Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:13])[NH:8]2.[CH:14]1([N:17]2[CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=[N:18]2)[CH2:16][CH2:15]1>>[C:3]([N:8]1[C:9]2[C:4](=[C:3]([O:2][C:1]3[CH:10]=[CH:9][CH:4]=[CH:5][C:6]=3[C:7]#[N:8])[C:12]([C:20]3[CH:19]=[N:18][N:17]([CH:14]4[CH2:15][CH2:16]4)[CH:21]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[CH3:13])(=[O:2])[CH3:12]
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Reactant: COc1cccc2c1CC[C@H](C)N2
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(Oc3ccccc3C#N)c2CC[C@@H]1C

Procedure:
(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile was synthesized according to the procedures described above for Example 36, with the following changes: (1) in Step 2, 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3) Step 3 (removal of the Boc-protecting group) was eliminated. 1H NMR (300 MHz, CD3OD) δ ppm 0.92-1.05 (m, 4H), 1.16 (d, J=6.30 Hz, 3H), 1.35-1.52 (m, 1H), 2.10-2.40 (m, 5H), 2.58-2.80 (m, 1H), 3.55-3.65 (m, 1H), 4.68-4.8 9 (m, 1H), 6.40-6.55 (m, 1H), 7.05-7.15 (m, 1H), 7.30-7.52 (m, 2H), 7.55-7.65 (m, 1H), 7.70-7.80 (m, 2H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 413 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:31][CH3:32])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7])[CH3:2].[Li+].[OH-]>>[CH2:1]([C:3]1[C:4]([O:31][CH3:32])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2CCc2ccccc2)c(C(=O)OC)c1OC
Agent: [Li+]
Agent: [OH-]
Product: CCc1ccc(NS(=O)(=O)c2ccccc2CCc2ccccc2)c(C(=O)O)c1OC

Procedure:
A mixture of Example 575A and Example 576A (0.10 g) was treated with LiOH according to the procedure of Example 385I, giving the title compound, 12.4 mg, and Example 576B, 42 mg. 1H NMR (DMSO-d6) δ 1.06 (t, 3H), 2.42 (q, 2H), 2.84 (t, 2H), 3.15 (t, 2H), 3.62 (s, 3H), 6.74 (d, 1H), 7.18-7.22 (m, 2H), 7.14-7.30 (m, 4H), 7.35 (t, 1H), 7.45 (d, 1H), 7.55 (t, 1H), 7.80 (d, 1H), 9.95 (s, 1H), 13.20 (br s, 1H); MS (ESI(−)) m/e 438 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6](=[N:7]O)[CH2:5][C:4]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:9][CH3:10])[O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:20][C:2]1([CH3:1])[CH:6]([NH2:7])[CH2:5][C:4]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:9][CH3:10])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(=NO)C(C)(C)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCC1(COCc2ccccc2)CC(N)C(C)(C)O1
Reaction time: 1 h

Procedure:
1.9 g of the hydroxyimino compound of Example 7 in 5 ml of diethyl ether was added to 260 mg of lithium aluminium hydride in 25 ml of diethyl ether, and the resulting mixture was stirred at reflux temperature for 2 hours. A further 100 mg of lithium aluminium hydride was added and stirring at reflux temperature was continued for 1 hour. 0.36 ml of water was then added to the reaction mixture, followed by 0.36 ml of 15% solution of sodium hydroxide and a further 1.08 ml of water. The mixture was then filtered and evaporated to dryness. Thin layer chromatography indicated that the residue contained some unconverted starting material. The desired amine product was obtained from the residue by extracting the residue twice into dilute hydrochloric acid, washing the extracts with diethyl ether, rendering the aqueous phase alkaline by addition of dilute sodium hydroxide solution, saturating the aqueous phase with sodium chloride and extracting the amine by washing three times with diethyl ether. The combined ether extracts were dried over magnesium sulphate and evaporated to give 1.0 g (50%) of the desired product. The product was a mixture of two isomers which were shown to be separable using thin-layer chromatography on silica gel using 20% acetone in petrol as eluant.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:23]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CCOCC.O>[C:2]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=[CH:6][C:5]([C:8]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:23]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCCNc1nccc(-c2c(-c3ccc(Br)cc3)nn3c(NCCCC)cccc23)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCNc1nccc(-c2c(-c3ccc(-c4ccccc4)cc3)nn3c(NCCCC)cccc23)n1
Yield: 68.6 %

