Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=[O:14])[NH:13][C:4]=2[CH:3]=1.[C:18]1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([O:14][CH3:18])=[N:13][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)c2sccc12
Reactant: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1nc2cc(Cl)ccc2c(=O)c2sccc12
Temperature: 108 °C
Reaction time: 5 h

Procedure:
A 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel and a condenser with nitrogen inlet-outlet is charged with 7-Chloro-9H-3-thia-9-aza-benzo[f]azulene-4,10-dione (559.6 g), toluene (6.8 kg) and dimethylformamide (100.73 g). To the stirred suspension phosphorus oxychloride (357.2 g) is added over 5 min at 20-25° C. The pipes are flushed with toluene (774 g), then the temperature is raised to 108° C. over 1 hour and stirring continued for about 5 hours. Then the mixture is cooled to −5° C. and a 30% solution of sodium methylate (1.43 kg) is added over 30 min at −5° C. After addition the mixture is warmed to 40° C. over an hour and the solvent is distilled at 20-45° C. under reduced pressure. To the residue deionized water (6.7 kg) is added and the mixture is concentrated under reduced pressure to 7 L. Then heptane (3.06 kg) is added and the temperature is raised to 70° C. over 1 hour, followed by additional stirring of 10 min. The suspension is then cooled to 0° C. and the solid is collected by filtration, washed with heptane (2×383 g) and deionized water (2×1.1 kg) and dried under vacuum at 65° C. to yield the title compound with a melting point of >195-197° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@:4]1([CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CC(O)(C)C.C(OCC)C>[CH:2]([C@@H:3]1[CH2:5][C@:4]1([CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: CN(C[C@]1(c2ccccc2)C[C@H]1CO)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C[C@]1(c2ccccc2)C[C@H]1C=O)C(=O)OC(C)(C)C
Yield: 84.6 %

Procedure:
1,1-dimethylethyl {[(1R,2R)-2-(hydroxymethyl)-1-phenylcyclopropyl]methyl}methylcarbamate (3.8 g, 13.0 mmol), accessed via the method of Preparation 13B, was dissolved in 35 mL DCM with 1.1 mL 2-methylpropan-2-ol and treated with Dess-Martin Periodinane (8.8 g, 20.8 mmol, 1.6 eq) in 35 mL DCM at ambient temperature for 2 h. The reaction mixture was diluted with 50 mL diethyl ether and treated with 50 mL 1N NaOH at ambient temperature for 15 min. The organic phase was separated, the aqueous phase extracted twice with diethyl ether, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted EtOAc/hexanes (3:7)) to give the title compound (3.2 g, 11.0 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ 8.49-8.47 (m, 1H), 7.29-7.24 (m, 5H), 3.62-3.58 (m, 1H), 3.33-3.22 (m, 1H), 2.72-2.58 (m, 3H), 1.84-1.81 (m, 1H), 1.71-1.53 (m, 1H), 1.34-1.25 (m, 10H). ES-LCMS m/z 312.2 (M+Na).
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: CC(C)(O)CN
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NCC(C)(C)O)cn1
Yield: 17 %

Procedure:
As described for example 125f, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 1-amino-2-methyl-propan-2-ol instead of 2,2,2-trifluoroethylamine, to the title compound (40 mg, 17%) which was obtained as a colourless oil. MS: m/e=418.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10][CH:11]=C)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[O:15]=[O+][O-].[BH4-].[Na+]>CO.CCOCC.O>[F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:15])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: C=CCc1cc(C#N)c(OC)cc1F
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COc1cc(F)c(CCO)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-fluoro-2-methoxy-5-(prop-2-en-1-yl)benzonitrile (1.2 g, 6.0 mmol) in methanol (50 mL) was cooled in a dry ice acetone bath and treated with ozone. Since the starting material was contaminated with some tributylstanane residue from the previous reaction, the reaction turned brown at first. The mixture was flushed with nitrogen and quenched with dimethylsulfide (4 mL). The solution was allow to warm to about 0° C. which resulted in a clear yellow solution and then sodium borohydride (0.27 g, 7.2 mmol) was added under nitrogen and the reaction was stirred for 30 minutes at room temperature. TLC of an aliquot in ether/water (30% ethyl acetate in hexanes) indicated a product band without evidence of starting material. After a total of 1 hour, the reaction was quenched with 18% aqueous citric acid and concentrated in vacuo to remove the methanol. The residue was partitioned between ethyl acetate and 18% citric acid, washed with brine, dried over sodium sulfate and evaporated. Purification of the residue with a Biotage 40+M column (10 to 60% ethyl acetate in hexanes) gave the title alcohol as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 1.60 (br s, 1H), 2.842 (t, J=6.5 Hz, 2H), 3.853 (t, J=6.5 Hz, 2H), 3.904 (s, 3H), 6.682 (d, J=11.2 Hz, 1H), 7.487 (d, J=8.1 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:39]=[CH:38][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12](C(OC(C)(C)C)=O)[CH2:13][C@H:14]([O:23][Si](CC)(CC)CC)[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.[ClH:40]>C(OCC)(=O)C>[ClH:40].[OH:1][CH2:2][C:3]1[CH:39]=[CH:38][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([NH:12][CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(CO)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: OCc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Reaction time: 1 h

