), which was chromatographed over silica gel, obtaining 0.545 g (63.1% yield) of 3-(4-hydroxyphenyl) propionic acid. Recrystallisation in methanol gave m.p.=121° C.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:20]1[CH2:24]C[CH2:22][CH2:21]1>CS(C)=O>[CH2:21]([O:20][CH2:24][N:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC#Cc1cc(C)nc(N(COCC)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 2-anilino-4-methyl-6-(1-propynyl)-pyrimidine (2.5 g) in dimethyl sulfoxide (2.5 ml) were added to a suspension in 50 ml of tetrahydrofuran of 0.5 g of sodium hydride (60%) of which oily component was removed, and the mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, 1.5 g of chloromethyl ethyl ether was added thereto and the resulting mixture was stirred for 5 hours. The reaction mixture was poured into water and extracted with 150 ml of toluene. The toluene layer was washed wit water, dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The rsidue was purified by silica gel column chromatography to obtain 1.6 g (yield: 62%) of 2-(N-ethoxymethylanilino)-4-methyl-6-(1-propynyl) pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([NH:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([N:18]([CH3:23])[CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1nc2c(OCc3ccccc3)cccc2n1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1nc2c(OCc3ccccc3)cccc2n1C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
To a solution of 4-benzyloxy-1-methyl-2-methylamino-1H-benzimidazole (200 mg) in dimethylformamide (2 ml) was added sodium hydride (32.9 mg) under ice-cooling, and the mixture was stirred for 15 minutes. To the mixture was added methyl iodide (127 mg), and the mixture was stirred for 15 minutes under ice-cooling and then for 2 hours at ambient temperature. Water was added to the reaction mixture, and extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (chloroform:methanol=50:1, v/v) to give 4-benzyloxy-1-methyl-2-dimethylamino-1H-benzimidazole (100 mg).
Reaction SMILES: C(O[C:4]([C:6]1(C)[C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>O1CCOCC1>[C:17]([O:16][C:14]([N:9]1[CH2:10][CH2:11][C:12](=[O:13])[CH:6]([CH3:4])[CH2:7][CH2:8]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of compound 4-methyl-5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.5 g, 8.36 mmol) in dioxane (20 mL) was added 2 M aqueous KOH (20 mL) at 25° C. The resulting solution was stirred at 100° C. for 24 hours before being cooled to RT and extracted twice with EtOAC. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give 1.8 g of 4-methyl-5-oxo-azepane-1-carboxylic acid tert-butyl ester (95% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([CH:14]=O)=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[BH3-]C#N.[Na+]>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([CH3:14])=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C=O)sc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc2cc(C)sc2[nH]1
Reaction time: 168 h
Yield: 49.7 %

Procedure:
Using a procedure by C. K. Lau et. al. (J. Org. Chem., 51: 3038-3043 (1986)), a mixture of 2-formyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (Soth, S. et al., Bull. Soc. Chim. Fr., 2511-2515 (1975); 500 mg, 2.24 mmol), Znl2(1.08 g, 3.36 mmol), and NaBH3CN (1.06 g, 16.8 mmol) in dichloroethane (25 mL) was stirred for 7 d and quenched with saturated aqueous NH4Cl (25 mL). The resultant biphasic mixture was stirred for an additional 30 min, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The product was purified by Chromatotron-chromatography (3:2 hexanes:ether) and obtained as a white foam (233 mg, 50%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([Cl:28])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 180 °C
Yield: 232.2 %