Procedure:
To a solution of 2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine (52 mg, 0.11 mmol) in tetrahydrofuran was added phenylboronic acid (26 mg, 0.21 mmol), sodium carbonate (0.21 mL, 2 M aqueous, 0.42 mmol), and dichlorobistriphenylphosphine palladium (II) (7.5 mg, 0.01 mmol). The mixture was heated at reflux for 3.5 hours. The resultant solution was cooled to room temperature and diluted with ether and water was added. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography provided 2-[1,1′-biphenyl]-4-yl-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (37 mg, 73%) as a yellow solid. 1H NMR (CDCl3): δ 8.05 (d, 1 H), 7.83–7.69 (m, 7 H), 7.51 (m, 2 H), 7.43–7.33 (m, 2 H), 6.44 (d, 1 H), 6.12 (t, 1 H), 6.05 (d, 1 H), 5.16 (broad, 1 H), 3.52 (m, 2 H), 3.42 (m, 2 H), 1.84–1.43 (m, 8 H), 1.05–0.99 (m, 6 H); MS m/z 491 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12](=O)[NH:13][CH:14]1[CH:21]2[CH2:22][CH:17]3[CH2:18][C:19]([OH:24])([CH2:23][CH:15]1[CH2:16]3)[CH2:20]2)(C)(C)C>C1COCC1>[CH3:12][NH:13][CH:14]1[CH:21]2[CH2:22][CH:17]3[CH2:18][C:19]([OH:24])([CH2:23][CH:15]1[CH2:16]3)[CH2:20]2
Reactant: CC(C)(C)OC(=O)NC1C2CC3CC1CC(O)(C3)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1C2CC3CC1CC(O)(C3)C2
Temperature: 0 °C
Yield: 89.5 %

Procedure:
Lithium aluminium hydride (0.711 g, 0.018 mol) was added to a solution of (5-hydroxy-adamantan-2-yl)carbamic acid tert-butyl ester (1 g, 0.0037 mol) in THF (50 ml) at 0° C. under a nitrogen atmosphere. The slurry was heated under reflux for 5 h. It was then cooled to 0° C. and quenched with 30% NaOH solution (12 ml) and filtered. The filtrate was concentrated to give 2-methylaminoadamantan-5-ol as a white solid (0.6 g, 90%). LC-MS (m/z): 181.9 (M+1). 1H NMR (300 MHz, DMSO-d6): δ 4.3 (s, 1H), 4.2 (s, 1H), 2.4 (s, 0.7H), 2.3 (s, 0.3H), 2.2 (s, 3H), 1.8-2.0 (m, 5H), 1.5-1.6 (m, 5H), 1.4-1.5 (m, 2H), 1.2 (m, 2H).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[S:15][CH:14]=[N:13][C:11]=2[N:12]=1.[I:22]I>CCCCCC.C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:10]2[S:15][C:14]([I:22])=[N:13][C:11]=2[N:12]=1
Reactant: II
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Following the procedures in U.S. Pat. No. 6,492,383, 2.5 M of n-butyllithium (9.4 mL, 22.48 mmol) in hexane solution was added to a mixture of 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 (3.0 g, 11.74 mmol) in 60 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g, 23.48 mmol) in 10 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The mixture was quenched by diluting with dichloromethane and extracting with H2O (2×100 mL). The organic layer was washed with Na2S2O3(2×100 mL), H2O (2×100 mL), dried over MgSO4, filtered and evaporated to afford 4-(5-chloro-2-iodothiazolo[4,5-d]pyrimidin-7-yl)morpholine 27.
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][P:11](=[O:22])([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])C1C=CC=CC=1.C>C(O)C.[Pd]>[ClH:1].[NH2:9][CH2:10][P:11](=[O:22])([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCOP(=O)(CNCc1ccccc1)OCCCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCOP(=O)(CN)OCCCC
Reaction time: 2 h

