Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH3:16][NH:17][NH2:18]>O1CCOCC1>[CH3:16][N:17]1[C:10](=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:18]1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CNN
Solvent: O
Solvent: C1COCCO1
Product: CN1N=C(c2ccccc2)CC1=O
Temperature: 500 °C
Reaction time: 8 h

Procedure:
To a mixture of 17.3 ml of ethyl benzoylacetate and 10 ml of water heated to 500° C. was added dropwise 5.3 ml of methyl-hydrazine over a period of 10 minutes (temperature rose to 70° C.) and the resulting mixture was heated at 60° C. for 2 hours. After adding 10 ml of dioxane the mixture was stirred at 55°-65° C. overnight, filtered, and the white solid was washed with water and dried in vacuo (P2O5) to afford 13.23 g of 2,4-dihydro-2-methyl-5-phenyl-3H-pyrazol-3-one (Formula III: R1 =CH3 ; R2 =Ph; R3 =H) as a white solid, m.p. 207° C.(d)
Reaction SMILES: CC(C)([O-])C.[CH:6]1([C@H:9]([OH:31])[C:10]([N:12]2[CH2:16][C:15]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])=[CH:14][C@H:13]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])[CH2:8][CH2:7]1.C(N(CC)CC)C.[P:39](Cl)([O:43]C)([O:41]C)=[O:40]>ClCCl>[P:39]([OH:43])([OH:41])([O:31][C@@H:9]([CH:6]1[CH2:8][CH2:7]1)[C:10]([N:12]1[CH2:16][C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][C@H:13]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:11])=[O:40]
Reactant: O=C([C@@H](O)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reactant: COP(=O)(Cl)OC
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([C@@H](OP(=O)(O)O)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 2 h

Procedure:
Titianium(IV) tert-butoxide (0.022 mL, 0.065 mmol, 0.100 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanol (6-2,230 mg, 0.647 mmol, 1 equiv) in dichloromethane (5 mL) at 23° C. followed by triethylamine (0.271 mL, 1.94 mmol, 3.00 equiv) and dimethyl chlorophosphate (0.140 mL, 1.29 mmol, 2.00 equiv). The resulting mixture was stirred for 2 h, then partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was dissolved in dimethyl sulfide (0.5 mL) and to the resulting solution was added methanesulfonic acid (1 mL). The resulting mixture was stirred for 10 min, then diluted with acetonitrile (3 mL). Purification by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) provided (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl dihydrogen phosphate (10-1) as a white solid. 1H NMR (500 MHz, CDCl3) major rotamer: δ 7.42-7.04 (m, 8H), 6.46 (s, 1H), 5.95 (m, 1H), 5.14 (br d, 1H, J=14 Hz), 5.04 (br d, 1H, J=14 Hz), 4.46 (t, 1H, J=8.2 Hz), 1.32 (m, 1H), 0.62 (m, 4H). LRMS m/z (M+H) 436.4 found, 436.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:39][CH:38]([OH:40])[CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:39][CH:38]([OH:40])[CH2:37][NH:36][CH2:35][CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: OC1CNCCNC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCNCC(O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and [1,4]diazepan-6-ol following General Procedure B.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.Cl.[CH2:9]([N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][C:1]#[N:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CCc1nccn1Cc1ccccc1
Temperature: 23 °C
Yield: 70 %

