Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5]2[CH:7]=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.C([Li])CCC.[C:22](=[O:24])=[O:23].[OH-].[Na+]>C1COCC1.CCCCCC.O>[CH3:13][C:11]1([CH3:14])[O:10][C:9]2[C:15]([C:22]([OH:24])=[O:23])=[C:4]3[O:3][C:2]([CH3:16])([CH3:1])[O:6][C:5]3=[CH:7][C:8]=2[O:12]1
Reactant: CC1(C)Oc2cc3c(cc2O1)OC(C)(C)O3
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)Oc2cc3c(c(C(=O)O)c2O1)OC(C)(C)O3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole (10.0 g, 45.0 mmol; prepared according to WO-91/12024) was dissolved in dry THF (200 mL) under an argon atmosphere. The solution was cooled to -20° C. and n-butyllithium (20.0 mL, 50.0 mmol) in hexane was added. After attaining ambient temperature, the reaction mixture was transferred onto solid carbon dioxide (150 g) and allowed to stand overnight. Water (200 mL) was added and pH was adjusted to 10 using 2M aqueous NaOH. After washing with ether, the aqueous phase was acidified with 2M hydrochloric acid to pH 2 and extracted with ether (2*300 mL). The organic phases were dried (Na2SO4) and evaporated to give the pure product. Yield: 10.7 g (89%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CCO.O>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[N:16]=[CH:15][CH:14]=2)=[C:21]([F:29])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)c(F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(O)ccc23)c(F)c1
Temperature: 30 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
To a mixture of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)quinoline (16.38 g, 42 mmol) and HCOONH4 (26.46 g, 420 mmol) in a mixture solution of EtOH/H2O (84 mL, v/v=4:1) was added a catalytic amount of Pd/C (0.50 g, 5% amount, 53%˜55% water content, w/w). The reaction was stirred at 30° C. for 24 hours, and was monitored by LC-MS. After the complete consumption of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)quinoline, 6 M HCl (80 mL) was added to the reaction mixture until the solid was dissolved. The resulted solution was filtered. Saturated aqueous NaHCO3 solution (210 mL) was added to the filtrate to adjust the final pH to 6.0˜6.5 followed by the addition of a mixture of water (20 mL) and CH2Cl2 (50 mL). The resulted mixture was stirred at room temperature for 4 hours. The solid was collected by filtration, washed with a mixture of MeOH/DCM (50 mL, v/v=1/1), and dried in vacuo at 45° C. to give the title compound as a light yellow solid (11.0 g, 92%).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=O.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:10]([O:9][C:7](=[O:8])[NH:1][CH2:2][CH2:3][C:4](=[O:6])[NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BOC-Beta-Ala-OH (25 g, 0.132 mol) is dissolved in DCM (500 ml) and then treated with EDC1 (30.4 g, 0.59 mol) followed by t-butylamine (16.7 ml, 0.159 mol) to give a pale orange solution. The reaction mixture is stirred at room temperature overnight and then partitioned between 20% citric acid (400 ml) and DCM (250 ml). The organic portion is separated and washed with water (400 ml), saturated NaHCO3 (400 ml), brine (400 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[N:22][CH2:21][CH2:20][O:16][N+:17]([O-:19])=[O:18])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: COC(=NC#N)c1ccco1
Solvent: O=[N+]([O-])O
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
Methyl N-cyano-2 furancarboximidate (0.32 g, 2.09 mmol) was dissolved in methanol (3 ml), 2-nitroxyethylamine nitrate (0.37 g, 2.19 mmol) and triethylamine (0.22 g, 2.19 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 25 g) eluting with dichloromethane. The eluted fractions were concentrated under reduced pressure and crystallized from dichloromethane to give the title compound (0.20 g, 0.89 mmol, yield: 45%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[O:13]=C1CCCSC1C(OCC)=O.[Na].O>C(O)C.C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2c(n1)CCCS2
Reactant: CCOC(=O)C1SCCCC1=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1nc(O)c2c(n1)CCCS2