Procedure:
A mixture of dibutyl N-benzyl-aminomethylphosphonate hydrochloride (122.4 g) and 10% palladium on powdered charcoal (5.0 g) in ethanol (1000 ml) is hydrogenated at 40 psi for 2 hours. The catalyst is removed by filtration and the filtrate is evaporated under reduced pressure to yield dibutyl aminomethylphosphonate hydrochloride.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:16]([O:18]CC)=[O:17].S1C2CCCN(C(OCC)=O)CC=2C=C1C(OCC)=O.[OH-].[K+]>C(O)C>[CH2:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH2:4][C:5]2[S:1][C:2]([C:16]([OH:18])=[O:17])=[CH:3][C:6]=2[CH2:7]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OCC)CC2
Agent: CCOC(=O)c1cc2c(s1)CCCN(C(=O)OCC)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CCCc2sc(C(=O)O)cc2C1

Procedure:
10 gm (0.034 mol) of an isomer mixture consisting of diethyl 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2,6-dicarboxylate and diethyl 5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepine-2,5-dicarboxylate were refluxed for 4 hours in a solution of 2.8 gm (0.05 mol) of potassium hydroxide in 150 ml of absolute ethyl alcohol. Then, the mixture was concentrated by evaporation in vacuo, the residue was taken up in water and extracted three times with ether. The ether extracts were discarded, and the aqueous phase was acidified with concentrated hydrochloric acid. It was extracted several times with ether, and the combined ether phases were washed with water and dried over sodium sulfate. After the ether had been distilled off, 9.2 gm of a yellowish oil remained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[H-].[Na+].[CH3:11][OH:12]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[CH:5]=[N:4][CH:3]=1
Reactant: CO
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 12 g of 3,5-dibromopyridine and 40 g of 60% NaH in DMF was added 4.05 mL of MeOH, and the reaction mixture was stirred for 4 hours at room temperature and 1 hour at 60° C. The DMF was removed under reduced pressure, and the residue was taken directly to the next step. MS (CI/NH3) m/z 188/190 (M+H)+, 205/207 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32 (d, J=1.8 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H), 7.42 (dd, J=1.8, 2.6 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[OH2:4]>>[CH2:2]([OH:4])[C@H:1]([C@H:2]([C@@H:1]([C@@H:2]([CH2:1][OH:3])[OH:4])[OH:3])[OH:4])[OH:3]
Reactant: CC=O
Reactant: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
There have been many attempts to fix aldehyde-generating volatile compounds in a variety of substrata. The most notable example is set out hereinbelow. The efficacy of such a fix is about 2% by weight. U.S. Pat. No. 3,314,803, issued to Dame et al. discloses a method for fixing acetaldehyde which includes first forming a solution of mannitol in water and preferably a super-saturated solution of mannitol, i.e., 25-45% mannitol solution. The super-saturated solution is formed by heating with agitation 2 to 10 parts by weight of mannitol with 10 parts by weight of water at 180°-212° F. until all of the mannitol is dissolved in water and no mannitol crystals remain in the solution. The mannitol solution is then cooled while acetaldehyde is added thereto, the acetaldehyde being continually refluxed and thereby condensed into mannitol solution until about 1 to 2 parts by weight of acetaldehyde are dissolved in a 10 parts by weight of water. The solution is then spray-dried with an initial acetaldehyde fix of approximately 4%-10% being obtained thereby. However, after one week exposure the level of acetaldehyde depleted to about 2.4% by weight of the total composition.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1-n1cccc1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3-n3cccc3)ccc12
Yield: 16.3 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 2-(1-pyrrolyl)benzylamine (122 mg, 0.708 mmol), Pd2(dba)3 (56 mg, 0.061 mmol), rac-BINAP (108 mg, 0.173 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (5 mL) was heated at 85° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2-pyrrol-1-yl-benzylamino)-2H-phthalazin-1-one (33 mg) as an off white solid, 1H (400 MHz, d6-DMSO) δ: 4.22 (d, 2H), 6.26 (t, 2H), 6.60 (bs, 1H), 7.04 (t, 2H), 7.08 (d, 1H), 7.35 (m, 1H), 7.40 (m, 2H), 7.49 (m, 1H), 7.62 (t, 1H), 7.91 (d, 1H) ppm; m/z (M+1) 350.97.
Reaction SMILES: Br[C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7](=[O:20])[CH2:8][N:9]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:28]([O:27][C:23](=[O:26])/[CH:24]=[CH:25]/[C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7](=[O:20])[CH2:8][N:9]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:4]=2[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1CN(CCCN2CCOCC2)Cc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Reaction time: 0.25 h
Yield: 54.4 %