Procedure:
Dry, powdered sodium cyanide (14 gm, 280 mmole) was added to 80 ml of dry dimethylsulfoxide with stirring at 23° C. Then 1-benzyl-2-chloromethylimidazole hydrochloride (14 gm, 63 mmole) was added portionwise over 10 minutes while maintaining the temperature below 40° C. After the addition was complete, the mixture was stirred at 40° C. for an additional hour. It was diluted with 250 ml methylene chloride and the resulting solution was washed with 4×200 ml of water, dried over MgSO4 and the solvent removed in vacuo. The residue was collected by filtration, dissolved in warm methanol and precipitated with ether to obtain needle-like crystals (8.7 g) of N-benzyl-2-cyanomethylimidazole. m.p. 102.5°-104° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[C:23]=1[Cl:31].O>C1COCC1>[C:17]([C:4]1[CH:3]=[C:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[Cl:31])=[O:30])[N:6]([C:7]2[CH:15]=[C:14]3[C:10](=[CH:9][CH:8]=2)[CH2:11][CH2:12][C:13]3=[O:16])[N:5]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)CC3)n1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(=O)CC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of the 6-(5-amino-3-t-butyl-pyrazol-1-yl)indan-1-one (1.5 g, 5.6 mmol) in THF (30 mL) was added a solution of 1,2-dichloro-3-isocyanato-benzene (1.2 g, 6.4 mmol) in THF (5.0 mL) at 0° C. under N2. The resulting mixture was stirred at RT overnight then poured into H2O. The mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated and purified via column chromatography to afford 1-[5-t-butyl-2-(3-oxo-indan-5-yl)-2H-pyrazol-3-yl]-3-(2,3-dichlorophenyl)urea as a solid (1.1 g, 43% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.68 (s, 1H), 7.94 (t, J=5.1 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.24 (d, J=4.8 Hz, 2H), 6.34 (s, 1H), 3.14-3.05 (m, 2H), 2.78-2.66 (m, 2H), 1.22 (s, 9H); MS (ESI) m/z: 457 (M+H+).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.O.O.O.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>>[O:11]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCC2OC2C1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Product: OC1CCCCC1Oc1ccccc1
Temperature: 25 °C

