Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([Si:17]([CH3:28])([CH3:27])[C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([F:25])[C:19]=1[F:26])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[C:35]([C:36](N(OC)C)=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C1COCC1>[Si:17]([C:18]1[C:19]([F:26])=[C:20]([F:25])[N:21]=[C:22]([C:36]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:37])[C:23]=1[F:24])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:28])[CH3:27]
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(=O)c2cccnc2F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (66.78 g, 92.49 mL, 659.9 mmol) in THF (1.360 L) was cooled to −20° C. under nitrogen. nBuLi (2.5M in hexane) (253.0 mL of 2.5 M, 632.4 mmol) was added dropwise via cannula at such a rate as to maintain the internal temperature below −15° C. The solution was warmed to 0° C. then immediately re-cooled to −90° C. Tert-butyl-dimethyl-(2,3,5-trifluoro-4-pyridyl)silane (136 g, 549.9 mmol) was added dropwise via cannula at such a rate as to maintain the internal temperature below −85° C. After complete addition the solution became an orange suspension. The reaction mixture was stirred at −85° C. for 1 h then 2-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (116.5 g, 632.4 mmol) was added dropwise over 1 h keeping the internal temperature below −85° C. The mixture turned dark green then dark red during addition. The mixture was stirred at −85° C. for 45 min after which time Lc/Ms indicated the reaction was complete. The cooling bath was removed and the mixture warmed to −50° C. Saturated ammonium chloride solution NH4Cl (300 mL) was added and the mixture allowed to warm up to RT. The mixture was diluted with EtOAc (2.5 L). The aqueous phase was separated and extracted with more EtOAc (500 ml). The combined organics were washed with brine and partially concentrated in vacuo. The solution was dried over magnesium sulfate, filtered and concentrated in vacuo to a brown oil. The crude was purified on silica gel, eluting with 0-20% ethyl acetate in petroleum ether. This gave the title compound as a yellow oil which solidified on standing (159.6 g, 78%); 1H NMR (CDCl3) 0.35 (6H, s), 0.88 (9H, s), 7.29 (1H, m), 8.13 (1H, m), 8.37 (1H, m); 19F NMR (decoupled) −112.47, −106.7, −89.3, −61.95; MS ES (+) 371.14 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)[O:4]1)[CH3:2].C1C(=O)N([Br:25])C(=O)C1>C(#N)C>[Br:25][C:6]1[CH:7]=[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[C:10]2[C:5]=1[O:4][CH:3]([CH2:1][CH3:2])[CH2:12][CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC1CCc2cc(NS(C)(=O)=O)ccc2O1
Solvent: CC#N
Product: CCC1CCc2cc(NS(C)(=O)=O)cc(Br)c2O1
Temperature: 25 °C
Reaction time: 7 h
Yield: 47.1 %

Procedure:
To a solution of the title compound from Step 5 (170 mg, 0.667 mmol) in ACN (6 mL) was added NBS (156 mg, 0.867 mmol). The mixture was stirred for 7 h at rt. It was then extracted with DCM, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified with prep-TLC (PE/EA 3:1) to give the title compound (105 mg, 47%) as a gray solid. 1H NMR (400 MHz, CDCl3): δ 7.23 (d, J=2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.24 (s, 1H), 4.01-3.99 (m, 1H), 2.97 (s, 3H), 2.84-2.77 (m, 2H), 2.04-1.99 (m, 1H), 1.85-1.66 (m, 3H), 1.09 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH:9]1([C:14]2[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:16]=[CH:15][C:14]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: OB(O)c1ccc(C2CCCC2)cc1
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: O
Solvent: COCCOC
Product: Clc1cc(-c2ccc(C3CCCC3)cc2)ccn1
Yield: 67.9 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (6.43 g, 26.3 mmol), (4-cyclopentylphenyl)boronic acid (5.0 g, 26.3 mmol), Pd(Ph3P)4 (0.0.91 g 0.79 mmol), sodium carbonate (8.37 g, 79 mmol), DME (257 mL) and water (64 mL) was degassed with nitrogen and then refluxed overnight. The reaction mixture was concentrated and extracted with ethyl acetate. The the ethyl acetate layer was dried on Na2SO4 and then further purified by column chromatography using dichloromethane in hexanes and then vacuum distilled to give 2-Chloro-4-(4-cyclopentylphenyl)pyridine (4.6 g, 68% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[CH:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[N:7]3)[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: C1CCC(N2CCNCC2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(c1)nnn2CCCCN1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-cyclohexyl)piperazine (5.1 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.5 g compound (I-46) with a yield of 63.7%. ESI-MS [M+H]+: m/z 341.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:40][CH2:39][C:38]5[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: COc1ccc(CNC(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)cc1
Yield: 68.7 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-methoxybenzylamine (available from Aldrich Chemical Company, Inc.; 85 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(4-methoxy-benzylcarbamoyl)-biphenyl-2-carboxylic acid (85 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br s, 1H), 9.08 (t, J=5.9 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.95 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 4.44 (d, J=6.0 Hz, 2H), 3.73 (s, 11H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]>CCOCC.CCCCCC>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:12]([CH2:13][CH2:14][CH3:15])[C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[C:3]([OH:27])=[O:2])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CCCN(c1c(C)cc(C)cc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCN(c1c(C)cc(C)cc1C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Yield: 79.3 %

