Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH2:35][CH2:36][OH:37])[CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:30]3[CH:31]=[N:32][N:33]([CH2:35][CH2:36][OH:37])[CH:34]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(CCO)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A mixture of (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.050 g, 0.141 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (0.050 g, 0.211 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (XPhos 2nd generation precatalyst) (5.54 mg, 7.04 μmol), and cesium carbonate (0.138 g, 0.422 mmol) in 1,4-dioxane (2.0 mL) and water (0.40 mL) was stirred in the microwave at 100° C. for 1 h. The reaction mixture was filtered through Celite and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-10% methanol-ethyl acetate) to afford (S)-isopropyl 4-acetyl-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.052 g, 96%) as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][NH2:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](OC)=O.C(N)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.ClCCl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][NH:13][CH3:16])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: COC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: NC=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCCc1ccc(-c2ccccc2)cc1
Reaction time: 20 h
Yield: 18 %

Procedure:
4-Phenylphenethyl amine, 0.48 g (2.4 mmol), was added to an excess of methyl formate (5 mL) and dichloromethane (5 mL) was added to improve solubility. The heterogeneous reaction mixture was refluxed to give a solution within 20 hours. NMR analysis of a sample showed almost complete conversion to N-formyl amine. The reaction mixture was evaporated to give 0.47 g (87%). The formyl compound, 0.47 g (2.09 mmol), was dissolved in THF and 2.1 mL of 1.0 M lithium aluminium hydride (2.1 mmol) in THF was added. TLC analysis after 20 hours showed only starting material and 2 mL (2 mmol) of lithium aluminium hydride solution was added. Analysis after 1 hour showed starting material and the mixture was heated to reflux. After 1.5 hours a precipitate was formed, the starting material consumed and tetrahydrofuran (15 ml) was added. The mixture was quenched by successive addition of water (0.15 g), 15% aqueous sodium hydroxide (0.15 g) and water (0.45 g). The mixture was filtered and evaporated to give 0.33 g crude product. The crude product was purified by silica gel chromatography (100 mL) using dichloromethane/methanol/concentrated ammonia (90+10+1) as eluant. Evaporation of pure fractions gave 78 mg (18%) of the sub-titled compound.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([OH:9])[C@@H:7]([OH:10])[CH2:6][O:5][CH:3]1[OH:4].S(=O)(=O)(O)O>CO>[F:1][C@@H:2]1[C@@H:8]([OH:9])[C@H:7]([CH2:6][OH:5])[O:10][CH:3]1[OH:4]
Reactant: OC1OC[C@H](O)[C@H](O)[C@H]1F
Agent: O=S(=O)(O)O
Solvent: CO
Product: OC[C@@H]1OC(O)[C@H](F)[C@H]1O
Yield: 80 %

Procedure:
Treatment of unprotected 2-deoxy-2-fluoro-L-arabinopyranose with one equivalent of either sulfuric or hydrochloric acid at room temperature failed to give the desired furanoside. Only unreacted starting material was detected. Using nine equivalents of hydrochloric acid gave the desired product 2-deoxy-2-fluoro-L-arabinofuranose, which was contaminated with starting material (2:1 ratio). The best result, so far, was achieved by refluxing 2-deoxy-2-fluoro-L-arabinopyranose with 1 equivalent of sulfuric acid in dry methanol. After 6 hours all of the starting material had disappeared affording 2-deoxy-2-fluoro-L-arabinofuranose as an oil in 80% yield. 1H-, 13C- and 19F-NMR indicated a 3:1 α:β mixture of anomers, with some minor impurities. L-ribo- and L-arabinopyranoside as well as L-ribofuranoside are the possible side products. The D-isomer of 2-deoxy-2-fluoro-L-arabinofuranose was previously made by two different groups, but in less efficient ways (Wright, J. A.; Taylor, N. F.; Fox, J. J. J. Org. Chem 1969, 34, 2632. and Wysocki, R. J.; Siddiqui, M. A.; Barchi, J. J.; Driscoll, J. S.; Marquez, V. E. Synthesis 1991, 1005).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH:13]=[CH:12]3)(=[O:3])[CH3:2].[NH4+].[Cl-].[CH2:26]1[CH2:30]OC[CH2:27]1>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:27][CH2:26][CH3:30])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Product: CCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Reaction time: 0.5 h