Procedure:
Cyclohexene oxide (10 g, 0.102 mol) was added dropwise to an aqueous solution of sodium phenoxide trihydrate (31.6 g, 0.186 mol; 250 mL). The mixture was refluxed overnight, cooled to room temperature, and a precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate. The organic phase was washed with 1 M NaOH, brine, dried (over MgSO4), and concentrated to give solid 2-phenoxy-cyclohexanol (a compound of general Formula II) (13.84 g, 70%). The melting point of this compound was determined to be 79-80° C. 1HNMR (CDCl3 ): δ7.3 (m, 2H), 6.9 (m, 3H), 4.0 (m, 1H), 3.7 (m, 1H), 2.1 (m, 2H), 1.8 (m, 4H), 1.4 (m, 4H) ppm.
Reaction SMILES: CC(=CC)C.P([O-])(O)(O)=O.[Na+].Cl([O-])=[O:13].[Na+].[F:16][C:17]1[CH:18]=[C:19]([C@:23]2([CH2:28][O:29][C:30]3[C:35](=[O:36])[N:34]([CH2:37][O:38][CH3:39])[C:33]([CH3:40])=[N:32][C:31]=3[CH3:41])[CH2:25][C@H:24]2[CH:26]=[O:27])[CH:20]=[CH:21][CH:22]=1>C(Cl)(Cl)Cl.O.CC(C)=O.O>[F:16][C:17]1[CH:18]=[C:19]([C@:23]2([CH2:28][O:29][C:30]3[C:35](=[O:36])[N:34]([CH2:37][O:38][CH3:39])[C:33]([CH3:40])=[N:32][C:31]=3[CH3:41])[CH2:25][C@H:24]2[C:26]([OH:13])=[O:27])[CH:20]=[CH:21][CH:22]=1
Reactant: COCn1c(C)nc(C)c(OC[C@@]2(c3cccc(F)c3)C[C@H]2C=O)c1=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: COCn1c(C)nc(C)c(OC[C@@]2(c3cccc(F)c3)C[C@H]2C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
2-methyl 2-butene (1.14 ml), sodium dihydrogen phosphate (389 mg) and sodium chlorite (305 mg) were added to an acetone-water mixed solvent (8 ml-2 ml) of the compound 326-8 (779 mg). The obtained mixture was stirred at room temperature for 1 hour. Thereafter, water was added to the reaction solution, and chloroform was added to the reaction solution to carry out liquid separation and extraction. A small amount of 1 N hydrochloric acid was added to the obtained extract, and chloroform was further added to the reaction solution to carry out liquid separation and extraction. The obtained organic layer was dried over magnesium sulfate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, so as to obtain a crude product of the title carboxylic acid (814 mg).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1O.[I:16]Cl>O.Cl>[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][CH3:12])[CH:7]=[C:6]([I:16])[C:5]=1[Cl:1]
Reactant: CCC(C)(C)c1ccc(O)c(CN)c1
Reactant: ClI
Reactant: Cl
Solvent: O
Product: CCC(C)(C)c1cc(I)c(Cl)c(CN)c1
Temperature: -10 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
2-Aminomethyl-4-(1,1-dimethylpropyl)phenol hydrochloride (4.6 g., 0.02 mole) is dissolved in water (15 ml.) and a solution of iodine monochloride (3.28 g.) in 3N hydrochloric acid (10 ml.) is added. The mixture is kept for 3 hours and then cooled to -10° C. The solid that separates is crystallized from ethanol- 12N hydrochloric acid (1:10) to obtain 2-aminomethyl-4-(1,1-dimethylpropyl)-6-iodophenyl hydrochloride (4.15 g.), m.p. 203°-204° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:21][O:22][CH2:23][CH2:24][OH:25])[CH3:20])=[CH:15][N:14]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:27]1[CH:59]=[CH:58][C:30]([CH2:31][CH:32]2[S:36][C:35](=[O:37])[N:34]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]2=[O:57])=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:21][O:22][CH2:23][CH2:24][O:25][C:27]3[CH:59]=[CH:58][C:30]([CH2:31][CH:32]4[S:36][C:35](=[O:37])[N:34]([C:38]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:33]4=[O:57])=[CH:29][CH:28]=3)[CH3:20])=[CH:15][N:14]=2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(N(C)S(=O)(=O)c2ccc(C)cc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(N(C)S(=O)(=O)c2ccc(C)cc2)nc1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 1.22 g of 2-(1-{2-[N-(4-methylphenylsulfonyl)-N-methylamino]pyridin-5-yl}ethylideneaminooxy)ethanol (prepared as described in Preparation 34), 1.52 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 0.97 g of triphenylphosphine and 0.63 g of diethyl azodicarboxylate, 2.33 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [Si:1]([CH2:8][CH2:9][C@H:10]([O:16]C(=O)C)[C:11]([CH3:15])([CH3:14])[C:12]#[N:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[Si:1]([CH2:8][CH2:9][C@H:10]([OH:16])[C:11]([CH3:15])([CH3:14])[C:12]#[N:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)O[C@@H](CC[Si](C)(C)C(C)(C)C)C(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C#N)[C@@H](O)CC[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.8 g (16 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)-acetoxy-pentane-nitrile is dissolved in 50 ml of ethanol and mixed with 1.28 g of NaOH (32 mmol). It is stirred for 3 hours at 25° C., added to 200 ml of water, extracted with 2×200 ml of MTB ether, dried on sodium sulfate and concentrated by evaporation.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:10][CH:9]=1
Reactant: CNS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
To a stirred solution of 45.0 g (0.347 mole) of methylsulfamoyl chloride (Example 2, pt. a) in 100 ml of methylene chloride was added in a thin stream a solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis, Inc., Windham, N. H. 03087) in 30 ml (0.369 mole) of pyridine and 100 ml of methylene chloride and the reaction mixture was stirred at ambient temperature for 3 days. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a brown, viscous residue. The residue was partitioned between water and ethyl ether (400 ml each). The organic layer was washed twice with 300 ml portions of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a solid residue. The solid was triturated with 100 ml of isopropyl ether and the solid was recollected by filtration. The solid was recrystallized from isopropyl ether to give 12.9 g (34%) of title compound as a white solid, mp 101°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:18][NH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:18][N:19]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: NN
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1Cl
Solvent: O
Product: COc1ccc(C2=NNC(=O)CC2)cc1Cl
Yield: 84 %

Procedure:
This compound was prepared in 84% yield by reaction of 3-(3-chloro-4-methoxybenzoyl)propionic acid with hydrazine hydrate in ethanolic solution at reflux temperature for 5 hours. It had mp 194°-195°C after crystallisation from ethanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:8])[CH2:4][CH2:3]1.[C:22]([Cl:25])(=[O:24])[CH3:23]>CCOCC>[ClH:25].[C:22]([O:8][C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CN1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Solvent: CCOCC
Product: CC(=O)OC1(c2ccccc2Cc2ccccc2)CCN(C)CC1
Product: Cl
Reaction time: 94 h