Procedure:
A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 93 mg), 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 15, 135 mg) and DIPEA (0.26 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (435 mg). NMR: 10.64 (s, 1H), 8.91 (s, 3H), 8.30 (s, 1H), 5.97 (s, 1H), 5.17 (s, 1H), 1.83-1.97 (m, 1H), 1.56 (d, 3H), 0.93-1.09 (m, 2H), 0.63-0.77 (m, 2H). m/z 413.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:10][C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[O:12]=[CH:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of the methyl ester from Example 11, Step A (2.0 mmol, 594 mg) in 20 mL of dry DCM cooled to −78° C under nitrogen was added dropwise over 20 min. Diisobutylaluminum hydride (4 mmol, 4 mL of a 4 M solution in toluene). The reaction was stirred for 2 h at −78° C. after which time MeOH (4 mL) cooled to −78° C. was canulated into the reaction mixture. After 10 min. the solution was allowed to reach room temperature. DCM (30 mL) was added to the reaction, and the solution was poured into 60 mL of 2N HCl. The organic phase was collected and the aqueous phase was extracted with DCM (2×20 mL). The combined organic phase was dried with MgSO4 and concentrated under reduced pressure. The aldehyde was further purified by flash chromatography on silica gel (40 g) using a step gradient of 0% to 16% EtOAc/hexanes, increasing in 4% increments. The aldehyde eluted in 12-16% EtOAc/hexanes, affording a white waxy solid. 1H NMR (500 MHz, CDCl3): δ 9.76 (s, 1H), 7.28-7.4 (m, 1H); 7.11 (d, 1H, J=7.7 Hz); 7.04 (dd, 1H, J=9.8 Hz, 2.0 Hz), 6.96-7.02 (m, 1H), 5.25 (br s, 1H), 2.92-3.1 (2H, m), 1.45 (s, 9H). MS (ESI): m/z 250 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH:19]3[CH2:20][CH2:21][CH:15]2[CH2:16][O:17][CH2:18]3)[N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[N:8]1([C:6]2[N:5]=[C:4]([N:14]3[CH:19]4[CH2:20][CH2:21][CH:15]3[CH2:16][O:17][CH2:18]4)[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([NH2:22])=[CH:24][CH:25]=3)[N:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1nc(N2CCOCC2)nc(N2C3CCC2COC3)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Temperature: 130 °C
Yield: 76 %

Procedure:
To a 10 mL vial were added 8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3,2,1]octane (311 mg, 1.0 mmol), 4-aminophenylboronic acid pinacol ester (328 mg, 1.5 mmol), Pd(PPh3)4 (58 mg, 5 mol %), 1,2-dimethoxyethane (DME, 2.5 mL) and 2M Na2CO3 aqueous solution (1.5 mL). The resulting mixture was heated at 130° C. for 30 min in microwave oven. The reaction mixture was cooled to room temperature. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over (MgSO4). The solvent was removed under reduced pressure and the residue was subjected to HPLC separation to give the title compound as off-white solid (280 mg, 76% yield). MS (ESI) m/z 369.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[N+:22]([C:25]1[CH:26]=[C:27](/[C:31](/[CH3:35])=[CH:32]/[CH2:33]O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>C(#N)C>[Br:20][CH2:33]/[CH:32]=[C:31](/[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1)\[CH3:35]
Reactant: BrBr
Reactant: C/C(=C\CO)c1cccc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C/C(=C\CBr)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of triphenylphosphine (5.15 g, 19.7 nimol) in acetonitrile (140 ml) was added dropwise over 5 minutes a solution of bromine (3.15 g, 19.7 mmol) in acetonitrile (5 ml) at a rate such that the temperature did not exceed −10° C. The mixture was allowed to warm to room temperature, then to this was added a solution of (E)-3-(3-nitrophenyl)-2-buten-1-ol (Preparation 2, 4 g, 20.7 mmol) in acetonitrile (5 ml). The mixture was warmed gently to 65° C. for 1 h, cooled to room temperature and then poured onto diethyl ether (50 ml). The mixture was concentrated in vacuo, then diethyl ether (200 ml) was added. The mixture was filtered, concentrated again in vacuo and the residue purified by silica column (300 g) chromatography, eluting with 3:1 hexane/dichloromethane then 1:1 hexane/dichloromethane. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (4 g, 75%)
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:10]=1)=[O:5])C.[Li+].[OH-]>>[CH3:21][N:18]1[CH2:17][CH2:16][N:15]([C:11]2[CH:10]=[C:9]([CH:7]3[CH2:8][CH:6]3[C:4]([OH:5])=[O:3])[CH:14]=[CH:13][CH:12]=2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)C1CC1c1cccc(N2CCN(C)CC2)c1
Agent: [Li+]
Agent: [OH-]
Product: CN1CCN(c2cccc(C3CC3C(=O)O)c2)CC1