Procedure:
To N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (200 mg) was added 4N hydrogen chloride in ethyl acetate (6 ml) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After evaporation in vacuo, the residue was dissolved into a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, chloroform:methanol=5:1) and followed by treatment with 4N hydrogen chloride in ethyl acetate to give (2S)-1-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol hydrochloride (45 mg).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH2:20][OH:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>[C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:20]=[O:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N[C@@H]2[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H](CO)C[C@@H]2O1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of (3 aS,4R,5R,6R,7aS)-6-(hydroxymethyl)-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (1.76 g, 4.28 mmol) in dry DCM (40 mL) at 0° C. was added DMP (2.72 g, 6.42 mmol). The mixture was then stirred at room temperature for 4 h. The reaction was diluted with saturated aqueous NaHCO3 (20 mL) and 1 M Na2S2O3 (30 mL) and extracted with EtOAc (2×50 mL). The extracts were dried over MgSO4 and the solvents were evaporated to give (3aS,4R,5R,6S,7aS)-6-formyl-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (1.75 g, 100%) which was carried onto next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.95 (d, J=7.8 Hz, 2H), 7.88 (d, J=7.8 Hz, 2H), 7.47-7.54 (m, 2H), 7.32-7.38 (m, 4H), 6.48 (s, 1H), 5.66 (t, J=8.2 Hz, 1H), 5.50 (dd, J=7.7 Hz, 5.8 Hz, 1H), 4.94-4.97 (m, 1H), 4.00 (t, J=6.6 Hz, 1H), 3.26-3.32 (m, 1H), 2.56 (dt, J=12.1 Hz, 2.5 Hz, 1H), 2.10-2.18 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:22])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:5]/[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+]>C(O)C>[CH:7]1([CH2:6]/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)/[C:3]([OH:22])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)/C(=C/CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1
Temperature: 47.5 °C
Yield: 99.4 %

Procedure:
A solution of (E)-4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid methyl ester (1.00 g, 3.1 mmol) in ethanol (17 mL) was treated with a 1N aqueous sodium hydroxide solution (7 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and thc residue was diluted with water (30 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid (0.95 g, 99%) as a white solid: mp 162-165° C.; EI-HRMS m/e calcd for C16H10O4S (M+H)+309.1160, found 308.1158.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16](=[O:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][Mg]Br.O1CCCC1.[Cl-].[NH4+]>[Na].CCOCC.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([CH3:26])([OH:24])[C:17]([F:22])([F:23])[C:18]([F:19])([F:21])[F:20])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[Mg]Br
Reactant: O=C(C(O)(Cn1cncn1)c1ccc(F)cc1F)C(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(O)(C(O)(Cn1cncn1)c1ccc(F)cc1F)C(F)(F)C(F)(F)F

