Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[F:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11]Br>CN(C)C=O>[F:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCO
Reactant: Fc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
In a 10 ml flask, under a nitrogen atmosphere, 2-methoxyethanol (0.125 ml, 1.60 mmol) was dissolved in N,N-dimethylformamide (2 ml). Sodium hydride (60%, 72 mg, 1.81 mmol) was added and the mixture was stirred at ambient temperature for about thirty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (285 mg, 1.06 mmol) as a solution in N,N-dimethylformamide (2 ml). The resulting mixture was stirred at ambient temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic fractions were combined, washed with brine (7×) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].[CH2:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[CH:24][C:23]=1I)[CH3:21].C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[CH:24][C:23]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)[CH3:21]
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Reactant: CCc1c(I)cnn1-c1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1c(C#Cc2cnn3cc(-c4cnn(C)c4)cc(OC)c23)cnn1-c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (20 mg, 0.080 mmol), 5-ethyl-4-iodo-1-phenyl-1H-pyrazole (24 mg, 0.08 mmol), copper (I) iodide (4.5 mg, 0.024 mmol), and tetrakis(triphenylphosphine)palladium (0) (9.2 mg, 0.0079 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.022 ml, 0.16 mmol). The mixture was sparged with argon for 3 minutes and heated to 70° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 3-[(5-ethyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Cl:5])/[Cl:3].C([O-])([O-])=O.[Na+].[Na+].Cl.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18]>O>[C:17]([N:21]1[C:6](=[O:7])[C:4]([Cl:5])=[C:2]([Cl:3])[CH:1]=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)NN
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Yield: 92.2 %

Procedure:
To mucochloric acid (4.0 g, 23.6 mmol) in water (35 ml) at 0° C. was added anhydrous Na2CO3 (1.21 g, 11.5 mmol). This was stirred till a clear solution was obtained and to this was added tert-butylhydrazine hydrochloride (2.94 g, 23.6 mmol). A precipitate started to form after a few minutes. The reaction was stirred for a further 2.5 hrs after which it was filtered. The yellow precipitate was washed with cold water and dried to give 4.81 g of the crude hydrazone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:26])[CH2:24][CH3:25])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc(OC)c(OC)c1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.525 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, saturated sodium bicarbonate solution 50 ml, and a saturated sodium chloride solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 311.6 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:11][C@@H:12]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([O:8][CH2:13][C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:11])=[N:6][CH:7]=1
Reactant: C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: Oc1ncc(Br)cc1F
Product: C[C@@H](COc1ncc(Br)cc1F)N1C(=O)c2ccccc2C1=O

