Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1>CC(O)CC>[CH2:5]1[C:1]2([CH2:5][C:1](=[O:6])[CH2:2][CH2:3][O:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCCC1
Solvent: CCC(C)O
Product: O=C1CCOC2(CCCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
At ambient temperature, 5 g of (E)-3-[(tert-butyl-dimethylsilanyloxy)buta-1,3-dienyl]dimethylamine are added to a solution of 3.9 g of cyclopentanone in 11 ml of 2-butanol. The reaction mixture is stirred for 18 h at ambient temperature. The solvent is evaporated off and then the residue is taken up in 100 ml of diethyl ether. The mixture is cooled to −78° C. and then 1.9 ml of acetyl chloride are added slowly. The mixture is stirred for 10 min at −78° C. and then the reaction is stopped by adding 100 ml of a saturated solution of ammonium chloride. The resulting mixture is extracted with 200 ml of diethyl ether, and the organic phases are combined, and then dried over anhydrous sodium sulphate. The residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). The residue is dissolved in 50 ml of methanol, and then 200 mg of palladium-on-charcoal at 10% are added. The reaction mixture is stirred for 2 hours under a hydrogen atmosphere. The reaction mixture is filtered and then the methanol is evaporated off. 600 mg of 6-oxaspiro[4.5]decan-9-one are obtained. Yield=18%.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:4]1[C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[C:1]([OH:11])=[N:2][CH:3]=1)([O-:14])=[O:13]
Reactant: O=c1[nH]ccc2ccncc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc(O)c2cnccc12
Temperature: 85 °C
Yield: 87 %

Procedure:
To a stirred solution of 2H-[2,7]naphthyridin-1-one (300 mg, 2.05 mmol) (Baldwin, J. J.; Mensler, K.; Ponticello, G. S, J. Org. Chem. 1978, 43(25), 4878-80.) in 98% sulfuric acid (2 ml), 60% nitric acid (0.30 ml) was added dropwise and the mixture was warmed to 85° C. during 3 h. Addition, of ice-cold water and basification to pH 7, gave a precipitate which was filtered and washed with ethyl ether to yield the title product as a yellow solid (87%).
Reaction SMILES: C([Li])(CC)C.[C:6]1([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[C:17]([F:23])[CH:16]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:24][C:25]([F:30])([F:29])[C:26]([CH3:28])=[O:27].O>C1COCC1>[OH:27][C:26]([CH3:28])([C:25]([F:30])([F:29])[F:24])[C:22]#[C:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:14])=[O:13])=[CH:16][C:17]=1[F:23]
Reactant: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1F
Reactant: CC(=O)C(F)(F)F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1F)C(F)(F)F
Temperature: 25 °C
Yield: 33.2 %

Procedure:
s-Butyllithium (0.24 ml of a 1.3M solution in hexanes) was added dropwise to a solution of 4-phenylsulphonyl-2-fluorophenylethyne (Method 28) (0.08 g) in dry THF (3 ml) at −50° C. After 25 minutes a solution of 1,1,1-trifluoroacetone (0.035 g) in dry THF (0.5 ml) was added and the mixture was allowed to warm to ambient temperature overnight. Water (10 ml) was added and THF was evaporated off under reduced pressure. The residue was diluted with water (30 ml) and extracted with ethyl acetate (30 ml). The organic layer was washed with brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-30% ethyl acetate/hexane then triturated with hexane to give the title compound (0.038 g) as a solid. NMR (CDCl3): 1.75 (s, 3H), 2.75 (s, 1H), 7.5-7.75 (m, 6H), 7.93 (d, 2H); EA: C17H12F4O3S requires C, 54.8; H, 3.3%; found: C, 54.4; H, 3.4%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1N.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[I:24].[PH:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>Cl[Si](C)(C)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=1[I:24].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:20]([P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])([F:22])[F:23]
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: CCO[PH](=O)OCC
Agent: C[Si](C)(C)Cl
Agent: FC(F)(F)c1ccc(Br)c(I)c1
Product: CCOP(=O)(OCC)C(F)(F)c1cc(C(F)(F)F)ccc1Br

