Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[OH:17][CH2:16][C:15]1[CH:20]=[CH:21][C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(CCc2csc(NC(C)=O)n2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CO)cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a stirred solution of methyl 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzoate (1.8 g) in dry tetrahydrofuran (36 ml) was added dropwise 1.0 M diisobutylaluminium hydride solution in toluene (20.7 ml) at −78° C. over 15 minutes under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 hours, and then the reaction was quenched with water (1 ml). The mixture was stirred at room temperature for 30 minutes, dried over anhydrous magnesium sulfate, and filtered through a pad of Celite. The solvent was evaporated in vacuo. The residual solid was washed with ethyl ether to give N-(4-{2-[4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1.03 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2([O:24][CH3:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.Cl.[NH2:27][OH:28]>>[NH2:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12](/[C:15](=[N:27]/[OH:28])/[CH3:16])=[CH:13][CH:14]=2)[CH:5]=[C:4]([C:18]2([O:24][CH3:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:3]=1
Reactant: NO
Reactant: COC1(c2cc(Sc3ccc(C(C)=O)cc3)nc(N)n2)CCOCC1
Agent: Cl
Product: COC1(c2cc(Sc3ccc(/C(C)=N/O)cc3)nc(N)n2)CCOCC1
Yield: 75 %

Procedure:
Using an analogous procedure to that described in Example 43, 4'-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-yl-thio]acetophenone oxime in 75% yield, m.p. 237°-240° C.;
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.CC(C)([O-])C.[K+].[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:36][CH3:37])=[C:27]([C:29]([CH3:35])([CH3:34])[CH2:30][C:31](=[O:33])[CH3:32])[CH:28]=1>C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:36][CH3:37])=[C:27]([C:29]([CH3:34])([CH3:35])[CH2:30][C:31]([CH2:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)([OH:33])[CH3:32])[CH:28]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(C)=O
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(C)(O)Cc1cc2ccccc2[nH]1
Temperature: -20 °C
Reaction time: 0.03 h
Yield: 31.2 %

Procedure:
To a solution of 2-methylindole (130 mg) in THF (2 mL) stirred under argon cooled on dry ice/acetone was added n-butyl lithium (2M in pentane, 1.6 mL). After 2 minutes, potassium tert-butoxide (1M in THF, 2 mL) was added and the mixture was allowed to warm to approximately −20° C. After 5 minutes, precipitate was noted and the mixture was cooled to −70° C. 4-(5-Fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 17) (440 mg) in THF (1.5 mL) was added all at once. The cooling bath was removed and the mixture was stirred for 10 minutes and then quenched with EtOH (0.5 mL). The mixture was diluted with EtOAc, washed with water, dried, filtered, and evaporated. Chromatography over silica gel (EtOAc-hexanes (1:9)) gave product which solidified on trituration with hexanes-ether. The solid was recrystallized from ether-hexanes, collected by filtration and dried under vacuum to give 0.11 g of the title compound, m.p. 118° C.-120° C.
Reaction SMILES: [C:1]([N:4](CC1C=CC(OC)=CC=1)[CH2:5][C:6]([C:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:28])[C:16]([CH3:27])([S:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH3:17])[O:11][N:10]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2].C(#N)C>O>[C:1]([NH:4][CH2:5][C:6]([C:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:28])[C:16]([CH3:17])([S:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH3:27])[O:11][N:10]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: COc1ccc(CN(CC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)C(C)=O)cc1
Solvent: O
Solvent: CC#N
Product: CC(=O)NCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 4 %

Procedure:
To a solution of N-(3-{2-[acetyl-(4-methoxy-benzyl)-amino]-1,1-dimethyl-ethyl}-isoxazol-5-yl)-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (116 mg, 0.22 mmol) in the mixture of acetonitrile (2 mL) and water (0.7 mL) is added ceric ammonium nitrate (476 mg, 0.87 mmol). The reaction mixture is stirred at room temperature for 40 minutes. After this time, the reaction mixture is quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by preparative HPLC provides the title compound. Yield: 4%; m/z 416 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][N:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([C:27]([F:30])([F:29])[F:28])=[N:22]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][C:17]2[C:18]3[C:23](=[N:22][C:21]([C:27]([F:30])([F:29])[F:28])=[CH:20][CH:19]=3)[N:24]=[CH:25][CH:26]=2)[CH:7]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Product: FC(F)(F)c1ccc2c(Nc3cc(Cl)ccc3Oc3ccccc3)ccnc2n1

