Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]=1[N+:20]([O-])=O)([O-])=O.[OH-].[Na+].[H][H]>[C].[Pd].C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]=1[NH2:20]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Yield: 97.6 %

Procedure:
A 500 ml. electromagnetically stirred glass reactor was charged with 5.0 g of dinitroanthraquinone (a mixture of 1,5-isomer and 1,8-isomer), 50 g of a 4% aqueous solution of sodium hydroxide, 50 g of toluene and 0.25 g of 5% palladium-carbon, and the dinitroanthraquinone was hydrogenated with stirring at a pressure of 40 to 30 Kg/cm2.G and a temperature of 40° to 50° C. The reaction was stopped in 5 hours with the absorption of 0.1169 mole of hydrogen. 50 g of a 4% aqueous solution of sodium hydroxide was added, and the reaction mixture was filtered in a stream of nitrogen to separate the catalyst. The filtrate was separated into an aqueous pahse and a toluene phase. The aqueous phase was oxidized with air with stirring at 20° to 30° C. for 2 hours. The crystals precipitated were filtered and dried to afford 3.9 g of diaminoanthraquinone in a yield of 97.5%.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([S:13][CH2:14][C:15](OCC)=[O:16])=[CH:6][C:5]=1[Br:20].COC(=O)C1C=C([N+]([O-])=O)C(F)=CC=1Br.CCN(CC)CC.C(OC(=O)CS)C>C(Cl)Cl.CCOC(C)=O>[Br:20][C:5]1[C:4]([C:3]([OH:2])=[O:21])=[CH:9][C:8]2[NH:10][C:15](=[O:16])[CH2:14][S:13][C:7]=2[CH:6]=1
Reactant: CCOC(=O)CSc1cc(Br)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: CCOC(=O)CS
Agent: COC(=O)c1cc([N+](=O)[O-])c(F)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CSc2cc(Br)c(C(=O)O)cc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
2-Bromo-4-ethoxycarbonylmethylsulfanyl-5-nitro-benzoic acid methyl ester. To a 0° C. solution of 2-bromo-4-fluoro-5-nitro-benzoic acid methyl ester (4.8 g, 17.3 mmol) in CH2Cl2 (87 mL) was added Et3N, followed by mercapto-acetic acid ethyl ester, and the resulting mixture was stirred at RT for 4 h. The mixture was diluted with EtOAc (250 mL), washed with brine (50 mL), dried (MgSO4), and concentrated. The crude material was purified on SiO2 (0-35% EtOAc/hexanes) to provide 5 g (77%) of the title compound. 1H NMR (500 MHz, CDCl3): 8.75 (s, 1H), 7.79 (s, 1H), 4.24 (q, J=7.2, 2H), 3.96 (s, 3H), 3.78 (s, 2H), 1.30 (t, J=7.2, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH:2]1[C:11]#[N:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH:2]1[CH2:11][NH2:12]
Reactant: N#CC1CNc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CNc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
Add 3,4-dihydro-2H-1,4-benzoxazine-2-carbonitrile (600 mg, 3.75 mmol) to THF (20 mL) and then slowly add lithium aluminum hydride (1.0 M in THF; 1 mL, 1.0 mmol). Stir the mixture at ambient temperature for 30 minutes. Add H2O (1 mL) to quench the reaction; filter; and wash the filter cake with EtOAc. Dry the filtrate over Na2SO4; filter; and concentrate the filtrate under reduced pressure to afford a residue. Purify the resulting compound via flash column chromatography using a gradient of 20-50% of MeOH in DCM. Combine the desired fractions and remove the solvents under reduced pressure to provide the title compound as a white solid (390 mg, 63.1%). MS (m/z): 165 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:27]([CH3:44])[NH:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([N:27]([CH3:44])[NH:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33]([NH:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(NC(=O)CCNC(=O)NCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(NC(=O)CCNC(=O)NCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-benzyl 3-(4-(benzyloxy)phenyl)-2-(2-(3-(3-benzylureido)propanoyl)-1-methylhydrazinyl)propanoate (Compound XVII-1) 149 mg (0.25 mmol) in tetrahydrofuran:methanol=1:1.5 1.5 ml, a solution of lithium hydroxide monohydrate 16 mg in water 0.3 ml was added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was cooled to 0° C. and 1N HCl aq. 10 ml was added and the mixture was extracted with ethyl acetate 20 ml. The organic phase was washed with water 20 ml and brine 20 ml and dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo to obtain the title compound. The residue was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[N:14]=[C:13]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[OH:30])=[CH:7][CH:6]=1.Br[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[N:14]=[C:13]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)cc1
Reactant: BrCC1CCCC1
Product: COC(=O)Cc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from {4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-phenyl}-acetic acid methyl ester and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown sticky solid (61%). MS (Turbo Spray): m/z=525.4 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl[C:17]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=1[C:19]#[N:20].O>CN(C=O)C>[C:19]([C:18]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:17]=1[N:5]([O:4][CH3:3])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])#[N:20]
Reactant: CONS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(c1ccc([N+](=O)[O-])cc1C#N)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.09 g (2.25 mmol)) in 3.0 ml of DMF, N-methoxy-p-toluenesulfonamide (0.45 g (2.20 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 2-chloro-5-nitrobenzonitrile (0.37 g (2.03 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 18 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:5) as eluent to give 0.48 g (68%) of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.Cl.NO.C(=O)([O-])[O-:14].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:9])=[O:14])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(N)nc1
Yield: 24.1 %