Procedure:
1.41 g of 1-methyl-4-(α-phenyl-2-tolyl)-4-piperidinol, Example 1, is treated with 4.0 ml of acetyl chloride with cooling and stirring. The resulting suspension is stirred at ambient temperature under nitrogen for one hour and then permitted to stand for 94 hours. The mixture is diluted with 10 ml of ether and filtered. The filter cake is washed with ether and then recrystallized from absolute ethanol to give colorless crystals, mp 205°-206° C. of 4-acetoxy-1-methyl-4-(α-phenyl-2-tolyl)piperidine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([NH:14][CH:15]=[O:16])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C:5]([NH:14][CH:15]=[O:16])=[C:6]([Br:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(=Cc1ccccc1Br)NC=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC=O)=C(Br)c1ccccc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A 0.4 M solution of 3-(2-bromo-phenyl)-2-formylamino-acrylic acid ethyl ester (5.3 g; 17.8 mM) in anhydrous CH2Cl2, at 0° C., is added with N-bromosuccinimide (3.48 g; 19.6 mM). The mixture is left to slowly warm to room temperature. The reaction is completed in about 5 hours 30 mm. The equivalent amount of triethylamine is added drop by drop; after 30 minutes the mixture is washed with a NaHCO3 saturated solution and then with a NaCl saturated solution. The organic phase is dried over Na2SO4, the solid is filtered off and the clear solution is evaporated under reduced pressure to a residue. The crude (brownish oil) is purified by flash chromatography, using a 6:4 v/v mixture of hexane and ethyl acetate as eluent, thereby obtaining 2.68 g of 3-bromo-3-(2-bromo-phenyl)-2-formylamino-acrylic acid ethyl ester (white-pale yellow solid). (Yield: 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:16])([F:17])[F:15])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)cc(C(F)(F)F)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c(C(F)(F)F)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of 7-chloro-5-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (29 mg, 0.16 mmol) in concentrated H2SO4 (0.5 mL) at 0° C. was added KNO3 (11.6 mg, 0.115 mmol). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 12 h and it was poured into ice water (2 g). The precipitate was collected by filtration, affording 31 mg (91.4%) of crude title compound. It was dissolved in 1N KOH (1 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl to give a yellow precipitate, which was collected by filtration, and dried at 50° C. for 4 h, affording the title compound (23 mg, 67%) as a yellow powder. Recrystallization from DMSO/H2O gave pure title compound as yellow microcrystals. Mp: 278°-80° C., IR (KBr, cm-1): 3425, 3150, 3125, 1712, 1618, 1556; 1H NMR (DMSO-d6): δ7.531 (s, 1H), 11.803 (s, 1H), 12.459 (s, 1H). HRMS: calcd. for C9H3ClF3N3O4 (M+) m/z: 308.9763, found: 308.9759.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH3:33])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 42.2 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (85 mg, 0.198 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (55 m mg, 0.398 mmol, 2 eq) and methyl iodide (2M in t-butylmethyl ether, 0.100 mL, 1 eq). The reaction vial was capped, purged with nitrogen gas, and stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had progress by 70%. An additional 0.050 mL of 2M solution of methyl iodide was added and the reaction mixture was stirred at 80° C. for 6 h. Analysis by LC/MS displayed the reaction had progress by 95%. The reaction mixture was cooled to room temperature and then poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 23-55% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (37 mg, 42%). MS(ES)+ m/e 443.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[F-].[Cs+].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:19][CH2:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:10]=2)[O:3]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 17.5 h
Yield: 87 %

Procedure:
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.82 g), acetonitrile (50 ml), cesium fluoride (455.7 mg) and t-butyl acrylate (5.7 ml) were mixed at room temperature, and the mixture was stirred at 80° C. for 17.5 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the obtained residue were added water and ethyl ether, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl ether, and the organic layers were combined. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 4/6) to give the title compound (8.38 g, 87%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1.I([O-])(=O)(=O)=[O:13].[Na+].[OH2:18]>CC#N.[Ru](Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1)(=[O:13])=[O:18]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc([N+](=O)[O-])cn1
Reactant: O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A solution of 620 mg (3.64 mmol) of 2-methylsulfanyl-5-nitropyridine in 33 mL of MeCN and 9 mL of water was added 2.34 g (10.9 mmol) of sodium periodate followed by the addition of 15 mg (0.07 mmol) of ruthenium (III) chloride and the reaction was stirred at room temperature for 16 hours. The solids were filtered and the filtrate was diluted with 50 mL of water, extracted with 150 mL of ethyl acetate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The grey solid was purified by filtration through a silica column with DCM to afford 693 mg (94%) of 2-methanesulfonyl-5-nitropyridine.