Procedure:
In a manner similar to that described for step 3 of Example 172, Intermediate 173(a) was treated with 1 M aqueous LiOH to give crude 2-[3-(4-methyl-piperazin-1-yl)-phenyl]-cyclopropanecarboxylic acid. Crude 2-[3-(4-methyl-piperazin-1-yl)-phenyl]-cyclopropanecarboxylic acid was coupled to the title compound of Example 2 (71 mg, 0.3 mmol) also in a manner similar to that described for step 3 of Example 172. Extractive work-up from ethyl acetate and saturated aqueous NaHCO3 afforded the crude product, which was purified by silica gel chromatography, eluting with 3% MeOH\CH2Cl2, to furnish the title compound (38 mg, 0.086 mmol) in 22% yield.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([CH:11]([OH:13])[CH3:12])=[CH:3][CH:2]=1>CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([C:11](=[O:13])[CH3:12])=[CH:3][CH:2]=1
Reactant: CC(O)c1ccnc2ncccc12
Solvent: CCOC(C)=O
Product: CC(=O)c1ccnc2ncccc12
Temperature: 80 °C
Yield: 85.8 %

Procedure:
1-[1,8]Naphthyridin-4-yl-ethanol (1.44 g, 8.26 mmol) was dissolved in EtOAc (250 mL), treated with IBX (7.8 g, 24.8 mmol) and heated to 80° C. for 6 h. The solution was cooled to RT and the solids removed by filtration. The product was purified (SGC using MeCN eluant) yielding the title compound (1.22 g). MS (ESI+) for m/z 173 (M+H)+. 1H NMR (CDCl3) δ 9.13 (d, 1H), 9.03 (dd, 1H), 8.85 (dd, 1H), 7.70 (d, 1H), 7.46 (dd, 1H), 2.64 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]C(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][CH2:36][CH2:37][CH2:38][S:39]([NH:42][CH2:43][CH:44](OC)[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])(=[O:41])=[O:40]>>[C:1]([O:5][C:6]([NH:8][CH:44]([CH2:43][NH:42][S:39]([CH2:38][CH2:37][CH2:36][Cl:35])(=[O:40])=[O:41])[CH2:45][S:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)OC(C)(C)C