Procedure:
The product from Example 42b (60 mg, 0.27 mmol) was reacted with the product from Example 7d (63 mg, 0.27 mmol) for 24 h following the procedure from Example 1g giving the crude title compound as a solid which was triturated with 4:1 ether/THF giving the product as a hydrochloride salt (112 mg, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 6.82 (d, J=6.99 Hz, 1H) 6.98 (d, J=7.72 Hz, 2H) 7.13 (m, 2H) 7.32 (dd, J=7.73 Hz, J=8.82 Hz, 2H) 7.57 (dd, J=2.57 Hz, J=8.82 Hz, 1H) 7.71 (d, J=2.57 Hz, 1H) 8.36 (d, J=8.82 Hz, 1H) 8.69 (d, J=6.99 Hz, 1H) 9.42 (d, J=8.82 Hz, 1H) 11.47 (br s, 1H) 14.40 (br s, 1H); MS (ESI+) m/z 416 (M−Cl)+; (ESI−) m/z 414 (M−HCl)−.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:15][CH:16]=1)=[O:22]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15.6 h
Yield: 90.8 %

Procedure:
Ethyl difluoroacetate (2.78 g, 22.4 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (10 mL). To the stirred solution was added 25 weight % sodium methoxide (6.02 g, 27.8 mmol) followed by 4'-(trifluoromethyl)acetophenone (3.80 g, 20.2 mmol) and THF (20 mL). The reaction was stirred at room temperature overnight (15.6 hours), then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine, dried over MgSO4, concentrated in vacuo to give a brown oil (4.88 g, 91%). 1H NMR (acetone d6) 300 MHz 15.10 (br s, 1H), 8.03 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 6.59 (s, 1H), 6.02 (t, J=54.2 Hz, 1H); 19F NMR (acetone d6) 300 MHz: - 63.70 (s), -127.10 (d); M+266.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:5]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:7]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>N1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:5]=[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[C:3]=1[N:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)[C:42](=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCc2cccc(OC)c2)c(NS(=O)(=O)CCC)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(N(Cc2cccc(OC)c2)C(C)=O)c(NS(=O)(=O)CCC)c1
Reaction time: 17 h

Procedure:
A solution of propane-1-sulfonic acid [3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-methoxy-benzylamino)-phenyl]-amide (120 mg) in pyridine (3 ml) was treated with acetic anhydride (153 μl). After stirring for 17 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](OC)=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CC(C[AlH]CC(C)C)C>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: COC(=O)c1cnc(C(F)(F)F)c(C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(CO)cnc1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of methyl 5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate (552 mg, 2.52 mmol) in DCM (30 ml) stirred under N2 at 0° C. was added a solution of DIBAL-H (1.5 M solution in toluene, 5.04 ml, 7.56 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 h and at room temperature overnight. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was treated with a 1N HCl solution and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced. Purification by flash chromatography using a 10 g silica gel cartridge, and mixtures of DCM and MeOH as eluent afforded [5-methyl-6-(trifluoromethyl)-3-pyridinyl]methanol (297 mg, 54%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(O)(=O)C.N1CCCCC1>CC1CCCCC1.O>[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)CC(C)=O
Solvent: CC1CCCCC1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CC(=O)C=Cc1ccc(O)cc1
Yield: 82 %

Procedure:
##STR7## 232 g (2 mol) of methyl acetoacetate, 244 g (2 mol) of 4-hydroxybenzaldehyde, 24 g (0.4 mol) of glacial acetic acid and 6.8 g (0.08 mol) of piperidine were dissolved in 459 ml of methylcyclohexane. The reaction solution was heated to the boil, and the water of reaction was separated off for one hour in a water separator. After the solvent had been decanted, the product was taken up in diethyl ether, filtered off with suction and dried. 362 g (corresponding to a yield of 82%) of methyl 4-hydroxybenzalacetoacetate were obtained. 22 g (0.1 mol) of methyl 4-hydroxybenzalacetoacetate were dissolved in 100 ml of methanol, and 5.6 g (0.1 mol) of KOH in 38 g of methanol were added. Stirring was carried out for 2.5 hours at room temperature, after which the reaction mixture was evaporated down and the remaining residue was dried. 25 g (corresponding to a yield of 97% of the title compound were obtained in the form of a red solid. The purity of the product was >95%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].BrC1C2[O:22][CH2:21]N(C(C)(C)C)CC=2C=C(C(C)(C)C)C=1.C1N2CN3CN(C2)CN1C3.Cl>FC(F)(F)C(O)=O>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:5]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:7]=1)[CH:21]=[O:22]
Reactant: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (6.87 g, 30 mmol) and hexamethylenetetramine (20 g, 143 mmol) in trifluoroacetic acid (60 mL) was heated at 90° C. under nitrogen for 22 hours. The hot reaction mixture was poured into 1M aqueous hydrochloric acid (200 mL) and the mixture stirred vigorously for 6 hours. The resulting suspension was filtered to give 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (6.79 g, 88% yield) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]#[N:14])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN(C)C=O>[N:25]1([CH2:24][CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[C:10]([C:13]#[N:14])[S:11][CH:12]=3)=[CH:6][CH:7]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ClCCN1CCCCC1
Reactant: N#Cc1nc(-c2ccc(O)cc2)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nc(-c2ccc(OCCN3CCCCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 28 h
Yield: 93.1 %

