Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Br:4])[CH2:2][OH:3].N1C=CN=C1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C1C=CC=CC=1>CN(C)C=O>[Si:10]([O:3][CH2:2][CH2:1][Br:4])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCBr
Yield: 94 %

Procedure:
2 g of ethylene bromohydrin and 2.4 g of imidazole were dissolved in 40 ml of N,N-dimethylformamide, to which 2.65 g of t-butyldimethylsilyl chloride were added at room temperature. After completion of the reaction, benzene was added, followed by washing with water and a sodium hydrogencarbonate aqueous solution and drying with anhydrous magnesium sulfate. This was filtered and the solvent was distilled off, thereby obtaining 3.60 g of the captioned compound (yield 94%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:4][O:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl.O>[C:8]([C:3]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])=[C:6]([CH3:7])[O:5][N:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1onc(C(=O)c2ccccc2)c1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1onc(C(=O)c2ccccc2)c1NC(=O)CCl
Reaction time: 1 h

Procedure:
To a chilled (5° C.) mixture of 6.5 g of (4-amino-5-methylisoxazol-3-yl)phenylmethanone, 65 ml of 2N sodium carbonate, 163 ml of a saturated solution of sodium bicarbonate, and 150 ml of dichloromethane was added, dropwise, 5.1 ml of chloroacetyl chloride. The resulting mixture was stirred for one hour, diluted with dichloromethane and water, and separated. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to an oil. Flash chromatography of the oil (20% ethyl acetate/hexane as the eluent) afforded 7.15 g of N-(3-benzoyl-5-methylisoxazol-4-yl)chloroacetamide, m.p. 86°-88° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>C(O)(=O)C.CCO>[CH3:20][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C=NNC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) in abs. EtOH (10 mL) and p-tolualdehyde (0.24 g, 0.002 mol) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.49 g, in 96% yield, mp: 252.6° C. 1H NMR (CD3OD) δ 8.26 (s, 1H), 7.82 (d, 2H), 7.70 (d, 2H), 7.24 (d, 2H), 6.88 (d, 2H), 2.36 (s, 3H). 13C NMR (CDCl3) δ 166.8, 162.7, 150.0, 142.0, 132.0, 130.5, 128.8, 124.7, 116.3, 21.5. Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.01; H, 5.08; N, 11.73.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][NH:11][CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]([O:15]CC)=O.[O-:34][C:35]#[N:36].[K+].Cl>C(O)C.O>[CH2:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:12]1[N:11]([CH2:10][CH2:9][CH:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:35](=[O:34])[NH:36][C:13]1=[O:15])=[O:25])[CH3:28]
Reactant: N#C[O-]
Reactant: CCCCCC(CCNC(CCCCCCC(=O)OCC)C(=O)OCC)OC1CCCCO1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCC(CCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC)OC1CCCCO1
Yield: 94.2 %

Procedure:
To a solution of diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate (7.8 g) in ethanol (32 ml) was added a solution of potassium cyanate (3.0 g) in water (6 ml). The resulting suspension was stirred and cooled during the gradual addition of 2 N-hydrochloric acid (16.7 ml). The solution was allowed to stand at room temperature for 22 hours, most of the ethanol was evaporated, water was added, and the insoluble oil was extracted with ether. The ether solution was washed with water, dried over magnesium sulphate, and evaporated. The yellow oil so obtained (8.0 g) was dissolved in light petroleum (b.p. 60°-80° C.) and the solution was refluxed for 4 hours, evaporated to dryness, and the residual oil was heated on the steambath for 2 hours to give 5-(6-ethoxycarbonylhexyl)-1-(3-(tetrahydropyran-2-yloxy)octyl)hydantoin as a yellow oil (7.3 g), which was used without further purification.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1>[CH3:19][C:18]1[N:1]([N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[C:14]([CH3:16])=[CH:13][CH:17]=1
Reactant: NN1C(=O)c2ccccc2C1=O