Procedure:
The starting material, 2-amino-4-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine, was prepared in the following manner. 56.4 g of ethyl 3-oxotetrahydrothiopyran-2-carboxylate was added to a solution of 6.9 g of sodium metal in 300 ml of ethanol at room temperature while stirring. After stirring overnight, water was added to the mixture, and the mixture was rendered acidic with acetic acid. The precipitated crystals were filtered, washed with water and then with a small amount of isopropyl alcohol and air-dried to obtain 45 g of 2-amino-4-hydroxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless needles having a melting point above 300° C.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([NH2:10])[C:8]#[N:9].[OH-].[Na+].N1C=CC=CC=1.[CH3:19][C:20]1[CH:24]=[C:23]([C:25](Cl)=[O:26])[S:22][N:21]=1>C(OCC)(=O)C>[C:8]([CH:7]([NH:10][C:25]([C:23]1[S:22][N:21]=[C:20]([CH3:19])[CH:24]=1)=[O:26])[C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)#[N:9]
Reactant: Cc1cc(C(=O)Cl)sn1
Reactant: N#CC(N)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NC(C#N)c2ccco2)sn1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
5.0 g of alpha-(2-furyl)-alpha-aminoacetonitrile hydrochloride was dehydrochlorinated with sodium hydroxide in ethyl acetate by the same method as in the above Synthesis Example 6. Pyridine (2.5 g) was added, and furthermore, an ethyl acetate solution of 4.0 g of 3-methylisothiazole-5-carboxylic acid chloride was added dropwise After the addition, the mixture was stirred for 1 hour. The reaction mixture was washed with water, dilute hydrochloric acid and a dilute aqueous solution of sodium bicarbonate. Sodium sulfate, and active carbon were added to dehydrate and decolorize the reaction mixture. The solvent was removed under reduced pressure, and the residue was washed with ethyl ether to give 4.5 g (yield 74%) of the desired N-(alpha-cyanofurfuryl)-3-methylisothiazole-5-carboxylic acid amide.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:20][NH:21][C:22]1[CH:44]=[CH:43][C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:23]=1>CN(C)C=O>[ClH:42].[ClH:42].[CH3:20][N:21]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=3)[CH2:32][CH2:33]2)=[O:27])=[CH:43][CH:44]=1)[C:5](=[O:7])[CH2:4][S:3][CH2:1][CH3:2]
Reactant: CCSCC(=O)O
Reactant: CNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCSCC(=O)N(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Product: Cl
Reaction time: 0.25 h

Procedure:
1.3 g of ethylmercaptoacetic acid are dissolved in 25 ml of N,N-dimethylformamide, and 2.3 g of N,N-carbonyldiimidazole are added. After 15 minutes at RT, the mixture is heated for 5 minutes at 90° ET. Then 3.5 g of 1-[4-(N-methylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine (see European Patent Application No. 489 690, Example 9) are added thereto, and the reaction mixture is kept at 110° ET for 14 hours. The mixture is concentrated by evaporation and the oil is chromatographed over silica gel (eluant: dichloromethane/acetone 8:2). Treatment with alcoholic hydrochloric acid yields 1-{4-[N-methyl-N-ethylmercaptoacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 163°-164°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>CCOC(C)=O.CO>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:27])[C:20]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:30][N:31]([CH3:33])[CH3:32])=[CH:17][CH:18]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ncccc3n2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C=C(C(=O)c1ccc(OCc2ccc3ncccc3n2)cc1)c1ccncc1
Yield: 99.7 %