Procedure:
2-Bromo-5-(trifluoromethyl)-iodobenzene was synthesized from 2-bromo-5-(trifluoromethyl)benzeneamine according to the procedure described for Example 86. Diethyl [2-bromo-5-(trifluoromethyl)phenyl]difluoromethylphosphonate was synthesized from 2-bromo-5-(trifluoromethyl)-iodobenzene according to Example 25 except that chlorotrimethylsilane (several drops) was used in place of acetic acid. Compound 87 was synthesized according to procedures similar to those of Example 40 from this corresponding diethyl phosphonate. MS (ES−): m/z 353.0, 355.0 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.94 (d, J=8.2, 1H), 7.90 (s, 1H), 7.68 (d, J=8.2, 1H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([N:16]=[CH:17][C:18]=3[C:19](=[O:21])[CH3:20])[CH:15]=2)=[CH:6][CH:5]=1.Br.ClCCl>CC(O)=O>[Br:1][CH2:20][C:19]([C:18]1[CH:17]=[N:16][N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]=12)=[O:21]
Reactant: CC(=O)c1cnn2cc(-c3ccc(F)cc3)ccc12
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CBr)c1cnn2cc(-c3ccc(F)cc3)ccc12
Yield: 85.4 %

Procedure:
Bromine (57.9 μL, 1.13 mmol) was added to a solution of 1-[6-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-yl]ethanone (8, 197 mg, 0.775 mmol) in AcOH (1 mL) and hydrobromic acid (88 μL, 0.775 mmol). The reaction was heated to 50° C. for 2 hours after which an aqueous solution of 10% Na2S2SO3 (5 mL) and dichloromethane (10 mL) were added to the reaction. The organic was collected and washed with a saturated solution of sodium bicarbonate (10 mL), dried over sodium sulfate and concentrated. The reaction was purified by column chromatography (10% acetone in hexanes) to yield 2-bromo-1-[6-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-yl]ethanone (9, 220.4 mg, 0.662 mmol, 85% yield). MS APCI: [M+H]+ m/z 334.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([I:29])[CH:23]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=1[I:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(I)c1
Yield: 57.6 %

Procedure:
N-Bromosuccinimide (0.61 g, 3.4 mmol) and VAZO (0.10 g, 0.41 mmol) were added to a solution of 4-fluoro-2-iodotoluene (0.75 g, 3.2 mmol) in carbon tetrachloride (45 mL). The resulting suspension was stirred and heated under reflux for 18 hours. It was then cooled and filtered, the solid was rinsed with carbon tetrachloride (5 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with hexanes) to provide 322 (0.58 g, 58% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.51 (dd, J=8.0, 2.5 Hz, 1H); 7.38 (dd, J=8.4, 5.7 Hz, 1H); 7.00 (dt, J=8.2, 2.7 Hz, 1H); 4.54 (s, 2H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][B-:26]([F:29])([F:28])[F:27].[CH3:30][O+](C)C.C(O)C>ClCCl>[F:25][B-:26]([F:29])([F:28])[F:27].[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]([CH3:30])[CH:17]=3)=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[O+](C)C
Reactant: O=S(=O)(c1ccccc1)c1ccc(-n2cnc3ccccc32)cc1
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: Cn1c[n+](-c2ccc(S(=O)(=O)c3ccccc3)cc2)c2ccccc21
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of 1-(4′-phenylsulfonylphenyl)benzimidazole (6.7 g, 20 mmol) in dichloromethane (100 ml) is admixed at −10° C. with trimethyloxonium tetrafluoroborate (3.3 g, 22 mmol) and stirred under argon for 16 h. After adding ethanol, the precipitate which forms is filtered off and washed with cold petroleum ether. Yield: 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.S(Cl)([Cl:21])(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:21])[CH:10]=[N:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C(=O)O)c1ccc(-n2cccn2)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 91.2 %