Procedure:
A stirred mixture of commercially available 2-amino-5-cyano-pyridine [CAS-No. 4214-73-7] (5.0 g, 42 mmol), hydroxylamine hydrochloride (17.5 g, 0.25 mol) and sodium carbonate (31.1 g, 0.29 mol) in water (95 ml) and ethanol (21 ml) was heated under reflux conditions for 6 h. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (4×100 ml). The combined organic layers were washed with brine (150 ml), dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica gel (ethyl acetate/MeOH/NH4OH 4:1:0.5) and crystallization (ethyl acetate/MeOH/hexane) to yield 6-amino-nicotinamide (1.39 g) and the title compound (1.42 g, 22%) as an off-white solid. MS (EI) 152.1 [(M)+]; mp 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)[N:11]([CH:27]([CH3:29])[CH3:28])[C:10]=3[C@H:9]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:49](Cl)(=[O:53])[O:50][CH2:51][CH3:52]>C1COCC1>[CH2:51]([O:50][C:49]([C:9]1([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[C:10]2[N:11]([CH:27]([CH3:28])[CH3:29])[C:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)=[N:13][C:14]=2[C:15](=[O:16])[N:8]1[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:38])=[O:53])[CH3:52]
Reactant: CCOC(=O)Cl
Reactant: COc1ncc(-c2nc3c(n2C(C)C)[C@@H](c2ccc(Cl)cc2C)N(c2cc(Cl)ccc2C)C3=O)c(OC)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(Cl)cc2C)c2c(nc(-c3cnc(OC)nc3OC)n2C(C)C)C(=O)N1c1cc(Cl)ccc1C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product from example 76 (100 mg, 0.2 mmol) in THF (3 mL) at −78° C. was added NaHMDS (181 μL, 0.2 mmol) and the mixture was stirred at −78° C. for 15 min. Ethyl carbonochloridate (86 μL, 0.9 mmol) was added at −78° C. and the mixture was allowed to warm up to rt and stirred for 1 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, then was diluted in EtOAc and extracted with brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by preparative HPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 5-100% B in 20 min; A=0.1% TFA in water, B═CH3CN). tR: 1.39 min (LC-MS 2); ESI-MS: 624.4/626.4 [M+H]+ (LC-MS 2).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20]12([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=3[O:39][CH3:40])[C:33](Cl)=[O:34])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.O>C1COCC1>[C:20]12([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=3[O:39][CH3:40])[C:33]([O:12][C:10]3[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=3)=[O:34])[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(O)cc1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.4 %

Procedure:
Into a round bottom flask, there are introduced 1.68 g (10 mmoles) of methyl 2,4-dihydroxybenzoate, 1.55 ml (11 moles) of triethylamine and 50 ml of THF. There is then slowly added a solution of 3 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride in 50 ml of THF and the mixture is stirred at ambient temperature for 12 hours. The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column eluted by a 50:50 mixture of dichloromethane and hexane. After evaporation of the solvents, 2.55 g (59% yield) of methyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]-2-hydroxybenzoate having a melting point of 125°-127° C. are recovered.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[CH2:20][CH2:21]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[CH2:20][CH2:21][O:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCc1c(Cl)cccc1Cl
Reactant: Cc1cn2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn2cccc(OCCc3c(Cl)cccc3Cl)c2n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 23.4 %

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (296 mg), 1,3-dichloro-2-(2-mesyloxyethyl)benzene (645 mg) and potassium carbonate (828 mg) in N,N-dimethylformamide (12 ml) was stirred for 6 hours at 70° C. The mixture was treated according to a similar manner to that of Preparation 16 to give 8-[2-(2,6-dichlorophenyl)ethyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20])=O.[OH-].[K+]>CO>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[C:11]1[CH:10]=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: CC(=O)c1c(F)cccc1F
Reactant: Nc1ncccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Fc1cccc(F)c1-c1ccc2cccnc2n1
Yield: 78.4 %

Procedure:
2-Aminonicotinaldehyde (2.44 g, 20 mmol) and 2,6-difluoroacetophenone (3.28 g, 21 mmol) are dissolved in 20 ml of MeOH. The mixture is treated dropwise with 3 ml of 40% KOH and, after the exothermic reaction has subsided, it is poured onto water and the residue which is deposited is filtered off with suction. 3.8 g (79% yield) of the desired product are obtained. M.p. 100°-103° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(=O)C[C@H]1C(O)=O)=O)(C)(C)C.NOC[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(CON)cc1
Agent: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 85 %