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A stirred suspension of N-aminophthalimide (19.75 g), acetonylacetone (14.3 ml), p-toluenesulfonic acid (5 mg), and toluene (406 ml) was heated at reflux for 1 hour and cooled to room temperature. The reaction mixture was combined with another reaction mixture and the entire mixture decolorized with activated charcoal. Filtration through a bed of celite gave a solution which upon partial concentration resulted in crystallization of the desired product as a solid (11.0 g), m.p. 182.5°-183.5° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]=O)[C:17]=2[O:16][CH2:15]1.[O-]CC.[Na+]>C(O)C>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22](/[CH:23]=[CH:13]/[C:3]3[N:4]=[C:5]4[CH:12]=[CH:11][CH:10]=[CH:9][N:6]4[C:7](=[O:8])[C:2]=3[Br:1])[C:17]=2[O:16][CH2:15]1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Reactant: O=Cc1cccc2c1OCO2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(Br)c(/C=C/c2cccc3c2OCO3)nc2ccccn12

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.5 g, 6.271 mmol) and 1,3-benzodioxole-4-carbaldehyde (1.12 g, 7.463 mmol) in the presence of sodium ethoxide (640 mg, 9.401 mmol) in absolute ethanol (100 ml) as described in Intermediate 1 to give 1.5 g of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 4.48 (s, 2H), 6.83-6.89 (m, 2H), 7.05-7.10 (m, 2H), 7.19 (t, J=6.9 Hz, 1H), 7.69 (d, J=9.3 Hz, 1H), 7.78-7.85 (m, 1H), 7.97 (d, J=15.6 Hz, 1H), 8.94 (d, J=7.2 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.Br[C@H:19]([CH3:41])[C:20]([N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:21]>C(#N)C>[CH2:6]([O:5][C:3]([C@@H:2]([NH:1][C@@H:19]([CH3:41])[C:20]([N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:21])[CH2:8][CH2:9][CH3:10])=[O:4])[CH3:7]
Reactant: C[C@@H](Br)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1
Reactant: CCC[C@H](N)C(=O)OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC[C@H](N[C@@H](C)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1)C(=O)OCC

Procedure:
Introduce 123 g of ethyl (2S)-2-aminopentanoate, 160 ml of triethylamine and 160 ml of acetonitrile into a reactor, and then bring the mixture to 60° C., slowly add the solution obtained in Step A and reflux for 4 hours. After returning to ambient temperature, wash the mixture with water and with a dilute acetic acid solution, and then evaporate off the solvents to yield benzyl (2S)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In a 20 mL vial were combined 4-fluoronitrobenzene (1.1 mL, 10 mmol), imidazole (0.68 g, 10 mmol), and sodium carbonate (1.1 g, 11 mmol) in N,N-dimethylformamide (5 mL). The mixture is shaken at 100° C. for 24 hours and then allowed to cool to room temperature and then diluted with water. Concentrated hydrochloric acid is added to bring the pH to 1, and then the mixture is extracted thrice with chloroform (10 mL). The acidic aqueous phase is then treated with 2.5 M sodium hydroxide solution to give a pH of 10. A light yellow solid is collected and washed with water to give 1-(4-nitrophenyl)-1H-imidazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)OCc2ccccc2)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc(CNC(=O)OCc2ccccc2)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture comprising 20 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 17.43 g of ethyl bromoacetate, 14.43 g of potassium carbonate and 200 ml of 2-butanone, was refluxed under heating with stirring overnight. The mixture was cooled to room temperature. Then, inorganic substances were filtered off, and the filtrate was distilled under reduced pressure. The obtained residue was extracted with chloroform, and the organic layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was crystallized from diethyl ether/n-hexane to obtain 17.83 g of the above-identified compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH3:8])[C:3]=1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(O[C:21](=[N:23][C:24](=O)[O:25]CC)[CH3:22])C>C(O)(=O)C>[C:12]1([S:9]([C:3]2[C:4]([S:7][CH3:8])=[N:5][N:6]3[C:24](=[O:25])[NH:23][C:21]([CH3:22])=[N:1][C:2]=23)(=[O:11])=[O:10])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)N=C(C)OCC
Solvent: CC(=O)O