Procedure:
2-(2,4-Difluorophenyl)-2-hydroxy-4,4,5,5,5-pentafluoro-1-(1H-1,2,4-triazol-1-yl)pentan-3-one (0.5 g; 0.00135 moles) was dissolved in sodium-dried diethyl ether (50 cm3) and methylmagnesium bromide (1.35 cm3 of a 3M solution in ether; 0.00405 moles) was added. Dry tetrahydrofuran (15 cm3) was then added. The mixture was heated at reflux for 2 hours, cooled and 5% aqueous ammonium chloride (50 cm3) was added, followed by ethyl acetate (100 cm3). The phases were separated and the organic phase was dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on 230-400 mesh silica, eluting with ethyl acetate:diethylamine (95:5, 500 cm3). Two diastereomers were recovered by collection and evaporation of appropriate fractions. The first diastereomer to be eluted was called diastereomer I.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:15][CH3:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CS(C)=O.CCOC(C)=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[CH2:15][CH3:16])=[O:14])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCc1oc(-c2ccccc2)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-phenyl-5-ethyl-oxazole-4-carboxylic acid (180 mg, 0.829 mmol), 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (218 mg, 0.79 mmol), triethylamine (467 mL, 3.316 mmol), and BOP (366 mg, 0.89 mmol) in 5 mL DMSO was stirred at room temperature for 1.0 hr. The reaction was taken up in EtOAc (50 mL) and washed with hydrochloric acid (0.1N, 20 mL), water (20 mL), saturated sodium bicarbonate solution (20 mL), and brine (20 mL). The organic layer was dried with anhydrous magnesium sulfate and filtered to give 4-{4-[(2-phenyl-5-ethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester. ES-MS for C28H33N3O4 calcd. (m/e) 47.5, observed 476 (M−H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][OH:10])[O:5][CH2:4]2)[CH2:2]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=1[CH3:22]>CS(C)=O>[CH2:2]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:14]3[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=3[CH3:22])[O:5][CH2:4]2)[CH2:1]1
Reactant: OCC1OCC2(CC2)CO1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2OCC3(CC3)CO2)cc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
The 5,7-dioxaspiro[2.5]oct-6-ylmethanol (1.7 g, 11.8 mmol) obtained by the step (2b) was mixed with sodium hydride, in oil (708 mg, 17.7 mmol as the content was regarded as 60%) and dimethylsulfoxide (20 ml), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, 4-chloro-2,3-dimethylpyridine1-oxide (1.86 g, 11.8 mmol) was added and stirred at 50° C. overnight. After dimethylsulfoxide was distilled off, methanol and NH silica gel were added to the residue and methanol was distilled off. The mixture of the reaction mixture and NH silica gel was purified by silica gel column chromatography (NH silica gel: 200 g, elution solvent: ethyl acetate/heptane=1/1 to 4/1→methanol/ethyl acetate=1/9 to 1/4) to obtain the title compound (1.8 g, yield: 57.5%) as a red oil.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7](OCC)=[O:8])=[CH:5][N:4]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C(OCC)(=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[Br:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([CH:12]2[CH2:13][CH2:14][CH2:15]2)[N:3]=1
Reactant: CCOC(=O)c1cn(C2CCC2)nc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cn(C2CCC2)nc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of ethyl 3-bromo-1-cyclobutyl-1H-pyrazole-4-carboxylate (565 mg, 2.07 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. Diisobutylaluminum hydride (4.13 mL, 6.02 mmol, 1.5 M in toluene) was added slowly and the reaction was stirred at −78° C. for 1 hour. The reaction was then allowed to warm to room temperature and stir for an additional 2 hours. The reaction was diluted with ethyl acetate (20 mL) and saturated aqueous Rochelle's salt (20 mL). The mixture was stirred at room temperature overnight. The mixture was further diluted with ethyl acetate and was washed with water. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered, and concentrated to yield the title compound (478 mg, 100%) as a colorless oil. +APCI (M+H+1) 233.1; 1H NMR (400 MHz, CDCl3, δ): 7.40 (s, 1H), 4.62-4.71 (m, 1H), 4.51 (s, 2H), 2.39-2.59 (m, 4H), 1.74-1.92 (m, 3H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2OCC[O:17]2)=[CH:11][C:10]=1[CH3:21])C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCO.CCOC(C)=O.[Pd]>[NH2:8][C:9]1[C:10]([CH3:21])=[CH:11][C:12]([CH2:16][OH:17])=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C1OCCO1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(CO)c(C)cc1N
Reaction time: 3 h

Procedure:
A stirred solution of dibenzyl-[4-(1,3-dioxolan-2-yl)-2,5-dimethylphenyl)amine (2.00 g, 5.35 mmol) in EtOH (14.0 mL) and EtOAc (7.00 mL) was flushed with nitrogen for 3 min and then sodium bicarbonate (0.200 g, 2.38 mmol) and palladium on activated carbon (10 wt. %, ˜50% water; 0.800 g, 0.360 mmol) were added. The reaction mixture was flushed with hydrogen gas for 3 min and then stirred under a hydrogen atmosphere (balloon) for 3 h. The mixture was then filtered through a pad of Celite and the pad washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to give the title compound, which was used without any further purification.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=O)[C:12]#[N:13])([C:3](OCC)=[O:4])=[O:2]>C(O)C.[Pt]>[C:12]([C:11]1[CH:10]=[C:9]2[C:16](=[CH:15][CH:14]=1)[N:17]([OH:19])[C:3](=[O:4])[C:1](=[O:2])[NH:8]2)#[N:13]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: N#Cc1ccc2c(c1)[nH]c(=O)c(=O)n2O
Yield: 64.8 %