Procedure:
In a 5 mL round bottom flask equipped with a magnetic stirbar and a condenser with a calcium sulfate drying tube was stirred at reflux for 18 hours a mixture of Intermediate 4D, 1-(4-((1,5-naphthyridin-2-yl)methoxy)phenyl)-2-(pyridin-4-yl)ethanone (104 mg, 0.293 mmol) and N,N-dimethylformamide dimethyl acetal (1.0 mL, 7.53 mmol). The reaction mixture was checked by TLC (95:5 EtOAc/MeOH). The spot for starting material had been replaced by a lower Rf spot. Volatiles were removed under reduced pressure to give a brown oil, 1-(4-((1,5-naphthyridin-2-yl)methoxy)phenyl)-3-(dimethylamino)-2-(pyridin-4-yl)prop-2-en-1-one (120 mg, 0.292 mmol) that was dissolved in methanol (2.5 mL) and stirred at ambient temperature. Hydrazine monohydrate (0.02127 mL, 0.438 mmol) was added via syringe and the reaction mixture was stirred at reflux for 2 hours. Another 1.5 equivalents of hydrazine monohydrate was added and stirring at reflux was continued an additional 2 hours. Volatiles were removed under reduced pressure to give a tan solid that was rinsed with water 3 times then stirred with Et2O overnight. The Et2O was decanted away and the remaining solid was partitioned between CHCl3 and brine. The aqueous layer was extracted once more with CHCl3 and the combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a crude, bright yellow solid. This solid was purified by column chromatography on an Analogix IF-280 (Agilent SF15-24 g, 100% DCM to 98:2 DCM/2M NH3 in MeOH). Fractions #5-20 were combined and concentrated under reduced pressure to give a pale yellow solid. The solid was dissolved in warm CHCl3 and the resulting solution was filtered and concentrated under reduced pressure. The solid residue was rinsed with Et2O, then dissolved in a minimum of hot MeOH. The solution was placed in a 0° C. freezer to induce crystallization. Intermediate 4, 2-((4-(4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine was obtained by filtration as white crystals (16.5 mg, 14.9%). 1H NMR (300 MHz, methanol-d4) δ 8.98 (dd, J=4.2, 1.6 Hz, 1H), 8.48 (dd, J=8.6, 1.8 Hz, 2H), 8.36 (dd, J=4.7, 1.6 Hz, 2H), 8.02 (d, J=8.8 Hz, 1H), 7.97 (br s, 1H), 7.82 (dd, J=8.5, 4.3 Hz, 1H), 7.42-7.36 (m, 2H), 7.33 (d, J=5.9 Hz, 2H), 7.16 (d, J=7.3 Hz, 2H), 5.47 (s, 2H). MS (ESI) m/z=380 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15]O)[O:11][C@H:10]1[N:17]1[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15][Br:26])[O:11][C@H:10]1[N:17]1[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCc2ccccc2)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CBr)[C@@H](O)[C@H]2OCc2ccccc2)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
To a mixture of 2'-O-benzyluridine [Wagner et al. (1974), J. Org. Chem. 39, 24-30] (334 mg 1 mM) carbon tetrabromide (500 mg) and DMF (4 ml) at 20° C. under Argon was added over 5 mins a solution of triphenylphosphine (340 mg) in DMF (2 ml). The mixture was stirred at 20° C. for 2 hrs, poured into water (60 ml) and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried, and evaporated to an oil. This oil was chromatographed on 20 g of Merck silica gel (Art. 9385). Elution with 5% methanol in toluene gave 2'-O-benzyl-5'-bromo-5'-deoxyuridine (160 mg, 40%).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19].CC(O)C>CCCCCC>[CH:18]([C@@H:17]([C@H:5]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH:16]=[O:21])([CH3:20])[CH3:19]
Reactant: CC(C)CC=O
Reactant: O=[N+]([O-])/C=C/c1cccc2ccccc12
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC(C)[C@H](C=O)[C@@H](C[N+](=O)[O-])c1cccc2ccccc12

Procedure:
The title compound was prepared from (E)-1-(2-nitrovinyl)naphthalene and isovaleraldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 254 nm (2-propanol:hexane=10:90), 1 mL/min, tmajor=13.7 min, tminor 16.8 min, the diastereomeric ratio was determined by
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(O)(=O)C>[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccccc1
Yield: 801.2 %

Procedure:
A mixture containing 168 g (1 mol) of diphenylmethane, 16 g (0.1 mol) of N-hydroxyphthalimide, and 1000 mL of acetic acid was allowed to react at 100° C. for 20 hours in an atmosphere of oxygen to obtain a reaction mixture containing 146 g of benzophenone (yield 80%). From the reaction mixture, acetic acid was distilled off, and to the reaction mixture were added 1000 mL of dibutyl ether and 1000 mL of 0.4N sodium hydroxide aqueous solution. After stirring at 97° C. for 1 hour, an aqueous phase and an organic phase were separated. To the resulting organic phase was further added sodium hydroxide aqueous solution, and mixed completely at 97° C. to liquid-separate into an aqueous phase and an organic phase. The aqueous and organic phases were analyzed by gas chromatography and liquid chromatography, and, as a result, the extraction ratio of benzophenone into the organic phase was 89%, the extraction ratio of the oxidation catalyst and/or the deactivated oxidation catalyst (conversion into sodium phthalate) (on basis of the amount of N-hydroxyphthalimide used in the reaction) into the aqueous phase was 83%.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)[C:10]([N:12]([C@H:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:23](O)=[O:24])[C@@H:13](C(OC)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[F:51][C:52]([F:56])([F:55])[CH2:53][NH2:54]>CN(C)C=O>[CH2:41]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[C@H:9]1[NH:8][C:6](=[O:7])[C@@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:12]([C@H:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:23]([NH:54][CH2:53][C:52]([F:56])([F:55])[F:51])=[O:24])[C:10]1=[O:11]
Reactant: NCC(F)(F)F
Reactant: COC(=O)[C@@H](CC(C)C)N(C(=O)[C@H](NC(=O)OC(C)(C)C)C1Cc2ccccc2C1)[C@@H](C(=O)O)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NCC(F)(F)F)c1ccc(F)cc1
Reaction time: 0.03 h