Product: CSc1nn2c(=O)[nH]c(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A solution of 0.54 g (2 mol) of 5-amino-3-methylthio-4-phenylsulphonyl-pyrazole and 0.54 g (3.4 mmol) of ethyl 1-ethoxy-ethylidene-carbamate in acetic acid was stirred at 100° C. for 3 hrs. After cooling to RT the precipitate was filtered off, washed off with a copious amount of Et2O and dried in a high vacuum at 45° C. There was obtained 0.41 g (61%) of 8-benzenesulphonyl-2-methyl-7-methylsulphanyl-3H-pyrazolo[1,5-a][1,3,5]-triazin-4-one white crystals, m.p.>300° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])=[O:21].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>O1CCCC1>[F:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:16])([F:17])[F:15])[C:5]=1[C:20]([N:22]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)NC(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
Sodium hydride (80% by weight dispersion in mineral oil 0.208 g, 1.1 eq) was added to a stirred solution of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid, ethyl ester (2.26 g, 6.29 mmol) in anhydrous tetrahydrofuran (75 mL) at room temperature under a dry nitrogen atmosphere. After 45 minutes, the t-butyl bromoacetate (1.52 mL, 1.5 eq) was added and the reaction was heated to 60° C. After 11/4 hours of heating, the reaction was cooled to room temperature and the THF was removed. The residue was suspended in ether (150 mL), washed with water (2×75 mL) and saturated aqueous NaCl (1×50 mL), dried with MgSO4, and the ether was removed. The crude oil was flash chromatographed (4:1 petroleum ether:ethyl acetate, silica) then triturated with petroleum ether (3×30 mL) to provide the title compound as a white powder (2.40 g, 81%), m.p. 81°-83° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O.C(OCC)(=O)C>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of 4-chloro-3-nitrobenzoic acid (2.00 g, 10.0 mmol), 4-aminothiophenol (10.0 mmol), and cesium carbonate (6.52 g, 20.0 mmol) in anhydrous N,N-dimethylformamide (10 mL) was heated at 90° C. under a nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature and poured into 50 mL of ice water and ethyl acetate (100 mL). The mixture was stirred while adjusting the pH to 2 with concentrated hydrochloric acid. The layers were separated and the organic phase washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. The residue was co-evaporated with methylene chloride/hexanes and the residue triturated with methylene chloride to provide the title compound as a dark yellow solid (2.115 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:34]=[CH:33][C:16]([CH2:17][N:18]4[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:20]([O:30][CH2:31][CH3:32])=[N:19]4)=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:34]=[CH:33][C:16]([CH2:17][N:18]4[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]([O:30][CH2:31][CH3:32])=[N:19]4)=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(Cl)cccc4n3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3cn4c(Cl)cccc4n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
After a mixture of ethyl 3-[1-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (507 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionic acid (448 mg, yield 94%). This was recrystallized from ethanol. Melting point: 153–154° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.[CH:17]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])OCC>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]([F:14])([F:15])[F:16])[C:5]([O:10][CH3:11])=[C:6]([CH:17]([O:21][CH2:22][CH3:23])[O:24][CH2:25][CH3:26])[CH:9]=1
Reactant: COc1c(C=O)cc(Br)cc1OC(F)(F)F
Reactant: CCOC(OCC)OCC
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(Br)cc(OC(F)(F)F)c1OC

Procedure:
5-bromo-2-methoxy-3-trifluoromethoxybenzaldehyde (5.22 g) was dissolved in n-hexane (15 mL) and triethyl orthoformate (4.4 mL), and Amberlyst-15 (522 mg) was added to the solution, and then the mixture was refluxed for 3 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (6.19 g) as a brown oily substance.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:5])[CH3:3].O=[C:22]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C([BH3-])#N.[Na+].[ClH:40]>O.C(O)C>[ClH:40].[CH2:26]([O:25][C:23]([CH:22]([NH:1][C@H:2]([C:4]([N:6]([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:5])[CH3:3])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N(CCC(=O)O)C1Cc2ccccc2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CCC(=O)O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
