Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:14]3[N:15]=[C:16]([CH3:21])[C:17]([C:18]([OH:20])=O)=[C:13]3[CH:12]=[C:11]([CH3:22])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:31][NH2:32])([CH3:26])([CH3:25])[CH3:24]>S(Cl)(Cl)=O.ClCCl>[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:31][NH:32][C:18]([C:17]1[C:16]([CH3:21])=[N:15][N:14]2[C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:10][C:11]([CH3:22])=[CH:12][C:13]=12)=[O:20])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: Cc1cc(OCC2CCCCC2)n2nc(C)c(C(=O)O)c2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 110 mg (0.364 mmol) of 7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 120A in 1 ml of thionyl chloride was stirred at 100° C. for 1 h. After the reaction had ended, the solvent was drawn off under reduced pressure and the residue was suspended in 3 ml of dichloromethane and then added to a solution of 102.3 mg (0.473 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A in 2 ml of dry dichloromethane. The resulting solution was stirred at room temperature overnight. The solvent was drawn off under reduced pressure and the residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 40 mg (13% of theory, 59% pure) of the target compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[CH3:6][C:7]1([CH3:14])[CH2:12]C[C:10](=[O:13])[CH2:9][CH2:8]1.C(OCC)=O>C(OCC)C>[OH:5]/[CH:3]=[C:4]1\[C:10](=[O:13])[CH2:9][CH2:8][C:7]([CH3:14])([CH3:12])[CH2:6]\1
Reactant: CC1(C)CCC(=O)CC1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC=O
Product: CC1(C)CCC(=O)/C(=C\O)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 818.5 %

Procedure:
A dry round-bottomed flask was charged with sodium hydride (60% dispersion in mineral oil, 475 mg, 11.9 mmol) and diethyl ether (24 ml). The reaction was cooled to 0° C. and ethanol (0.06 ml, 1.03 mmol) was added dropwise. The suspension was stirred for at 0° C. for 20 min then a solution of 4,4-dimethylcyclohexanone (1.50 g, 11.9 mmol) and ethyl formate (1.45 ml, 17.8 mmol) in diethyl ether (3 ml) was added dropwise over 15 min. The yellow solution was stirred at 0° C. for 3 h then slowly allowed to warm to room temperature overnight. Ethanol (0.24 ml) was added and the mixture was stirred at room temperature for 1 h then quenched with water and extracted with diethyl ether. The aqueous layer was acidified with 6M HCl until pH=2 then extracted with diethyl ether (2×). The combined organic layers were washed with brine then dried over sodium sulfate, filtered and concentrated to give 1.30 g (71%) of 2-[1-hydroxy-meth-(Z)-ylidene]-4,4-dimethyl-cyclohexanone as a pale brown oil which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ (ppm) 14.40 (br. s., 1H), 8.58 (s, 1H), 2.39 (t, J=6.8 Hz, 2H), 2.13 (s, 2H), 1.48 (t, J=6.8 Hz, 2H), 1.00 (s, 6H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][OH:12].Cl[C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]3[N:26]=[C:27]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[N:28]=[C:29]([C:30]4[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=5)[CH2:37][C:38]5[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=5)=[N:34][CH:35]=4)[C:24]=3[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[H-].[Na+]>O>[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][O:12][C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]3[N:26]=[C:27]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[N:28]=[C:29]([C:30]4[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=5)[CH2:37][C:38]5[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=5)=[N:34][CH:35]=4)[C:24]=3[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: CN(C)CCO
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(OCCN(C)C)nc3)cn2)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a toluene solution (2 ml) of N,N-dimethylethanolamine (139 μl, 0.138 mmol) and {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (150 mg, 0.23 mmol) obtained in Step A in Example 1-D-48, 60% oily NaH (46 mg) was added, followed by refluxing for 4 hours. The reaction mixture was cooled to room temperature, and diluted with water, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, followed by filtering off the magnesium sulfate, and subsequently the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1), to obtain a crude product of (5-{7-[6-(2-dimethylamino-ethoxy)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-bis-(4-methoxy-benzyl)-amine as a yellow solid (67 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-72) as a yellow powder (12 mg, 29%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:30]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[CH3:31].C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[CH2:30]([N:32]1[CH:36]=[C:35]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:34]=[N:33]1)[CH3:31]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
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: CCn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)cn1
Temperature: 80 °C
Yield: 71.7 %