Procedure:
After stirring for an additional 0.5 hr , a solution of 5.2 g of (17 beta)-17-(acetyloxy)estra-4,6-dien-3-one (1) in 20 ml of THF was added dropwise at −40 C. Upon stirring for an additional 15 minutes the reaction was complete, and the mixture was poured onto 300 ml of saturated NH4Cl solution, followed by extraction with ethyl acetate. The organic material, isolated after washing, drying and evaporation of the solvent, was taken up in 30 ml of THF and stirred in the presence of 3 ml of 6N H2SO4 to isomerize some Δ5,6 isomer to Δ4,5 isomer. After 1 hr the mixture was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate. Chromatography of the crude product over silica gel (heptane/ethyl acetate 8/2) provided 2.1 g of 2, m.p. 97-100° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:6]2[NH:5]1.I[CH3:29]>C1COCC1>[CH3:29][N:5]1[C@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2NC(=O)c3c(cccc3C(F)(F)F)[C@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a suspension of NaH (8.5 mg of 60% in mineral oil, hexane-washed, 0.21 mmol) in 2 mL of THF at ambient temperature was added (3aR,9bS)-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 13, Part A (50 mg, 0.14 mmol) as a solution in 2 mL of THF. The reaction was stirred for 20 min, at which time gas evolution had ceased and the reaction mixture was homogeneous. Then there was added iodomethane (0.022 mL, 0.35 mmol) and the reaction was allowed to stir at ambient temperature for 18 h. The reaction was quenched with water, diluted with EtOAc and washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 3:1 hexane/EtOAc) to afford 40 mg (77%) of the title compound. LRMS (ESI): 371.12 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:29])[NH:24][CH2:25][C:26](=[O:28])[NH2:27])=[CH:17][CH:16]=1)C1C=CC=CC=1>CCO.C1COCC1>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:24][CH2:25][C:26](=[O:28])[NH2:27])=[O:29])=[CH:17][CH:16]=1
Reactant: NC(=O)CNC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCCc1ccc(OCC(=O)NCC(N)=O)cc1
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Compound 37 (130 mg, 0.314 mmol) was dissolved in EtOH and THF (14 mL, 1/1 ratio). The reaction vessel was purged with nitrogen both before and after the catalyst (100 mg, 10% Pd/C, 50% wet) was added. The mixture was stirred under hydrogen atmosphere (1 atm) overnight. After purging with nitrogen, the catalyst was vacuum filtered and washed with ethanol (3×5 mL). The combined filtrates were concentrated under vacuum. The residue was chromatographed on silica gel, eluting with a mixture of concentrated ammonium hydroxide/methanol/dichloromethane (2:20:88, v/v), to afford the desired product 38 (80 mg, 91% yield) as a white solid. 1H NMR (300 MHz, CD3OD): δ 1.62 (m, 4H), 2.60 (t, 2H), 2.75 (t, 2H), 3.92 (s, 2H), 4.54 (s, 2H), 6.92 (d, 2H), 7.14 (d, 2H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>ClCCl>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]
Reactant: C1=COCCC1
Reactant: N#Cc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc(COC2CCCCO2)c1
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
Add p-toluene sulphonic acid (2.11 g, 12.2 mmol) to a solution of 3-hydroxymethyl-benzonitrile (16.30 g, 122.4 mmol) and 3,4-dihydro-2H-pyran (51.5 g, 612 mmol) in dichloromethane (500 ml) and stir. After 90 minutes, pour reaction into saturated sodium bicarbonate, remove organics, dry with sodium sulfate, filter and concentrate to give a dark brown oil. Purify the residue by flash chromatography eluting with a gradient of 10-15% ethyl acetate:hexanes to yield the title product as a clear oil (16.20 g, 61%): 1H NMR (CDCl3) δ 1.53-1.91 (m, 6H), 3.56 (m, 1H), 3.88 (m, 1H), 4.53 (d, 1H), 4.72 (t, 1H), 4.81 (d, 1H), 7.45 (t, 1H), 7.58 (m, 2H), 7.69 (s, 1H)
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:15]2[C:19]([Cl:20])=[C:18]([O:21][CH:22]([F:24])[F:23])[N:17]([CH3:25])[N:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14])(=O)C.Cl>O1CCOCC1.O>[Cl:20][C:19]1[C:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([CH2:7][OH:6])[CH:9]=2)=[N:16][N:17]([CH3:25])[C:18]=1[O:21][CH:22]([F:24])[F:23]
Reactant: CC(=O)OCc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(Cl)c(CO)c2)c(Cl)c1OC(F)F
Reaction time: 1 h