Procedure:
The same method as employed in the preparation of Intermediate 7, but starting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (Intermediate 1) and 1-[(aminooxy)methyl]-4-methoxy-benzene (Intermediate 10) gave the title compound as a gum in a 85% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH2:17][CH3:18])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH2:17][CH3:18])[C:9]2[C:14]([C:15]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cccnc2n(CC)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCN(C)CC2)c2cccnc2n(CC)c1=O

Procedure:
A stirred mixture of 4.2 g. (0.015 mole) of 1-ethyl-1,2-dihydro-4-chloro-2-oxo-1,8-naphthridine-3-carboxylic acid ethyl ester (prepared in the manner described in Example 30), 1.5 g. (0.015 mole) of N-methylpiperazine and 1.6 g. (0.015 mole) of sodium carbonate in 20 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 50 ml. of 20% aqueous sodium carbonate and this mixture was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was diluted with 50 ml. of ethanol. This solution was slowly acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was recrystallized from ethanol to give 2.5 g. of product as the hydrochloride, m.p. 230°-233° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]2[CH2:13][CH:12]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:10]2=[O:30])[CH2:4][CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[O:30]=[C:10]1[CH:9]([CH2:8][CH:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)[CH2:13][CH:12]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]1[C:21]1[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1cc(C)c(C2C(=O)C(CC3CCC(O)CC3)CC2OC(=O)C(C)(C)C)c(C)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c(C2C(=O)C(CC3CCC(=O)CC3)CC2OC(=O)C(C)(C)C)c(C)c1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
The 2,2-dimethyl-propionic acid 4-(4-hydroxy-cyclohexylmethyl)-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopentyl ester (100 mg) is dissolved in acetone and cooled to 0° C. The Jones reagent (1.3 ml, 167 M) is added dropwise over a period of 30 minutes. The reaction is allowed to warm to room temperature over 1 hour. The reaction is poured into water and extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure to give a white crystalline solid. The solid is purified by flash chromatography to give the 2,2-dimethyl-propionic acid 3-oxo-4-(4-oxo-cyclohexylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentyl ester (72 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1.CO.[CH3:18][NH2:19]>CO>[CH3:18][NH:19][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1
Reactant: CN
Reactant: FC(F)(F)Oc1ccc(OCCBr)cc1
Solvent: CO
Product: CNCCOc1ccc(OC(F)(F)F)cc1
Yield: 79 %

Procedure:
1-(2-Bromoethoxy)-4-(trifluoromethoxy)benzene (2.2 g, 7.72 mmol) was dissolved in methanol (20 ml), to which 40% methylamine methanol solution (20 ml) was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride, and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to afford N-methyl-N-[2-(4-trifluoromethoxyphenoxy)ethyl]amine (1.44 g, yield 79%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([NH:26][C:27]1[CH:39]=[C:38](Br)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:18]([NH:26][C:27]1[CH:39]=[C:38]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: OB(O)c1c(F)cccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2c(F)cccc2F)cc1NC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 14.2 %

Procedure:
0.10 g of 2,6-difluorophenylboronic acid, 0.52 g of cesium carbonate, 2.4 mg of palladium acetate and 2.2 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl were added to 2.5 mL of toluene solution containing 0.20 g of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature sequentially, and stirred under nitrogen atmosphere at 80° C. for 1 hour and 10 minutes and then heated to reflux for 1 hour. After the reaction mixture was cooled to room temperature, 2.4 mg of palladium acetate and 2.2 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour. After the reaction mixture was cooled to room temperature, 2.4 mg of palladium acetate and 2.2 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour. After the reaction mixture was cooled to room temperature, were added 2.0 mL of toluene, 0.04 g of 2,6-difluorophenylboronic acid, 2.4 mg of palladium acetate and 2.2 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=20:1] to obtain 31 mg of tert-butyl 2-(benzamido)-4-(2,6-difluorophenyl)benzoate as white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH2:18]>CC#N>[C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:18][C:17]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:15]([F:14])[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Solvent: CC#N
Product: Cc1ccc(NCC(O)CCO[Si](C)(C)C(C)(C)C)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a solution of (RS)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (4.4 g, 200 mmol; prepared as in J. Org. Chem. (2008), 73, 1093) in MeCN (60 mL) was added LiClO4 (6.31 g, 3 eq.). 3-fluoro-4-methylaniline (commercial; 2.28 g, 0.92 eq.) was added and the mixture was stirred at 50° C. for 5 h. The solvent was removed under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2) to afford the title intermediate as a brown oil (5.56 g, 86% yield).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:32](Cl)(=[O:34])[CH3:33]>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][C:32](=[O:34])[CH3:33])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CC(=O)Cl
Product: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 72 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide (100 mg, 0.25 mmol) was reacted with acetyl chloride to yield 82 mg (72%) of the title compound.