Procedure:
A solution of 0.5 g (1.9 mmol) 3-ethoxalylamino-4-nitrobenzonitril in 50 ml ethanol was hydrogenated at atm. pressure by using 25 mg 5% Pt-C as a catalyst. The catalyst was filtered off, and the filtrate was evaporated in vacuo. Cyclization was achieved by evaporation with acetic acid. Recrystallization (dimethylformamide-water) gave 0.25 g (65%) of 6-cyano-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. 250° C. decomp. 1H-NMR (DMSO-d6) 7.53 (s) and 7.40 (s)--a total of 3H.
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[S:6])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[O:18][N:17]=[C:16]([CH2:19][NH:20][CH3:21])[N:15]=2)[CH:11]=[CH:12][CH:13]=1>CCO>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[O:18][N:17]=[C:16]([CH2:19][N:20]([CH3:21])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[S:6])[N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CNCc1noc(-c2cccc(Cl)c2)n1
Reactant: S=C=NC1CC1
Solvent: CCO
Product: CN(Cc1noc(-c2cccc(Cl)c2)n1)C(=S)NC1CC1
Yield: 77.7 %

Procedure:
Cyclopropyl isothiocyanate (650 mg, 6.6 mmol) was added to 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]-N-methylmethanamine (1.47 g, 6.5 mmol) in EtOH (20 mL). After 3 h the formed precipitate was filtrated off and washed with cold EtOH to give 1.63 g (78%) of the title compound. LC-MS (M++1): 323.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(O)(C)(C)C>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=3)[N:5]=[CH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2ccc(Cl)nc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (0.5 g, 1.85 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (0.45 g, 2.22 mmol) were dissolved in the mixture of DCM (5 mL) and tert-butyl alcohol (5 mL). Potassium carbonate (0.612 g, 4.43 mmol) was added to the solution. The reaction mixture was stirred at ambient temperature for 24 h and filtrated under reduced pressure. The solid was washed by DCM. The filtrate was concentrated under reduced pressure. The residue was recrystallized in diethyl ether to give a faint yellow solid (0.73 g, 90.9% yield).
Reaction SMILES: CO.[CH2:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O>[CH3:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]/[CH:12]=[CH:11]\[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: CO
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A 12 l flask equipped with a reflux condenser, Firestone valve, mechanical stirrer, and addition funnel was flushed with N2. 500 g of oleyl alcohol and 1500 ml of tetrahydrofuran were added to the flask and the reaction mixture was cooled to 0° C. 1330 ml of n-butyllithium (1.6M in hexane) was added dropwise while maintaining the temperature below 5° C. The addition of butyllithium was completed in approximately 45 min. 420.6 g of p-toluenesulfonyl chloride was then added and the temperature was increased to 35°-40° C. using a heating mantle. The temperature was held at 40° C. for 3 hr. The reaction mixture was then cooled to 0° C. using a dry ice/isopropanol bath. 10 g of cuprous bromide was added followed by the dropwise addition of 1120 ml of n-pentylmagnesium bromide (2.5M in diethyl ether). This addition was completed in 48 min and the temperature was maintained near 0° C. during this time. The reaction mixture was stirred for 1 hr following the addition of n-pentylmagnesium bromide, then warmed to room temperature and held overnight under N2. 6.5 l of 4M HCl was added followed by phase separation. The organic phase was washed with 3 l of saturated sodium bicarbonate solution, followed by 2 volumes of a 1M KOH/MeOH solution (an aqueous KOH/MeOH solution as prepared by mixing one part of methanol and one part of water, with a final KOH concentration of 1M) the aqueous phase is then decanted. The organic solvent was removed by rotor evaporation and the residue distilled at 0.1 mm Hg vacuum. The distilled yield based on pure oleyl alcohol was 92.3%, with the final product containing 75% cis isomer.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N+](=[CH2:15])=[N-]>O1CCCC1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:15])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc2[nH]ncc2c1
Reaction time: 1 h

Procedure:
Under ice-cooling, to a solution of 910 mg of 1H-5-indazolecarboxylic acid in 60 ml tetrahydrofuran was added an excess amount of a solution of diazomethane in diethyl ether, and the mixture was stirred at the same temperature for 1 hour. After removing the solvent by distillation, the residue was added with 50 ml of ethyl acetate, sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 923 mg of the title compound as pale yellow crystals.