Procedure:
6.3 ml (16 mmol) of 10% strength sodium hydroxide solution were added dropwise to a solution of 3.2 g (8.8 mmol) of 3-(3-acetoxymethyl-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 10 ml of dioxane and 10 ml of water. The mixture was stirred for 1 hour and then neutralized with 3N hydrochloric acid. The product was extracted from the aqueous phase with ethyl acetate, after which the organic phase was dried over magnesium sulfate and then concentrated. The crude product thus obtained was purified by column chromography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 1.3 g.
Reaction SMILES: [NH:1]([C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([N+:17]([O-])=O)=[C:10]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27].[H][H]>[Pd].C.CO>[ClH:27].[ClH:27].[NH2:14][C:13]1[C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:10]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:11]([NH2:17])[CH:12]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccccc2)nc1Nc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cc(N)c(Nc2ccccc2)nc1Nc1ccccc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 181.8 %

Procedure:
A 500 ml Parr bottle was twice charged with 2,6-dianilino-3,5-dinitropyridine (13.5 g, 0.0385 mole), 300 ml of methanol containing HCl (10 g) and 5% Pd/Charcoal catalyst (1.1 g). The mixture was placed under 55 psig. hydrogen pressure and kept at 25°-40°C until no further uptake of hydrogen was observed. The combined reduction mixtures were cooled, precipitated product and catalyst filtered under nitrogen, and the filter cake washed with 10% HCl in isopropyl alcohol. The filter cake was added to 500 ml of warm (55°C) conc. HCl, stirred well for 5 minutes, filtered and the insolubles washed with conc. HCl. The clear filtrate was cooled (0°C), diluted with 500 ml cold (-15°C) isopropyl alcohol with good stirring to precipitate product. The solid was filtered, washed with 10% HCl in isopropyl alcohol and vacuum dried over P2O5 to afford 3,5-diamino-2,6-dianilinopyridine dihydrochloride (25.5 g, 92%). Anal. Calcd. for C17H17N5.2HCl: C, 56.0; H, 5.2; N, 19.2; Cl, 19.5. Found: C, 54.0; H, 5.4; N, 19.4; Cl, 20.0.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].CC(N(C)C)=O.[CH3:13][N:14]([CH:16]=O)[CH3:15]>>[CH3:15][N:14](/[CH:16]=[C:3](/[C:2](=[O:1])[CH3:6])\[C:4]#[N:5])[CH3:13]
Reactant: CC(=O)CC#N
Reactant: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CC(=O)/C(C#N)=C/N(C)C

Procedure:
3-Oxo-butyronitrile (113 g, 1.36 mol) and DMF.DMA (215 g, 1.81 mol) were heated to 80° C. for two hours. The solvents were then removed under vacuum to yield a solid. The solid was partitioned between ethyl acetate (1.5 L) and saturated sodium bicarbonate solution (1 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (1.5 L). The organic layers were combined and the solvent removed under vacuum to yield the title compound as a solid.
Reaction SMILES: OS(O)(=O)=O.[N-:6]=[N+]=[N-].[Na+].[F:10][C:11]([F:30])([F:29])[C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[CH2:20]2)[CH2:16][CH2:15]1)=[O:13].C([O-])(O)=O.[Na+]>O.C(Cl)(Cl)Cl>[F:10][C:11]([F:30])([F:29])[C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:6][C:21](=[O:28])[CH2:20]2)[CH2:16][CH2:15]1)=[O:13]
Reactant: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Concentrated H2SO4 (1.1 mL) was added slowly to sodium azide (2.49 g, 38.3 mmol) in water (2.7 mL) and chloroform (15 mL) keeping the temperature between 0-5° C. After 10 min the cold bath was removed and the reaction was stirred for 3 h at rt. Na2SO4 was added to the solution to dry it and the resulting chloroform solution (containing HN3) was then decanted into a solution of 19a (4.55 g, 15.3 mmol) in chloroform (16 mL). Concentrated H2SO4 (4.1 mL) was added and the reaction was stirred for 30 min. at rt. The mixture was heated to 50° C. for 45 min. and then stirred at rt for 2 h. The reaction was poured into sat. NaHCO3 solution and extracted with CH2C12 (3×) and with EtOAc (2×). The combined organics were dried (MgSO4), filtered and evaporated to give the crude product. The crude product was purified by flash chromatography on Biotage using EtOAc/CH2C12 (50-80%) to give 19b as lightly colored foam (2.6 g, 54%). (M+H)+=313. 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (s, 1H); 7.29 (d, J=7.8 Hz, 1H); 7.24 (t, J=7.8 Hz, 1H); 7.10 (t, J=7.6 Hz, 1H); 6.83 (d, J=7.8 Hz, 1H); 4.44 (d, J=13.9 Hz, 1H); 3.92 (d, J=14.1 Hz, 1H); 3.48 (t, J=13.2 Hz, 1H); 3.18 (t, J=11.9 Hz, 1H); 2.77 (m, 2H); 2.00 (m, 2H); 1.85 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[NH:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:16][C:17]([Cl:21])([Cl:20])[S:18]Cl>O>[C:1]1([N:7]2[C:8](=[O:13])[N:9]([S:18][C:17]([Cl:21])([Cl:20])[Cl:16])[N:10]([S:18][C:17]([Cl:21])([Cl:20])[Cl:16])[C:11]2=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: O=c1[nH][nH]c(=O)n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1n(-c2ccccc2)c(=O)n(SC(Cl)(Cl)Cl)n1SC(Cl)(Cl)Cl