Procedure:
A suspension of 4-(4-hydroxyphenyl)-thiazole-2-carbonitrile (7 g), crushed potassium carbonate (13.1 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.78 g) in dry dimethylformamide (60 ml) was stirred at room temperature for 28 h, and then added to water (400 ml). The precipitated solid was filtered, and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulphate, filtered, and evaporated to dryness to give 4-[4-[2-(piperidin-1-yl)ethyloxy]phenyl]-thiazole-2-carbonitrile (10.1 g), m.p. 85°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:11][C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:6]C(F)(F)F.C(C1C(OC)=NC(CC[O:30][CH2:31][C:32]([F:35])([F:34])[F:33])C(OC)=N1)(C)C>>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:11][C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:6][O:30][CH2:31][C:32]([F:35])([F:34])[F:33]
Reactant: COC1=NC(C(C)C)C(OC)=NC1CCOCC(F)(F)F
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)OC
Product: COC(=O)NC(CCOCC(F)(F)F)C(=O)OC

Procedure:
This compound was made by the same procedure as 5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoic acid methyl ester, using 2-Isopropyl-3,6-dimethoxy-5-[2-(2,2,2-trifluoro-ethoxy)-ethyl]-2,5-dihydropyrazine as the starting material. 1H-NMR: 400 MHz, (CDCl3) δ: 5.51-5.43 (br, 1H), 4.51-4.43 (m, 1H), 3.83-3.63 (m, 10H), 2.22-2.13 (m, 1H), 2.13-2.03 (m, 1H) ppm.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[C:13](=[O:30])[N:12]([CH3:31])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:31][N:12]1[C:11]2[N:10]=[CH:9][NH:8][C:16]=2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][P:22](=[O:29])([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])[C:13]1=[O:30]
Reactant: CCOP(=O)(CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CCCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC

Procedure:
15.7 g (0.035 mol) of diethyl [4-(7-benzyl-3-methylxanthin-1-yl)butyl]-phosphonate were hydrogenated in 150 ml of ethanol over 1 g of palladium (10%) on active carbon at room temperature in the course of 8 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure and the residue was crystallized from diisopropyl ether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1.[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26].C(=O)([O-])[O-].[K+].[K+].C(O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:24]=[CH:23][CH:22]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: O=Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C=O)c2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
A mixture of tert-butyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate (3.5 g, 8.94 mmol), 2-formylphenylboronic acid (1.47 g, 9.83 mmol), tetrakistriphenylphosphine palladium (413 mg, 0.36 mmol), 2N potassium carbonate aqueous solution (7 mL), ethanol (7 mL) and toluene (70 mL) was stirred under an argon atmosphere at 80° C. for 14 hrs. The reaction mixture was cooled, diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (3.62 g, 97%) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[N:19]([CH3:20])[C:18]([O:21][CH:22]([C:24]3[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[O:26][N:25]=3)[CH3:23])=[N:17][N:16]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>C(O)C.[Pd].ClCCl>[Cl:35][C:31]1[CH:30]=[C:29]([C:27]2[O:26][N:25]=[C:24]([CH:22]([O:21][C:18]3[N:19]([CH3:20])[C:15]([C:13]4[CH:12]=[CH:11][NH:10][C:9](=[O:8])[CH:14]=4)=[N:16][N:17]=3)[CH3:23])[CH:28]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(Oc1nnc(-c2ccnc(OCc3ccccc3)c2)n1C)c1cc(-c2cccc(Cl)c2)on1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(Oc1nnc(-c2cc[nH]c(=O)c2)n1C)c1cc(-c2cccc(Cl)c2)on1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
The title compound of example 35.1 (125 mg, 0.256 mmol) was stirred in ethanol (2 mL). Palladium on carbon (10%, 50 mg) was added and the reaction was stirred under hydrogen (balloon pressure) overnight. The reaction mixture was then diluted with dichloromethane and filtered to remove the palladium catalyst. The filtrate was concentrated, then chromatographed in 10% methanol in ethyl acetate to yield the desired product (38.5 mg, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[N+:15]([O-])=O>C1COCC1.C(O)C.[Pd]>[NH2:15][C:3]1[CH:4]=[C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reaction time: 2 h