Procedure:
Using 5-bromo-3-fluoropyridin-2-ol and 2-((2S)-1-hydroxypropan-2-yl)-1H-isoindole-1,3(2H)-dione, and in the same manner as in Step C of Example 1, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:17][CH2:16][CH:14]2[CH2:13][O:15]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COCC2CO2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
p-Methoxybenzyl chloride (2.326 g, 14.85 mmol) was added slowly to a suspension of sodium hydride (60% dispersion in mineral oil, 0.594 g, 14.85 mmol) in DMF (25 mL) at 0° C. and the mixture stirred for 25 mins. Glycidol (1 g, 13.50 mmol) was then added dropwise over 25 mins, the mixture was allowed to warm to room temperature and stirred for 3 days. The mixture was diluted with EtOAc (50 ml) and washed with saturated NH4Cl (aq) (30 ml), saturated NaHCO3 (aq) (50 ml) and brine (100 ml). The organic phase was dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-10% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([Mg]Br)[CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1.CCOCC>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC[Mg]Br
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (300 mg, 1.19 mmol) in dry toluene (12 mL) under nitrogen was cooled to 0° C. (ice/water bath) and treated with n-pentylmagnesium bromide (0.66 mL of a 2M solution in Et2O, 1.31 mmol) and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was then quenched by the cautious addition of aqueous HCl (2M, 2 mL) and the solvent was removed under vacuum and the residue partitioned between EtOAc (2×50 mL) and aqueous HCl (2M, 50 mL). The organic solution was washed with water (60 mL) then brine (60 mL), dried (MgSO4) and reduced. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 19:1) afforded the title compound as a colourless oil (131 mg).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[OH:18][C@@H:19]1[CH2:24][O:23][C@@H:22]([CH3:25])[O:21][C@H:20]1[CH2:26][N:27]([CH2:42][C@H:43]1[C@H:48]([OH:49])[CH2:47][O:46][C@@H:45]([CH3:50])[O:44]1)[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[OH:18][C@@H:19]1[CH2:24][O:23][C@@H:22]([CH3:25])[O:21][C@H:20]1[CH2:26][N:27]([CH2:42][C@H:43]1[C@H:48]([OH:49])[CH2:47][O:46][C@@H:45]([CH3:50])[O:44]1)[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[NH:17])=[CH:35][CH:36]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: C[C@@H]1OC[C@@H](O)[C@H](CN(CCOc2ccc(CCCCN)cc2)C[C@@H]2O[C@H](C)OC[C@H]2O)O1
Agent: I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1OC[C@@H](O)[C@H](CN(CCOc2ccc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)cc2)C[C@@H]2O[C@H](C)OC[C@H]2O)O1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methylisothiourea hydriodide (0.39 g, 1.0 mmol) was added to a solution of 13 (0.49 g, 1.07 mmol) in THF (8 mL) containing diisopropylethylamine (0.18 mL, 2 mmol). The reaction mixture was stirred at reflux for 2.5 h and at room temperature overnight. After this time, the solvent was removed under reduced pressure. The brown residue was washed with ether (2×30 mL) and methylene chloride (2×10 mL). The residue was dissolved in a minimal volume of methanol (approx. 2 mL) and poured into water. The precipitate was collected, washed with water and dried overnight to give crude 11 (0.5 g) as a yellow solid. The compound 11 (0.4 g, 54%) was purified by flash chromatography on silica gel (eluent: chloroform/methanol/ammonium hydroxide=10:1:0.1) as a yellow solid. [α]D25=−20.4° (c=1.0, MeOH).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=2)(=[O:21])=[O:20])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A well-stirred slurry consisting of 4.64g (31 mmol) of 4-carboxybenzaldehyde and 5.92 g (31 mmol) of 4-chlorobenzenesulfonamide and 20 mg of p-toluenesulfonic acid (TsOH) in 130 mL of toluene was heated to reflux for a total of 5 hours. The water formed from the reaction was removed by a Soxhlet extractor packed with 3A molecular sieves as described above. The mixture was allowed to cool to room temperature and was filtered to provide 9.76 g (98%) of SULF-1 as a white powder: mp>245° C.; IR (Nujol) 3300-2300 (br), 3090, 1689, 1616, 1168, 1013 cm-1 ; 1H NMR (DSMO-d6, TMS ext standard, 60 MHz) δ9.15 (s, 1), 8.01 (s, 4), 7.79 (AB, 4, JAB =11, Δγ=16).
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.O1CCCC1.[Br:18]N1C(=O)CCC1=O>CO>[Br:18][C:10]1[N:6]2[C:7]([C:2]([Cl:1])=[N:3][C:4]([S:11][CH3:12])=[N:5]2)=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1nc(Cl)c2cccn2n1
Solvent: CO
Solvent: C1CCOC1
Product: CSc1nc(Cl)c2ccc(Br)n2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a Round bottom flask, [A] 4-Chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (25.47 g, 0.1276 mol), Tetrahydrofuran (1000 mL), and Methanol (640 mL) were added. N-Bromosuccinimide (22.7 g, 0.128 mol) was added portionwise to the reaction for 1 hour at 0° C. The reaction was stirred at room temperature for 1 hour and the solvent was removed under vacuum. The solid was partitioned with water and DCM (500 mL). The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The filtrate was then reduced under vacuum to afford 7-Bromo-4-chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid. 7-Bromo-4-chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine was suspended in Isopropyl alcohol (410 mL) at 55° C. Sodium borohydride (10.1 g, 0.268 mol) was added and heated at 60° C. for 3 hours. The reaction was allowed to cool to RT. The solid was filtered and washed with DCM. The solvent was partially removed to ensure the intermediate stayed in solution. (The intermediate is not stable out of solution). Methylene chloride (800 mL) was added to the viscous oil. Dichlorodicyanoquinone (31.8 g, 0.140 mol) was then added portion wise over 15 minutes. The mixture was stirred for 30 minutes. The solid was filtered through Celite, washed with DCM and the filtrate was removed under vacuum. The crude reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as an eluant (0 to 8% EtOAc). The collected fractions afforded 12.2 grams of 7-Bromo-4-chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a light yellow solid. 1H NMR (400 MHz, DMSO, d6) δ 8.95 (s, 1H), 7.09 (s, 2H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[CH:15]=[N:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[S:11][C@H:10]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[ClH:26].C([OH:29])C>>[ClH:26].[ClH:26].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]2[C:15](=[O:29])[NH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[S:11][C@H:10]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: CCO
Reactant: CN1CCN(C[C@H]2C=Nc3ccccc3S[C@H]2c2ccccc2)CC1
Agent: Cl
Product: CN1CCN(C[C@H]2C(=O)Nc3ccccc3S[C@H]2c2ccccc2)CC1

Procedure:
5.2 g of cis-(-)-2,3-dihydro-3-[(4-methylpiperazinyl)-methyl]-2-phenyl-1,5-benzothiazepine prepared as described in Example 18 or 19 was dissolved in 15 ml of ethanol and 3.6 ml of concentrated hydrochloric acid was added to the solution with stirring. The precipitated crystals were separated by filtration and recrystallized from aqueous methanol to obtain cis-(-)-2,3-dihydro-3-[(4-methylpiperazinyl)methyl]-2-phenyl-1,5-benzothiazepin-4(5H)-one dihydrochloride as colorless needles having a melting point of 231° C. (with decomposition). [α]D20 =-56° (c=0.4, water).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3]C1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:14]([Cl:17])(Cl)[Cl:15]>>[Cl:15][C:14]1([Cl:17])[CH2:3][CH2:4][CH2:5][NH:6][C:1]1=[O:7]
Reactant: O=C1CCCCN1
Reactant: ClC(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C1NCCCC1(Cl)Cl