Procedure:
A suspension of 7-bromo-4-(3-morpholin-4-yl-propyl)-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (5.70 g, 15.4 mmol) in propionitrile (120 mL) and DMF (30 mL) was de-oxygenated with Ar for 15 min. The mixture was treated with tert-butyl acrylate (9.0 mL, 61 mmol) and (i-Pr)2EtN (5.7 mL, 33 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (0.35 g, 1.6 mmol) and P(o-tol)3 (0.94 g, 3.1 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The mixture was diluted with Et2O (200 mL). The organic solution was filtered through Celite, washed with H2O (200 mL), dried over Na2SO4, filtered and then concentrated in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 96:4) gave the title compound (3.49 g, 55%) as a tan solid: MS (ESI) m/e 417 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:15]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:13])[N:8]=[CH:7]1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:13])[N:8]=[CH:7]1)[CH3:2]
Reactant: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)c2cccc([N+](=O)[O-])c2C(=O)OCC)c1
Agent: [Pd]
Product: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)c2cccc(N)c2C(=O)OCC)c1
Yield: 98.4 %

Procedure:
A mixture of 5.1 g of α-hexyl-4-{[(3-nitro-2-ethoxycarbonylphenyl)carbonyl]amino}imidazole-1-acetic acid ethyl ester and 2.1 g of 5% palladium-on-carbon were hydrogenated in the presence of 150 ml of methanol until consumption of hydrogen ceased. The catalyst was removed by filtration and the filtrate concentrated in vacuo to provide 4.7 g of the desired subtitled intermediate. NMR.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13].Br[CH2:15][C:16](=O)[CH2:17][CH3:18].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:17]([C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH2:11][CH2:12][CH3:13])[CH:4]=2)[O:7][CH:15]=1)[CH3:18]
Reactant: CCCc1cc(C(N)=O)ccc1O
Reactant: CCC(=O)CBr
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCc1cc(-c2nc(CC)co2)ccc1O
Yield: 48.8 %

Procedure:
A mixture of 4-hydroxy-3-propylbenzamide (200.0 mg, 1.1 mmol) (Example 43), 1-bromo-2-butanone (0.19 mL, 1.7 mmol), toluene (1.5 mL), and 1,4-dioxane (1.5 mL) was heated at reflux for 8 h with a Dean-Stark trap. The solvents were evaporated. The crude product was purified on HPLC to yield a solid (124.2 mg, 48%). LC/MS m/z 232 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.56-7.76 (m, 3H), 6.85 (d, J=8.4 Hz, 1H), 2.46-2.56 (m, 4H), 1.52-1.61 (m, 2H), 1.18 (t, J=7.6 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:17]([OH:19])=O)[CH:13]=[C:14]([C:15]#[N:16])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:53][C@@H:54]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:17]([NH:53][C@@H:54]([CH2:68][C:69]3[CH:70]=[C:71]([F:76])[CH:72]=[C:73]([F:75])[CH:74]=3)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=3)=[O:19])[CH:13]=[C:14]([C:15]#[N:16])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN1CCOc2c(C#N)cc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN1CCOc2c(C#N)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h
Yield: 7 %