Procedure:
A mixture of Example C1 (0.15 g, 0.40 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.088 g, 0.40 mmol), and K2CO3 (0.2 g, 1.44 mmol) in 4:1 dioxane/water (5 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.040 g, 0.036 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, treated with brine, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with Et2O, allowed to stand at RT and the resulting solid collected via filtration to afford N-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (137 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.30 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 7.97 (s, 1 H), 7.71 (dd, J=9.0, 2.9 Hz, 1 H), 7.24 (d, J=2.4 Hz, 1 H), 6.69 (dd, J=5.7, 2.4 Hz, 1 H), 4.13 (q, J=7.3 Hz, 2 H), 3.86 (m, 5 H), 3.40 (m, 4 H), 1.71 (m, 2 H), 1.59 (m, 2 H), 1.37 (t, J=7.3 Hz, 3 H); MS (ESI) m/z: 478.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:26]([CH3:28])[CH3:27].O>CN(C=O)C>[CH3:27][CH:26]([N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18])[CH3:28]
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 21 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 mmoles) and potassium carbonate (83 mg, 0.6 mmoles) in 10 ml DMF was added dropwise 2-iodopropane (0.075 ml, 0.75 mmoles) under an atmosphere of nitrogen and stirred overnight at 21° C. The reaction mixture was poured into 50 ml water and after stirring for one hour the white precipitate was collected and dried. Crystallization from methanol gave 60 mg (40% yield) of the desired 6-(2-propyl)-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 163.5°-164.5° C.; TLC 1:4 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ1.454 (d, 6H, J=6.8), 5.3 (m, 1H, J=6.8), 7.36-7.60 (m, 6H), 8.77 (dd, 1H, J=8.3, 1.7), 8.93 (dd, 1H, J=4.4, 1.7); 13C NMR (75 MHz, CDCl3) δ154.20, 151.13, 137.54, 136.85, 134.18, 129.99,129.55, 128.28, 127.69, 121.95, 119.70, 46.57, 21.87; IR (KBr) vmax 1647, 1614, 1591, 1566, 1552, 1487, 1468, 1441, 1419, 1400, 1388, 1273, 1242, 1182, 1170, 796, 783, 711, 700, 605 cm-1 ; mass spectrum (EI), m/e 298. Anal. (C17H15ClN2O) Calcd.: C, 68.34; H, 5.06; N, 9.38. Found: C, 68.25; H, 5.11; N, 9.38.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[NH:28][CH2:29][CH2:30][CH2:31][NH2:32]>C(O)(C)C>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:22]2[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])=[CH:11][CH:10]=1
Reactant: Cc1cccc(C)c1NCCCN
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NCCCNCC(O)COc1ccc(O)cc1

Procedure:
4.23 g. 4-Benzyloxyphenyl glycidyl ether, 5.9 g. N-(2,6-dimethylphenyl)-1,3-diaminopropane and 5 ml. isopropyl alcohol are stirred for 24 hours at ambient temperature. The reaction mixture is worked up by chromatography on silica gel.
Reaction SMILES: [NH2:1][C@H:2]([CH3:28])[CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[N:11][C:12]([NH2:13])=[C:7]2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][C:15]=2[F:27])=[N:5]1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:13][C:12]1[N:11]=[CH:10][N:9]=[C:8]2[N:4]([CH2:3][C@H:2]([NH:1][C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH3:28])[N:5]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:16][C:15]=3[F:27])[C:7]=12
Reactant: N#CCC(=O)O
Reactant: C[C@@H](N)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
To a solution of 1-[(2R)-2-aminopropyl]-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (1826.mg, 4.83 mmol), 2-cyanoacetic acid (821 mg, 9.7 mmol) and TEA (2.0 mL, 14.5 mmol) in DMF (25 mL) was added HATU (2.75 g, 7.24 mmol). The reaction mixture was stirred at room temperature for 20 hr. The mixture was then evaporated to an oil and dissolved in ethyl acetate (100 mL) and washed with 5% citric acid (50 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. The crude material was purified by Isolera (10 g col, 2%-6% MeOH/DCM) to obtain 2.1 g (98%) of N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]-2-cyano-acetamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](O)=[O:20].C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:19](=[O:20])[CH:18]([CH3:17])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(Cc1ccccc1)C(=O)O
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: CC(Cc1ccccc1)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 2-methyl-3-phenylpropanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.13 (dd, J=7.0, 21.3, 1H), 7.40 (ddd, J=7.5, 15.5, 25.3, 4H), 7.31-7.22 (m, 6H), 4.42-4.27 (m, 1H), 3.58 (dd, J=6.6, 13.1, 1H), 3.45 (dd, J=13.1, 21.0, 1H), 3.25-3.15 (m, 1H), 2.81-2.67 (m, 3H), 2.49-2.19 (m, 5H), 2.04 (ddd, J=6.0, 12.1, 24.6, 1H), 1.82-1.64 (m, 1H), 1.57-1.40 (m, 1H), 1.40-1.30 (m, 1H), 1.28 (d, J=6.4, 3H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:40]2[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]2)=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:7]=1.FC1C=C(C2C=C3C(C4C=NN(CC5C=CC=C(F)C=5)C=4)=CNC3=NC=2)C=NC=1N1CCNCC1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:31])=[O:32])[C:11]3=[N:12][CH:13]=2)[CH:5]=[N:4][C:3]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cl
Agent: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5cnc(N6CCNCC6)c(F)c5)cc34)cn2)c1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCNCC5)c(F)c4)cnc32)cc1
Yield: 72.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-fluoro-5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (step 1 product of example 173) (550 mg, 0.758 mmol) was deprotected in methanol/HCl in dioxane (5/5 ml) to afford 342 mg (72% yield) of the titled compound. MS: m/z=626.5 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH3:12])[O:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][N:6]=1.Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[CH3:23][O:22][C:20]1[CH:21]=[C:16]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([O:4][CH:3]([CH3:12])[C:2]([F:1])([F:13])[F:14])[CH:10]=2)[N:17]=[N:18][CH:19]=1
Reactant: CC(Oc1cc(O)ccn1)C(F)(F)F
Reactant: COc1cnnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: COc1cnnc(Oc2ccnc(OC(C)C(F)(F)F)c2)c1
Yield: 43.1 %