Procedure:
Part A. To valerolactam (5.6 g, 55 mmol) in CHCl3 was added PCl5 (34.6 g, 166 mmol) and the reaction was heated to reflux 24 h. The reaction was cooled, quenched with H2O, extracted with CHCl3 and dried (MgSO4) to afford crude 3,3-dichloro-2-piperidinone.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:22]([N:23]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:25][CH2:24]4)=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:35]([O:37]CC)=[O:36])[CH:19]=4)[N:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:22]([N:23]4[CH2:24][CH2:25][CH:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:27][CH2:28]4)=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:35]([OH:37])=[O:36])[CH:19]=4)[N:14]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc2nc(N3CCC(c4ccccc4)CC3)c(N3CCC(c4ccccc4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(N3CCC(c4ccccc4)CC3)c(N3CCC(c4ccccc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of ethyl 2,3-bis(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.29 mmol, 1.00 equiv) in methanol (25 mL) and a solution of sodium hydroxide (58 mg, 1.45 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred for 3 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 30 mL of water. The pH value of the aqueous solution was adjusted to 3 with 1N hydrochloric acid. The resulting solids were collected by filtration. The solid was dried in an oven under reduced pressure and purified by re-crystallization from methanol. This resulted in 80 mg (56%) of 2,3-bis(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]=[C:17]([CH3:22])[C:18]([O:20]C)=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>O>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]=[C:17]([CH3:22])[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)=CCc1cccc(C(=O)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=CCc1cccc(C(=O)c2ccccc2)c1)C(=O)O
Yield: 49 %

Procedure:
A mixture of 615 mg of methyl 4-(m-benzoyl-phenyl)-2-methyl-2-butenoate, 6.2 ml of ethanol, 0.6 ml of water and 0.4 ml of a concentrated aqueous solution of potassium hydroxide was refluxed for 1 hour and then was evaporated to dryness under reduced pressure. The residue was taken up in water and the solution was treated with activated carbon, filtered and acidified to a pH of 1 with 2 N hydrochloric acid. The solution was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel with 90-10 ether-methylene chloride eluant to obtain 287 mg of 4-(m-benzoyl-phenyl)-2-methyl-2-butenoic acid in the form of an oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[S:3][CH:4]=1
Reactant: Clc1ccccc1-c1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3Cl)cs2)CC1
Yield: 67 %

Procedure:
A solution of 2-bromo-4-(2-chlorophenyl)-1,3-thiazole (4.48 g, 16.3 mmol), tert-butyl piperazine-1-carboxylate (6.08 g, 32.6 mmol) and potassium carbonate (2.26 g, 16.3 mmol) in dimethylformamide (50 ml) was stirred at 120° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 4.15 g (66.9%) of the desired product as a solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[CH3:29][N:28]1[C:24]([CH:10]2[CH2:9][CH:8]([C:6]3[O:7][NH:33][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[N:25][N:26]=[N:27]1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnnn2C)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nnnc1C1CC(c2cc(=O)[nH]o2)CCN1C(=O)OCc1ccccc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 55.7 %

Procedure:
Benzyl 4-(3-ethoxy-3-oxopropanoyl)-2-(1-methyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (0.947 g, 2.28 mmol) was dissolved in MeOH (10 mL) and cooled to −40° C. 3.8 M NaOH (0.600 mL, 2.28 mmol) dissolved in water (1 mL) was added and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.140 mL, 2.28 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. warm solution of 6 M HCl (11.40 mL, 68.38 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Benzyl 2-(1-methyl-1H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (488 mg, 56%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.86-1.99 (m, 1H), 2.18-2.30 (m, 1H), 2.33-2.54 (m, 2H), 3.01-3.12 (m, 1H), 3.78-4.09 (m, 5H), 5.05 (s, 2H), 5.20-5.30 (m, 1H), 5.67 (s, 1H), 7.20-7.27 (m, 2H), 7.27-7.39 (m, 3H). MS m/z 385 (M+H)+
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[CH3:28][CH2:27][C:26]([N:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: c1ccc(CCN2CCC(Nc3ccccc3)CC2)cc1
Reactant: CCC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCC(=O)N(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5.5 parts (w/w) of 4-anilino-N-phenethyl-piperidine preferably 1 to 3 parts in 5 to 15 parts (w/w) of dichloroethane preferably 8 to 12 parts was taken in a two neck round bottom flask fitted with a reflux condenser, pressure equalizing funnel and calcium chloride guard tube. To this stirred solution, 2 to 20 parts 9 w/w) of propionyl chloride preferably 5 to 15 parts was added drop wise through pressure equalizing funnel. After 2 to 6 hrs, preferably 4 to 5 hrs stirring at room temperature, the reaction mixture was washed with 20% sodium hydroxide solution. The washings were extracted with 2×50 parts, preferably 65 to 70 parts dichloroethane. The combined organic phase was dried over sodium sulphate and concentrated to give fentanyl. The crude compound was recrystallised from petroleum ether (60 to 80° C.) to give colourless crystals of pure fentanyl having mp 82 to 83° C.