Procedure:
Ethyl 2-(4-hydroxy-3-nitrophenyl)propanoate (260 mg, 1.09 mmol) in THF (6 mL) and ethanol (6 mL) was slowly added 10% Pd/C (29 mg) at room temperature. The mixture was hydrogenated for 2 hours at 43 psi and then filtered with celite pad and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=1/1.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4]CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[O:4]=[C:5]1[CH2:10][CH2:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:7][CH2:6]1
Reactant: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C2=CCC(=O)CC2)cc1

Procedure:
A solution of Example 420B (2.2 g) and p-toluenesulfonic acid (100 mg) in acetone (10 mL) was heated to reflux for 10 hours, filtered through a pad of silica gel (20 g), and concentrated to provide the desired product.
Reaction SMILES: [Br-:1].[C:2]([CH2:5][CH2:6][N+:7]1[C:11]2[CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)[CH3:3].C(#N)C>CCOCC>[Br-:1].[CH3:3][C:2]1[CH2:5][CH2:6][N+:7]2[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)CC[n+]1c(Cc2ccccc2)oc2ccc(-c3ccccc3)cc21
Agent: [Br-]
Solvent: CCOCC
Solvent: CC#N
Product: CC1=C(c2ccccc2)c2oc3ccc(-c4ccccc4)cc3[n+]2CC1
Temperature: 30 °C
Reaction time: 124 h
Yield: 93 %

Procedure:
1,3-Dihydro-3-methyl-4-phenylpyrido[2,1-b]-5-phenylbenzoxazolium bromide is prepared by reacting 3-(2-acetylethyl)-2-benzyl-5-phenylbenzoxazolium bromide (5.0 g.) dissolved in 75 ml. of acetonitrile. The reaction mixture is stirred at about 30° C for about 124 hours, after which ether is added to the solution and the resultant precipitate is filtered, washed and dried to give 4.27 g. (93% yield) of 1,2-dihydro-3-methyl-4,8-diphenylpyrido[2,1-b]benzoxazolium bromide having a melting point of 269° C. This product is dissolved in 20 ml. of dimethyl sulfoxide and heated for a few minutes on a hot plate. Sodium perchlorate (0.6 g.) in 20 ml. of ethanol is added with stirring. Excess diethyl ether is added, precipitating an oil. Crystallization of the oily substance is induced from a chloroform-ether solution. Recrystallization from ethanol affords a 70% yield of product having a melting point of 252°-254° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[C:22](F)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)CC)C>C(O)(C)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:22]3[C:21]([Cl:20])=[CH:26][C:25]([C:27]([F:30])([F:28])[F:29])=[CH:24][N:23]=3)[CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(c3ncc(C(F)(F)F)cc3Cl)C2)no1
Temperature: 175 °C
Reaction time: 8 h

Procedure:
A microwave reaction vial is charged with piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (94 mg; 0.327 mmol), 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.043 mL; 0.33 mmol), triethylamine (0.092 mL; 0.66 mmol) and t-butanol (0.5 mL). The vial is heated in microwave at 175° C. for 1 hour then left standing at room temperature overnight. The reaction mixture is concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride then recrystallization from hot methanol provides the title compound, m/z 431 [M+H+].
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:34][C:35](=[O:47])[C:36]([NH:39]C(=O)OC(C)(C)C)([CH3:38])[CH3:37])[C:11]([N:13]1[CH2:33][CH2:32][CH2:31][C:15]2([C:19](=[O:20])[N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH:16]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH2:39][C:36]([CH3:38])([CH3:37])[C:35]([NH:34][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([N:13]1[CH2:33][CH2:32][CH2:31][C:15]2([C:19](=[O:20])[N:18]([CH:21]([CH3:22])[CH3:23])[CH2:17][CH:16]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:14]1)=[O:12])=[O:47]
Reactant: CC(C)N1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O

Procedure:
A mixture comprising tert-butyl 1-((2R)-3-(benzyloxy)-1-(4-(4-fluorophenyl)-2-isopropyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (378 mg, 0.579 mmol) (step 1) and TFA (0.892 ml, 11.58 mmol) in DCM (4 ml) was stirred at room temperature for 4 hours. The solvent was removed in vacuo to afford a colourless oil. The oil was dissolved with methanol (3 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo to yield the title compound as diastereomeric mixture.