Procedure:
A solution of 4-Butyl-8-cyano-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (129 mg), HBTU (284 mg), and diisopropylethylamine (0.26 mL) was stirred in methylene chloride (6 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (204 mg) in methylene chloride (4 mL) was added and the reaction mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (15 mL), saturated sodium bicarbonate (15 mL), and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided 20 mg of the title compound: ESI MS m/z 577 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5](OCC)=[CH:6][NH2:7])C.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][NH:16][NH2:17]>>[NH2:7][C:6]1[NH:17][N:16]([CH2:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[Cl:12])[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C(=CN)OCC
Reactant: NNCc1ccccc1Cl
Product: Nc1cc(=O)n(Cc2ccccc2Cl)[nH]1
Yield: 40 %

Procedure:
35 g of β-amino--ethoxyacrylic acid ethyl ester and 32 g of 2-chlorobenzylhydrazine when reacted as described in Example 45 yield 17.5 g of the compound identified above as colorless crystals of melting point 153°. (Yield: 40% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.CN(C)C=O>O>[Si:14]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of 3-bromobenzyl alcohol (15.0 g, 80 mmol), tert-butylchlorodiphenylsilane (22.9 mL, 88 mmol), imidazole (12.0 g, 176 mmol) and 75 mL of dimethylformamide was stirred at room temperature overnight. The reaction mixture was poured into cold water, extracted with diethyl ether, the extracts washed with water and brine, dried over sodium sulfate and evaporated. The resulting oil was purified by chromatography on silica gel with hexane to give 23.7 g (70%) of 3-bromobenzyl tert-butyldiphenylsilyl ether as a colorless oil.
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[S:20][CH:21]=[C:22]([CH2:24][C:25](OCC)=[O:26])[N:23]=3)[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=C(OC2C3C(=CC=CC=3)C=CC=2)C=CN=1.NC1SC=C(CC(OCC)=O)N=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]1([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[S:20][CH:21]=[C:22]([CH2:24][CH2:25][OH:26])[N:23]=3)[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1csc(Nc2cc(Oc3cccc4ccccc34)ccn2)n1
Agent: CCOC(=O)Cc1csc(N)n1
Agent: Clc1cc(Oc2cccc3ccccc23)ccn1
Agent: [Al+3]
Solvent: C1CCOC1
Product: OCCc1csc(Nc2cc(Oc3cccc4ccccc34)ccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A solution of ethyl 2-(2-(4-(naphthalen-1-yloxy)pyridin-2-ylamino)thiazol-4-yl)acetate (prepared from 2-chloro-4-(naphthalen-1-yloxy)pyridine (1.18 g, 4.61 mmol) and ethyl 2-(2-aminothiazol-4-yl)acetate according to the method of example 1 step B; 0.370 g, 0.913 mmol) in THF (4 ml) was added to a 1M solution of lithium aluminum hydride in THF (5 mL) at 0° C. The reaction mixture was stirred at ambient temperature for one hour, then cooled in an ice bath and quenched carefully with an excess of sodium sulfate decahydrate and stirred overnight. The reaction mixture was filtered, the solids were washed with THF several times, and the combined filtrate was concentrated. The crude material was purified via MPLC, eluting first with 1:1 hexane:ethyl acetate, followed by ethyl acetate. The component which eluted with ethyl acetate was concentrated and triturated with hexanes:dichloromethane (4:1, 15 mL), filtered, washed with hexanes, and dried to afford the title compound (0.125 g, 37.7% yield). 1H NMR (d6-DMSO) δ 2.67 (t, 2H), 3.63 (q, 2H), 4.57 (t, 1H), 6.51 (s, 1H), 6.57 (m, 214), 7.36 (d, 1H), 7.55-7.63 (m, 3H), 7.85 (d, 1H), 7.92 (d, 1H), 8.05 (d, 1H), 8.17 (d, 1H), 10.97 (s, 1H).