Procedure:
In the same amn as described in Example 109, 0.602 g (1.54 mmol) of the product of Example 105 provided 0.461 g (79%) of the desired carboxylic acid as a white solid after trituration with ether/hexane. Electrospray Mass Spec 378.2(M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:19][NH2:20])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.Cl[C:22](OCC)=[O:23]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[C:22]([OH:23])[NH:20][N:19]=1
Reactant: CCOC(=O)Cl
Reactant: NN=C(Cc1ccnc2ccccc12)c1ccccn1
Solvent: c1ccncc1
Product: Oc1[nH]nc(-c2ccccn2)c1-c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1-pyridin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazine (2.0 g, 7.6 mmol) in pyridine (20 mL) at 0° C. is added ethyl chloroformate (2 mL) dropwise. The mixture is warmed to room temperature and stirred for 2 h. The solution is refluxed for 12 h and concentrated in vacuo. The residue is treated with dichloromethane/methanol and the precipitate collected by vacuum filtration. The precipitate is triturated with ethanol to yield the title compound, 300 mg (13%), as a white solid.
Reaction SMILES: [Br-].[C:2]1([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:33]1[O:43][C:36]2([CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]2)[O:35][CH2:34]1>>[C:2]1([CH:8]=[C:39]2[CH2:40][CH2:41][C:36]3([O:43][CH2:33][CH2:34][O:35]3)[CH2:37][CH2:38]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Br-]
Agent: [Li]CCCC
Product: C(=C1CCC2(CC1)OCCO2)c1ccccc1

Procedure:
For example, when n is the bridging group --CH2 --, an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 2-chlorophenylmethyl bromide, is reacted with triphenylphosphine in toluene, affording the corresponding phenylmethyltriphenylphosphonium bromide. The so-prepared phosphonium bromide is then treated with n-butyllithium, and reacted with 1,4-cyclohexanedione mono-ethylene ketal, yielding the appropriate 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane. The 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane is in turn reduced with hydrogen gas in the presence of 10% palladium on charcoal, giving the corresponding 8-phenylmethyl-1,4-dioxaspiro[4.5]-decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 2 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][C:5]1[S:13][C:12]2[C:11](Cl)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1>C(#N)C>[CH3:4][C:5]1[S:13][C:12]2[C:11]([S:2][CH3:1])=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1
Reactant: Cc1cc2ncnc(Cl)c2s1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC#N
Product: CSc1ncnc2cc(C)sc12
Yield: 97 %

Procedure:
A solution of sodium thiomethoxide (24S mg) and 6-methyl-4-chlorothieno[3,2-d]pyrimidine (Acta Pol. Pharm. (1986), 43(2), 97-100) (650 mg) in acetonitrile (50 mL) was stirred overnight. The mixture was filtered and the solid was washed with acetonitrile. The combined filtrate and washes were evaporated to give the title compound as a white solid (665 mg, 97%);
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]12([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][C:30]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: Nn1c(-c2ccccc2)nc2ccccc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1c(-c2ccccc2)nc2ccccc2c1=O