Procedure:
2.5 g (10 mmoles) of 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid are dissolved in 30 ml of methylene chloride. A solution of 2.01 g (15 mmoles) of sulfuryl chloride in 10 ml of chloroform is added dropwise, with cooling to the resulting solution; heating is effected gradually to room temperature; and this is followed by boiling under reflux for 2 hours. The reaction solution is allowed to cool; the solvent is distilled off; 50 ml of 2 N solution of sodium hydroxide are added to the thus-obtained residue, and boiling up is effected for a few minutes. The reaction solution is extracted with diethyl ether and then acidified with hydrochloric acid. After renewed extraction with diethyl ether, the combined ether phases are dried and evaporated to produce 2.6 g (90% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid, m.p. 102° to 103° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Br:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20]>>[CH3:18][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](\[Br:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:16]
Reactant: CCC(C)OC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: CCC(C)OC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,Z) 2,2-dimethyl-3-[2-bromo-3-oxo-3-(1-methylpropoxy)-1-propenyl]-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxybenzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[2-bromo-3-oxo-3-(1-methylpropoxy)-1-propenyl]-cyclopropanecarboxylate with a melting point of 76° C. and a specific rotation of [α]D20 =+21.5°±2° (c=0.7% in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.[CH2:9]([O:11][C:12](=[O:15])[CH2:13]Br)[CH3:10].[H-].[Na+]>C(#N)C>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][N:6]1[CH2:7][C:3]([O:2][CH3:1])=[CH:4][C:5]1=[O:8])[CH3:10]
Reactant: COC1=CC(=O)NC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN1CC(OC)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
11.3 g (0.1 mol) of 4-methoxy-3-pyrrolin-2-one and 24.2 g (0.137 mol) of bromoacetic acid ethyl ester (95 percent) were suspended in 150.0 ml of acetonitrile. The suspension was mixed with 4.1 g (0.137 mol) of 80 percent sodium hydride at 0° C. Then the reaction solution was allowed to warm to room temperature, and was stirred for 90 minutes more. After evaporation of the solvent, the residue was suspended with 150.0 ml of ice water and extracted four times, each with 400.0 ml of methylene chloride. After a conventional or usual working up, the residue was mixed with 100.0 ml of petroleum ether (50° to 70° C.) and kept in a refrigerator overnight. The product crystallized out, was filtered by suction and was dried in a high vacuum. 19.6 g of yellowish colored product with a melting point of 55° to 58° C. was obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N:10]#[C:11]Br>CCOCC.CCCCCC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][N:6]=[C:11]=[NH:10])[CH3:2]
Reactant: N#CBr
Reactant: CCOC(CN)OCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(CN=C=N)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of the aminoacetaldehyde diethyl acetal (5.32 g, 40 mmol) in ether (20 mL) was added to a suspension of CNBr (4.22 g, 40 mmol) in hexane (20 mL) at RT. The reaction mixture was stirred at RT overnight. The solid was removed by filtration and washed with ether. The combined filtrate was concentrated. Flash chromatography of the concentrated residue afforded 2.82 g (45%) of the N-(2,2-diethoxyethyl)carbodiimide (a). NMR (500 MHz, CDCl3): 4.58 (t, J=5.5 Hz, 1H), 3.85 (br s, 1H), 3.73 (m, 2H), 3.56 (m, 2H), 3.16 (J=5.5 Hz, 2H), 1.23 (t, J=7.0 Hz, 3H), MS: 156.8 (M−H)−; 180.9 (M+Na)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11]CC)=O.[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH2:20])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH:20][C:9](=[O:11])[CH2:8][N:3]1[C:4](=[O:7])[CH2:5][CH2:6][CH:2]1[CH3:1])[CH3:16]
Reactant: CCOC(=O)CN1C(=O)CCC1C
Reactant: CC(C)N(CCN)C(C)C
Product: CC1CCC(=O)N1CC(=O)NCCN(C(C)C)C(C)C

Procedure:
From 9.2 g. of ethyl 2-methyl-5-oxo-1-pyrrolidineacetate and 8.7 g. of 2-(diisopropylamino)ethylamine, following the procedure of Example 9, there is obtained N-[2-[Bis(1-methylethyl)amino]ethyl]-2-methyl-5-oxo-1-pyrrolidineacetamide; m.p. 73°-74° C. after recrystallization from hexane.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[OH:27])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].B(O)O>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([CH:19]=[O:20])[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: O=Cc1cc(B(O)O)ccc1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(O)c(C=O)c4)cc3CC[C@@H]12
Yield: 37.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-formyl-4-hydroxyphenylboronic acid (129 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. Additional palladium reagent and boronic acid was added, and the mixture was heated for an additional 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), followed by recrystallization from ethyl acetate, to give 85 mg (37%) of the title compound as a white solid. mp 184°-187°. FDMS: m/e=349.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:16]=[CH2:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[C].[Pd].C(O)C>[CH2:16]([C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][O:10][C:9]=1[C:12]([O:14][CH3:15])=[O:13])[CH3:17]
Reactant: C=Cc1c(-c2ccccc2)coc1C(=O)OC
Agent: [Pd]
Solvent: CCO
Product: CCc1c(-c2ccccc2)coc1C(=O)OC
Reaction time: 3 h
Yield: 99.1 %