Procedure:
2-(2,2,2-Trifluoro-1-methylethoxy)-4-pyridinol (0.64 g, 3.09 mmol), 3-chloro-5-methoxy-pyridazine (0.44 g, 3.09 mmol), potassium carbonate (0.85 g, 6.18 mmol) and CuBr (0.89 g, 6.18 mmol) were stirred under nitrogen in diglyme (5 mL) at 100° C. for 6 days. The mixture was then poured in water and extracted several times with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and evaporated in-vacuo. The crude product was purified by flash chromatography to give 5-methoxy-3-[[2-(2,2,2-trifluoro-1-methylethoxy)-4-pyridinyl]oxy]pyridazine (0.42 g, 43% yield, Compound No. 10) as a white solid, mp=100° C. -102° C.
Reaction SMILES: [O+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[O+]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl([O-])(=O)(=O)=O.[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[O+:27]=[C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=1>>[Cl:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[O:1]1[C:6]2[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=2[C:4](=[CH:13][C:14]([C:15]2[CH:33]=[CH:28][CH:29]=[CH:17][CH:16]=2)=[CH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[O+:27]=[C:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:25]=2)[CH:3]=[CH:2]1
Reactant: Cc1cc(-c2ccccc2)[o+]c2ccccc12
Reactant: c1cc[o+]cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: C1=CC(=CC(=Cc2cc(-c3ccccc3)[o+]c3ccccc23)c2ccccc2)c2ccccc2O1

Procedure:
This pyrylium salt was made in a manner identical to that set forth in Example 1 above, except the pyrylium perchlorate salt starting material of Example 1 was replaced with 4-methylflavylium perchlorate. The pyrylium salt product was identified as the above-noted salt having a melting point of 298°-299° C. and an empirical formula of C39H27ClO6.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][NH:18][CH2:19][C:20]1[CH:34]=[CH:33][C:23]2[N:24]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:25]=[N:26][C:22]=2[CH:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:18]([CH3:17])[CH2:19][C:20]4[CH:34]=[CH:33][C:23]5[N:24]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][O:28]6)[CH:25]=[N:26][C:22]=5[CH:21]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CNCc1ccc2c(c1)ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc2c(c1)ncn2C1CCCCO1)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C
Yield: 27.7 %

Procedure:
A tube was charged with 53 (846 mg, 3.6 mmol), 68 (880 mg, 3.6 mmol), DIPEA (5 mL) and IPA (10 mL), degassed, sealed and then heated at 120° C. overnight. The solvent was evaporated in vacuo to afford 444 mg (27%) N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methyl-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)-pyrimidine-2,4-diamine (70) as a yellow solid; MS (ESI) m/z=445.2 [M+1]+.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].Cl[C:21]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][C:11]1=[O:13])([O:8][CH3:21])=[O:7]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Yield: 60 %