Procedure:
3-Amino-2-phenyl-4(3H)-quinazolinone and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11-1.15 (m, 3H), 1.33-1.44 (m, 6H), 1.53-1.57 (m, 3H), 1.72-1.77 (m, 3H), 1.79-1.92 (m, 2H), 7.43-7.50 (m, 3H), 7.58-7.64 (m, 3H), 7.73-7.76 (m, 1H), 7.88-7.64 (m, 1H), 8.18-8.21 (m, 1H), 10.96 (s, 1H) ppm; MS (DCI/NH3) m/z 414 (M+H)+; Elemental Analysis: Calculated for C26H27N3O2.1.15H2O: C, 71.92; H, 6.80; N, 9.68. Found: C, 71.93; H, 6.79; N, 9.77.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncnc(O)c2c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
A mixture of 4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (60.0 g, 271.2 mmol, for preparation see WO 0071129), phosphorus oxychloride (30.3 mL, 325.4 mmol) and diisopropylethyl amine (37.7 mL, 217 mmol) in toluene (800 mL) was heated to reflux under argon for 18 h and then cooled to room temperature. The mixture was concentrated on rotovap and the residue was diluted with dichloromethane (1000 mL) and cold sodium bicarbonate solution (300 mL). The resulting mixture was stirred at room temperature for 10 min. The separated organic layer was washed with cold brine (300 mL), dried, and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with dichloromethane to provide the desired compound (64.8 g, 99%) as a yellow solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCOC(=O)CCC(=O)O
Yield: 77.7 %

Procedure:
2-Hydroxyethyl methacrylate (25 g, 0.195 mol) and succinic anhydride (19.5 g, 0.195 mol) were added to dichloromethane (200 mL) under nitrogen. Triethylamine (28.5 ml, 20.72 g, 1.05 equiv.) was then added dropwise over 20 minutes and the reaction mixture was refluxed for 1.5 hours. The reaction mixture was then diluted with dichloromethane (200 mL), washed with 2 M HCl (150 mL) and then finally with brine (100 mL). The organic phase was separated from the aqueous phase, dried (MgSO4 and Na2SO4) and evaporated to dryness, yielding a viscous, colourless liquid (34.9 g, 77.8% yield). 1H NMR δ 1.89 (s, 3H, CH3), 2.59-2.67 (m, 4H, 2×CH2CO), 4.31 (br. s, 4H, 2×CH2OCO), 5.55 (s, 1H, vinyl CH), 6.08 (s, 1H, vinyl CH). 13C NMR δ 17.96, 28.64, 28.73, 62.15, 62.29, 126.12, 135.79, 167.11, 171.90, 177.73.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].CN1CCOCC1.[NH2:35][CH2:36][C:37]#[N:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:36]([CH2:37][NH:38][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:11]1[CH2:10][CH2:9]2)#[N:35]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)O)ccc2-3)cc1
Reactant: N#CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)NCC#N)ccc2-3)cc1
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Example 127, 20 mg, 0.055 mmol) in DMF (1 mL) was added 4-methylmorpholine (0.036 mL, 0.33 mmol), 2-aminoacetonitrile (5.55 mg, 0.1 mmol) and BOP (43.8 mg, 0.1 mmol). The reaction mixture was stirred overnight and was then purified by preparative HPLC (Phenomenex Luna 5 u C18 21.2×100 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.9 min) to give N-(cyanomethyl)-2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (11.2 mg, 0.026 mmol, 46.9% yield): product HPLC ret. time=9.89 min. (condition G); LC/MS M+1=402.1; 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (1H, d, J=7.92 Hz), 7.72 (2H, d, J=8.36 Hz), 7.43-7.53 (2H, m), 7.37 (2H, d, J=8.36 Hz), 5.13 (1H, s), 4.19 (2H, d, J=1.76 Hz), 3.06 (4H, s), 2.67 (2H, t, J=7.59 Hz), 1.62-1.77 (2H, m), 0.97 (3H, t, J=7.37 Hz).
Reaction SMILES: [NH2:1][C@:2]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[C:20]([NH:22][CH2:23][C@H:24]3[CH2:26][C@@H:25]3[CH3:27])[N:19]=[C:18]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[CH:17]=2)=[N:13][CH:12]=1)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C(=O)N([Cl:41])C(=O)C1>C(Cl)Cl>[NH2:1][C@:2]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[C:20]([NH:22][CH2:23][C@H:24]3[CH2:26][C@@H:25]3[CH3:27])[N:19]=[C:18]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])[C:17]=2[Cl:41])=[N:13][CH:12]=1)([CH3:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@H]1C[C@@H]1CNc1cc(-c2ncc([C@](C)(N)Cc3ccccc3)o2)cc(N(C)S(C)(=O)=O)n1
Solvent: ClCCl
Product: C[C@H]1C[C@@H]1CNc1cc(-c2ncc([C@](C)(N)Cc3ccccc3)o2)c(Cl)c(N(C)S(C)(=O)=O)n1
Reaction time: 15 h