Procedure:
A solution of (2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid (73 mg) in N,N-dimethylformamide (2 ml) was sequentially treated with diisopropylethylamine (51 μl), phosphorusI (1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-(T-4)-hexafluorophosphate (80 mg) and then after 2 minutes, 2,2,2-trifluoroethylamine (25 μl). This reaction mixture was stirred for 2 hours before being partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before being dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in 4M hydrogen chloride in dioxane and stirred for 7 hours at room temperature. The reagent was removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic fraction was washed with brine before being dried over magnesium sulphate and evaporated in vacuo. The crude material was purified by column chromatography (silica) eluting with methanol:dichloromethane (1% to 3%) to furnish ((2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide (10 mg)
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:16]>C1(C)C=CC=CC=1.CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH3:16])=[O:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2)on1
Reaction time: 0.5 h

Procedure:
A solution of 5-phenylisoxazole-3-carboxylic acid (0.86 g, 4.55 mmol) in toluene (15.0 mL) and methanol (3 mL) was added a 2M solution of TMS-diazomethane in hexanes (3.1 mL, 6.14 mmol) dropwise at room temperature. The reaction mixture was stirred for 30 minutes and concentrated. The residue was dispersed in methanol (3 mL), stirred for 5 minutes, and filtered to give methyl 5-phenylisoxazole-3-carboxylate (897 mg). The compound had an HPLC ret. time=2.67 min.: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=204+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]([CH3:16])[CH3:15])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH2:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:22].N12CCCN=C1CCCCC2>C(#N)C>[CH2:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH:14]([CH3:16])[CH3:15])=[CH:3][C:2]=2[F:1])[CH2:26]1)[CH3:22]
Reactant: CCNCC1CCNC1
Reactant: CC(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C(C)C)c3c2F)C1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
A solution of 0.57 g (2.0 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylethyl)-4-oxo-3-quinolinecarboxylic acid, 0.32 ml (2.2 mmol) of 3-[(ethylamino)methyl]pyrrolidine, 0.30 ml (2.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 15 ml of acetonitrile was heated under reflux for one hour. After cooling to room temperature the mixture was filtered and the solid washed with acetonitrile and methanol to give 0.58 g of the title compound, mp 230°-231° C.
Reaction SMILES: Cl.C[NH:3][C@H:4]([C:15]([OH:17])=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C([N:20](CC)CC)C.CCOCC>CO>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@@H:4]([C:15]([NH2:20])=[O:17])[NH2:3])=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: CCN(CC)CC
Reactant: CN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Temperature: -10 °C
Reaction time: 42 h

Procedure:
A slurry of 1 (10.97 g, 42.1 mmol) in dry methanol (5 ml) was treated with triethylamine (6.45 ml). After clearing, anhydrous ether (200 ml) was added to the solution and cooled to -10° C. for one hour. Precipitated triethylamine hydrochloride was removed by filtration and the filtrate concentrated to a limpid yellow oil. The oil was added to dry methanol (250 ml) previously saturated with NH3 (g) at -10° C., tightly stoppered and left at -10° C. for 42 hours. The precipitated product was collected and dried under vacuum. The liquid filtrate was spotted on a TLC plate and developed with CHCl3 :MeOH (4:1) which revealed one spot at Rf =0.50, identical to that of the collected precipitate. The filtrate was therefore stripped to dryness and the remaining solid 2 combined with the precipitate (8.12 g, 92.3%): mp 160°-162° C.; 1H NMR (220 MHz, DMSO-d6), δ 8.07 (d, 2, J32 8.0), 7.5 (d, 2, J=8.0), 7.41 (s, 1), 7.00 (s, 1), 3.50 (t, 1, J=6.0), 3.09 (dd, 1, J=6.0, 16.0); 2.81 (dd, 1, J=6.0, 16.0) CI-MS 210 ((M+1)/z).
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([S:28][CH3:29])=[CH:22]2)=[O:18].[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH:33]=O>C(Cl)Cl>[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH2:33][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:20]=2)[NH:24][C:23]=1[S:28][CH3:29]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2[nH]c(SC)cc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2[nH]c(SC)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
To a methylene chloride (10 ml) solution of trifluoroacetic acid (1.238 g) and triethylsilane (2.52 g), added is a methylene chloride (10 ml) solution of 5-methoxycarbonyl-2-methylthioindole (0.800 g), which had been prepared according to the method described in “Tetrahedron, 42 (16), 4511 (1986)”, and 2,4-dichlorobenzaldehyde (0.760 g), in an ice-water bath. This is stirred for 3 hours in the ice-water bath. The crystal formed is taken out through filtration and dried to obtain 3-(2,4-dichlorobenzyl)-5-methoxycarbonyl-2-methylthioindole (152) (0.727 g).