Procedure:
An ethanol (10 ml) solution of methyl 4-phenyl-3-vinyl-2-furancarboxylate (0.20 g) was blended with 10% palladium carbon and hydrogenated for 3 hours at 25° C. while stirring. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure, thereby giving 0.20 g of methyl 3-ethyl-4-phenyl-2-furancarboxylate. This compound was reacted with hydrazine monohydrate in the same manner as in Reference Example 31, thereby giving 0.12 g of the desired compound.
Reaction SMILES: C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](Cl)([O-])(=O)=O.ClCCl.[OH:26][CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>C(OCC)C>[CH:27]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:35]=[CH:36][C:37]([C:38]#[N:39])=[CH:40][CH:41]=2)[CH2:30][CH2:29]1)=[O:26]
Reactant: N#Cc1ccc([C@H]2CC[C@H](CO)CC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1

Procedure:
Into a 3 l capacity three-necked flask were added pyridium chlorochromate (161.7 g, 0.75 mol) and dichloromethane(1,000 ml), followed by agitating these, adding a dichloromethane solution (800 ml) of 4-{trans-4'-(hydroxymethyl]cyclohexyl}benzonitrile(107.6 g, 0.5 mol) at 20° C., agitating these for 90 minutes while keeping the temperature at 20° C., adding diethyl ether (1,500 ml), decanting the supernatant, passing the supernatant through a Florisil (trademark of the Floridin Company) column, concentrating under reduced pressure to obtain the captioned compound (101.2 g). Its structure was confirmed according to NMR spectra.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([Cl:22])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 16.08 g of 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylic acid and 12 ml of thionyl chloride was heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and subjected to distillation under reduced pressure (125° C./3 mmHg) to obtain 14.2 g of 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride of the formula:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1.CO>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:15]([CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Cn2ccc3c([N+](=O)[O-])cccc3c2=O)C1
Temperature: 25 °C

Procedure:
Into a round bottom flask was combined 5-nitro-isochromen-1-one (0.5 g, 0.002 mol), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (0.975 g, 0.00523 mol), methanol (15 mL, 0.37 mol), and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature. LC-MS showed that the starting material was completely consumed. Volatiles were removed and the resulting oil was purified by silica-gel twice in a methanol:methylene chloride (0-10%) gradient and in a EtoAc:Hexane(30-80%). A light yellow solid was obtained (0.56 g). m/z=360.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:40])[C@@H:14]([C@@H:19]([C:29](=[O:39])[NH:30][O:31]CC1C=CC=CC=1)[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]>CO.[Pd]>[O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:40])[C@@H:14]([C@@H:19]([C:29](=[O:39])[NH:30][OH:31])[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 89.4 %

Procedure:
A solution of 0.160 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleramide in 10 ml of methanol was hydrogenated for 3 hours in the presence of 0.02 g of 10% palladium-on-carbon. The catalyst was removed by filtration and evaporation of the solvent gave 0.120 g of N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:26])[CH2:21]1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (63.5, 55%).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[NH:9](C(OC(C)(C)C)=O)[C@H:10]([C:12](O)=[O:13])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:41][C@H:42]([C:48]([OH:50])=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46].[OH-].[K+].C(=O)([O-])[O-].[Na+].[Na+].Cl>CCOCC.ClCCl.O.O1CCCC1>[NH2:9][C@H:10]([C:12]([NH:41][C@H:42]([C:48]([OH:50])=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46])=[O:13])[CH3:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 1.5 h
Yield: 45 %

Procedure:
Dissolve 20 mmol of hexachloroethane with 10 ml of tetrahydrofuran, drop it into a mixed system composed of 10 mmol of tert-butylcarbonylalnine (Boc-Ala), 20 mmol of triphenylphosphine and 20 ml of tetrahydrofuran. After reacting at 0° C. for 1.5 hours, drop it into a liquid mixture containing 20 mmol of glutamine, 20 ml of water and 15 ml of dichloromethane. While reacting, regulate pH to 10 with 20 mmol of potassium hydroxide and then with sodium carbonate successively, the reaction temperature is 8° C., the reaction time after dropping is 2 hours. And then acidify it to regulate pH=2.0 with concentrated hydrochloric acid. The aqueous phase, after concentrated, reacts with methylsulfonic acid at room temperature for 20 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 45% is obtained by recrystallizing the solids with methanol-water.