L-Alanyl-N-(indan-2-yl)-β-alanine (2.0 g) is dissolved in a mixture of 20 ml of water and 100 ml of ethanol, 10 g of ethyl 2-oxo-4-phenylbutyrate is added, and a solution of 0.94 g of sodium cyanoborohydride in 20 ml of ethanol is added dropwise over 2 hours. The mixture is stirred at room temperature for 3 hours and then adjusted to pH 4.0 with 10% hydrochloric acid, and the ethanol is distilled off under reduced pressure. The residue is extracted with 200 ml of ethyl acetate, washed with water and dried, and the ethyl acetate is distilled off under reduced pressure. The residue is dissolved in 2 ml of 20% ethanolic hydrochloric acid, 100 ml of ethyl ether is added, and the mixture is allowed to stand at room temperature. Thus is obtained 1.2 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)-β-alanine hydrochloride as colorless amorphous powder.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:25]([O:32][C:33]([NH:35][C@H:36]([C:52](O)=[O:53])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][CH:39]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Br.[CH3:56][O:57][C:58](=[O:63])[C@@H:59]([CH3:62])[NH:60][CH3:61]>O1CCCC1>[CH3:56][O:57][C:58](=[O:63])[C@@H:59]([CH3:62])[N:60]([C:52](=[O:53])[C@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:42][CH:43]=1)[NH:35][C:33]([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH3:61]
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Reactant: CN[C@H](C)C(=O)OC
Agent: Br
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)N(C)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
Diisopropylethylamine (1.29 g.), then diphenylphosphinic chloride (2.37 g.), were added to a solution of N-benzyloxycarbonyl-O-benzyl-L-tyrosine (4.05 g.) in tetrahydrofuran (30 ml.) maintained at -20° C., and the mixture was stirred at that temperature for 10 minutes. A solution of N-methyl-D-alanine methyl ester hydrobromide (1.98 g.) in tetrahydrofuran (20 ml.) was then added, followed by diisopropylethylamine (1.29 g.). The mixture was stirred for two hours at 0° C., then overnight at room temperature, then filtered, stripped of volatiles and distributed between ethyl acetate and aqueous citric acid (5%). The ethyl acetate layer was washed with water, saturated aqueous sodium bicarbonate, water again and saturated aqueous sodium chloride, then dried over magnesium sulfate and concentrated to a yellow gum (about 6 g.). Purification of the yellow gum by high pressure liquid chromatography on silica gel (350 g.) using hexaneethyl acetate (7:3) as the eluant afforded (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-N-methyl-D-alanine methyl ester as a clear gum (3.2 g.) containing about a one-sixth molar amount of ethyl acetate as shown by NMR spectral analysis.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH2:16][OH:17])=[CH:14][C:13]([CH2:18][OH:19])=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH:16]=[O:17])=[CH:14][C:13]([CH:18]=[O:19])=[N:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1nc(CO)cc1CO
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1nc(C=O)cc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a stirred solution of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-dimethanol (1.18 g, 4 mmol) in methylene chloride (20 ml), was added 4-methylmorpholine-N-oxide (2.89 g, 24 mmol) and molecular sieve 4A (4 g). The reaction mixture was stirred at room temperature for 10 min. and then treated with tetrapropylammonium peruthenate (0.15 g, 0.4 mmol). Stirring was continued for 2 hr. The methylene chloride solution was concentrated and diluted with ether (40 ml). The mixture was filtered through a pad of silica gel (40 g) and the filter pad was eluted with 2×20 ml ether. The combined eluent was washed with 1 N HCl and brine, dried over anhydrous sodium sulfate, and evaporated to give 0.79 g of a white solid; mp 63–64° C.; MS m/e 283 (MH+).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:28])[N:3]=1.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:10]=3)=[O:7])=[C:4]([CH3:28])[N:3]=2)[CH2:34][CH2:33]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)c(C)n2)CC1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methylnicotinamide (0.17 mmol) was used in general procedure 3 with 1-acetylpiperazine (0.868 mmol). The product was purified by RP-HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methyl-nicotinamide. MS (Q1) 510.1 (M)+