Procedure:
3-Hexadecylthio-2-tert-butoxycarbonylaminopropylamine IV e4 is allowed to react and worked up by the same procedure as described in (4). m.p. 100.5°-101.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:15]1[CH2:16][CH2:17][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: Fc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Product: CCCCN1CCN(c2cc(F)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and 1-bromobutane, the title compound was recovered by the procedure described in Example 2; MS m/z (rel. intensity, 70 eV) 304 (M+, 22), 261 (bp), 218 (22), 190 (21), 70 (46).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[O:17]CCCO2)[CH:6]=[C:7](I)[C:8]=1[O:9][CH3:10].C([Li])CCC.[C:23](=[O:25])=[O:24].C(OCC)C>C1COCC1.O>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:12]=[O:17])=[CH:6][C:7]=1[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: COc1cc(C2OCCCO2)cc(I)c1OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(C(=O)O)c1OC
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
2-(3,4-dimethoxy-5-iodophenyl)-1,3-dioxane (42) (FIG. 22) (1.7 g, 4.86 mmole) was dissolved in 40 ml dry THF and cooled to -78° C. under an argon atmosphere. n-butyllithium (4.3 ml of a 1.25M soln.) was added and the reaction was warmed to 0° C. and was stirred at that temperature for an additional 45 minutes. The aryl lithium solution was then poured onto solid carbon dioxide covered with anhydrous diethyl ether. A white precipitate formed immediately. Water was added and the organic solvent subsequently removed in vacuo. The remaining aqueous solution was extracted with ethyl acetate. The organic layer was washed with 5% sodium thiosulfate, water, and then stirred vigorously over an equivolume of 10% HCl overnight. The organic layer was separated and the product extracted into 10% K2CO3. The basic solution was acidified with 10% HCl and the product extracted into chloroform. The organic layer was dried over MgSO4, and concentrated in vacuo to a white solid (0.412 g, 40%). The solid can be recrystallized from hexane/ethyl acetate.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:31]3[CH:32]=[N:33][N:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=34)[C:8]=2[C:7]1=[O:40].C(O)(C(F)(F)F)=O>>[NH2:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:11]1[N:10]=[C:9]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)[C:8]2[C:7](=[O:40])[NH:6][CH2:14][C:13]=2[C:12]=1[F:15]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cnn3ccccc23)c2c(c1F)CNC2=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-4-(pyrazolo[1,5-a]pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (52 mg, 0.082 mmol) and TFA (1 mL, 12.98 mmol) was stirred at 65° C. for 30 min. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound as a white solid (15 mg, 47.8%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.21-2.07 (m, 8 H), 3.31 (br s, 1 H), 4.18-4.26 (m, 1 H), 4.46 (br s, 2 H), 6.61 (br s, 1 H), 7.09 (d, J=6.35 Hz, 1 H), 7.49 (d, J=7.32, 1 H), 8.36 (br s, 1 H), 8.59 (d, J=7.81 Hz, 1 H), 8.83 (d, J=6.83 Hz, 1 H), 9.56 (br s, 1 H). [M+H] calc'd for C20H21FN6O, 381; found, 381.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([C@@H:24]5[CH2:26][C@H:25]5[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[NH:21][N:20]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.O1CCCC[CH:34]1N1C2C=CC(CN)=CC=2N=C1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([C@@H:24]5[CH2:26][C@H:25]5[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:21][N:20]=4)[CH:15]=[CH:14][N:13]=3)[CH3:34])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc([C@@H]2C[C@H]2c2cc(Nc3ccnc(NCc4ccc5[nH]cnc5c4)n3)n[nH]2)cc1
Reactant: NCc1ccc2c(c1)ncn2C1CCCCO1
Product: C[C@H](Nc1nccc(Nc2cc([C@@H]3C[C@H]3c3ccccc3)[nH]n2)n1)c1ccc2[nH]cnc2c1

Procedure:
N2-(1H-Benzimidazol-5-ylmethyl)-N4-[5-[(trans)-2-phenylcyclopropyl]-1H-pyrazol-3-yl]pyrimidine-2,4-diamine (I-27) prepared analogously starting from 91 and condensing with (1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methanamine (28) and subsequently removing the pyran in accord with the procedure in steps 6 and 7 of example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>C1(C)C=CC=CC=1>[C:10]12([C:7]3[CH:6]=[CH:5][C:4]([OH:8])=[CH:3][C:2]=3[F:1])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: Oc1cccc(F)c1
Solvent: Cc1ccccc1
Product: Oc1ccc(C23CC4CC(CC(C4)C2)C3)c(F)c1
Yield: 66 %

Procedure:
Into a 300 ml egg plant-shaped flask, 87.3 g (779 mmole) of 3-fluorophenol, 83.8 g (389 mmole) of 1-bromoadamantane, 60 ml of toluene and a stirrer rod were placed, and the resultant mixture was stirred at 140° C. for 24 hours under the stream of nitrogen gas. The reaction fluid was left standing at the room temperature, and the formed solid substance was recovered by filtration. The recovered solid substance was washed with cold toluene and dried at 60° C. under a reduced pressure, and 63.2 g of 4-(1-admantyl)-3-fluorophenol was obtained.