Procedure:
To a solution of N-[4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3-oxazol-2-yl}-6-({[(1S,25)-2-methylcyclopropyl]methyl}amino)pyridin-2-yl]-N-methylmethanesulfonamide (0.009 g, 0.015 mmol) in 0.3 mL CH2Cl2 was added 0.09 mL of a 0.15M stock solution of NCS in CH2Cl2. After 15 h, a further 0.10 mL CH2Cl2 and 0.1 mL 0.15 M stock solution of NCS in CH2Cl2 were added. After 24 h, the reaction was concentrated, redissolved in DMF and purified by preparative HPLC to afford N-[4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3-oxazol-2-yl}-3-chloro-6-({[(1S,2S)-2-methylcyclopropyl]methyl}amino)pyridin-2-yl]-N-methylmethanesulfonamide as a yellow solid. 1H NMR (400 MHz, d4-MeOH) δ 7.30-7.29 (m, 3H), 7.24 (s, 1H), 7.04-7.02 (m, 3H), 3.47 (d, J=13.3 Hz, 1H), 3.28 (s, 3H), 3.26-3.20 (m, 5H), 1.71 (s, 3H), 1.06 (d, J=5.9 Hz, 3H), 0.85 (m, 1H), 0.71 (m, 1H), 0.43 (m, 1H), 0.27 (m, 1H). LCMS (M+H)=505 (chlorine pattern).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1[Br:42].Cl>CO.O1CCOCC1>[Br:42][C:9]1[C:10]([O:27][CH2:28][CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)=[N:11][C:12]2[N:13]([N:14]=[CH:15][C:16]=2[C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1c(Br)c(OCC2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
tert-Butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)methyl)piperidine-1-carboxylate (0.56 g, 68.9 mmol) was dissolved in methanol (6 ml) and treated with 4N hydrochloride solution in dioxane (4 ml) at 65° C. for 30 min. The reaction solution was concentrated and the crude product (0.48 g) was used in the next step without further purification. LC-MS: 453 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14]>FC(F)(F)C(O)=O>[C:11]([C:3]1[C:4](=[O:10])[O:5][C:6]([CH2:8][CH3:9])=[CH:7][C:2]=1[OH:1])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCc1cc(O)cc(=O)o1
Reactant: CCCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)c1c(O)cc(CC)oc1=O
Temperature: 90 °C
Yield: 64.5 %

Procedure:
According to the method of Douglas and Money (see: Can. J. Chem. 1968, 46, 695), 4-hydroxy-6-ethyl-2-pyrone (see: Hsung, et. al. Synthesis 2007, 749; 1.24 g, 8.85 mmol) was dissolved in trifluoroacetic acid (4 mL) in a pressure-safe vessel. Butyryl chloride (1.0 mL, 9.73 mmol) was added and the solution flushed with argon. The vessel was sealed and stirred in a 90° C. heating bath overnight. After cooling to room temperature, the solution was poured onto powdered sodium bicarbonate (9 g) before water (80 mL) was added carefully. Organics were extracted from the aqueous slurry with dichloromethane (3×80 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel with gradient elution (10→20% ether in hexanes) to afford 3-butyryl-6-ethyl-4-hydroxy-2-pyrone (1.20 g, 65%) as an oily solid. Used without further characterization.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:9])[CH2:5][N+:6]([O-:8])=[O:7].[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>>[CH2:10]([O:12][P:13]([CH2:2][CH:3]=[C:4]([CH3:9])[CH2:5][N+:6]([O-:8])=[O:7])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]
Reactant: CC(=CCBr)C[N+](=O)[O-]
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC=C(C)C[N+](=O)[O-])OCC

Procedure:
To 0.1 Mol of 1-bromo-3-methyl-4-nitro-2-butene was added 0.1 Mol of triethylphosphite. The reaction was started by immersing the mixture into a 50° C. bath and completed under continued removal of bromoethane by distillation. The residue was purified via column chromatography over silica gel using ether as solvent. The product was obtained as a yellowish liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[OH:37].[ClH:38]>CC#N>[ClH:38].[OH:37][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)=[CH:27][C:22]=1[O:21][CH3:20]
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: Cl
Solvent: CC#N
Product: COc1cc(-c2ccc3nc(NC(=O)c4cccnc4)nn3c2)ccc1O

Procedure:
The title compound was prepared following procedure described for example 56 but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 400 mg; 1.26 mmol; 1.0 eq.) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (629 mg; 2.51 mmol; 2.0 eq.) as a light yellow solid (249 mg, 55%). HPLC, Rt: 1.71 min. (purity 60.7%). LC/MS, M+(ESI): 362.0, M−(ESI): 360.0. CHN analysis: [C19H15N5O3.1 HCl.0.4 CH3CN.0.6H20] Corrected: C, 55.95%; H, 4.36%; N, 17.79%. Found: C, 55.95%; H, 4.76%; N, 17.53%.