Procedure:
Following the procedure of Preparation I, Part b, but substituting 2.0 gm. (0.0069 mole) of the dimethyl ester of 4-cyano-4-phenylpimelic acid (prepared in Part a, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 45 ml. of the tetrahydrofuran, 1.57 gm. (0.014 mole) of the potassium tert-butoxide, and 10 ml. of the 2.5 N acetic acid instead of the 700 ml., the 24.4 gm., and the 175 ml., respectively, there is obtained a residue which upon recrystallization from technical hexane gives 1.07 gm. (60% yield) of the desired 2-carbomethoxy-4-cyano-4-phenylcyclohexanone having a melting point at 79.5° to 81.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])#[N:2].[CH3:20][C:21](C)([O-:23])[CH3:22].[K+].C(C1OC1)Br>CC(N(C)C)=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]1[CH2:22][O:23]1)#[N:2]
Reactant: N#Cc1ccccc1CCCCc1ccccc1O
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1CCCCc1ccccc1OCC1CO1
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 1(a), 634 mg of 2-[4-(2-cyanophenyl)butyl]phenol (prepared as described in Preparation 11), 283 mg of potassium t-butoxide and 345 mg of epibromohydrin were reacted in 6 ml of dimethylacetamide. The crude product, extracted as described in Example 1, was purified as described in Example 1, to give 690 mg (yield 89%) of the title compound as an oil.
Reaction SMILES: [Cl-].[O:2]([CH:9]([CH3:13])[C:10]([OH:12])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>>[O:2]([CH:9]([CH3:13])[C:10]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][C:19]2[CH:27]=[CH:28][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH2:26][CH2:25]1)=[O:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2CCNCC2)cc1
Reactant: CC(Oc1ccccc1)C(=O)O
Agent: [Cl-]
Product: COc1ccc(CN2CCN(C(=O)C(C)Oc3ccccc3)CC2)cc1

Procedure:
By carrying out the preparation as in Example 12 (Stage A), but using the chloride of 2-phenoxypropionic acid and 1-(4-methoxybenzyl)piperazine, the title product is obtained.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:43]1([NH2:48])[CH2:47][CH2:46][CH2:45][CH2:44]1>C(#N)C>[CH:43]1([NH:48][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: NC1CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)NC1CCCC1
Yield: 79.9 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.212 g, 0.56 mmol, 1.0 eq), and triethylamine (96 uL, 65 mg, 0.65 mol, 1.15 eq), in acetonitrile (10 mL) was treated with isobutyl chloroformate (77 uL, 86 mg, 0.59 mmol, 1.05 eq) followed by cyclopentylamine (111 uL, 96 mg, 1.13 mmol, 2.0 eq). Workup as above provided 198 mg (79%) of L-isoleucine, N-[1-[2-(N-cyclopentylamino)-2-oxoethyl]-L-prolyl] benzylamide.
Reaction SMILES: [C:1]([C:4]1[C:20]([OH:21])=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]#[N:16])=[C:6]([CH2:22][CH3:23])[CH:5]=1)(=[O:3])[CH3:2].[OH-:24].[Na+]>C(O)C>[C:1]([C:4]1[C:20]([OH:21])=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:18])[C:15]([NH2:16])=[O:24])=[C:6]([CH2:22][CH3:23])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCC(C)(C)C#N
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(C(C)=O)c(O)cc1OCCCCCC(C)(C)C(N)=O

Procedure:
A mixture of 500 mg of 7-(4-acetyl-2-ethyl-5-hydroxyphenoxy)-2,2-dimethylheptanenitrile in 150 ml of 5N sodium hydroxide and 50 ml of ethanol was heated at reflux overnight. The ethanol was removed by evaporation, 100 ml of water were added, and the solution was extracted with diethyl ether. The organic layer was separated, dried, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 1:1 ethyl acetate/hexane to provide 34 mg of the desired title product, m.p.=73°-74° C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>C(#N)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[I:1])=[CH:18][CH:17]=1
Reactant: Nc1ccccc1I
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1ccc(CNc2ccccc2I)cc1

Procedure:
To a solution of 2-iodoaniline (280 mg, 1.82 mmol) in acetonitrile (6 mL) was added K2CO3 (212 mg, 1.54 mmol) and 4-chlorobenzyl bromide (276 mg, 1.34 mmol). After refluxing overnight under a nitrogen atmosphere, the reaction mixture was diluted with ethyl acetate and filtered. The solvent was removed under reduced pressure and the crude product was used in next step.