Procedure:
To a solution of 35.4g (0.2 mole) 4-phenyl urazole in 200 ml water was added a solution of 16g (0.4 mole) sodium hydroxide in 20 ml water. A mixture of 74.4g (0.4 mole)trichloromethylsulfenyl chloride and 3g of an emulsifier solution (EXEM 25, consisting of a mixture of alkyl benzene sulfonate and ethoxylated vegetable oil) in 50 ml water was added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The reactants were mixed so that the reaction mixture was kept at a pH greater than 7. The precipitate that formed was filtered and the filter cake was washed with water. After drying and recrystallizing from benzene there was obtained 4-phenyl-1,2-bis-(trichloromethylthio)urazole having a melting point of 175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1Oc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a stirred solution of 5-chlorosalicylaldehyde (8.56 g) in N,N-dimethylformamide (90 mL) under nitrogen was added, in portions, sodium hydride (1.37 g). To the resulting solution was added 2,5-dichloro-1-nitrobenzene (10.0 g) and N,N-dimethylformamide (10 mL), and the reaction was heated at 100° C. under nitrogen for 6 hours. The reaction was evaporated under vacuum, and the residue was partitioned between chloroform and 1 N NaOH. The layers were separated, and the aqueous layer was extracted once more with chloroform. The combined chloroform extracts were washed with 1 N NaOH, water, 1 N HCl, water, and brine, dried over magnesium sulfate, and evaporated under vacuum. Crystallization from methanol yielded the title compound as a yellow solid. Mp: 128°-130° C.
Reaction SMILES: [C-]#N.[K+].[Br-].[CH:5]1[C:14]2[CH:13]=[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]3=[CH:10][N+:9]=2[CH:8]=[CH:7][CH:6]=1.[Cl:19]([O-:23])(=[O:22])(=[O:21])=[O:20].[Na+]>O.C(O)C.O>[Cl:19]([O-:23])(=[O:22])(=[O:21])=[O:20].[CH2:14]([C:10]1[N+:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:14]=2[CH:13]=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=12)[CH2:5][CH2:6][CH3:7]
Reactant: c1ccc2c[n+]3ccccc3cc2c1
Agent: [Br-]
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCc1c2ccccc2cc2cccc[n+]12

Procedure:
A solution of KCN (3g, 0.046 mol) in a minimum of water was added to a solution of benzo[b]quinolizinium bromide (10 g; 0.0385 mol) in 200 ml water. The resulting solid was extracted with an equal volume of methylene chloride. The above organic layer was heated and a solution of bromine (6.4 g) in methylene chloride was added. The resulting yellow solid was isolated, dissolved in ethanol/water, and the resulting solution was treated with sodium perchlorate solution. The perchlorate salt was filtered and recrystallized from ethanol to afford 2 g of 6-cyano-benzo[b]quinolizinium perchlorate (Formula II: R1 =R7 =H; R2 =CN; X- =ClO4-) as a solid.
Reaction SMILES: [CH:1]([CH:3]([C:8]1[N:9]([CH3:18])[C:10]([CH3:17])=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:4]([O:6][CH3:7])=[O:5])=O.C([O-])(=O)C.[NH4+:23]>CO>[NH2:23][CH:1]=[C:3]([C:8]1[N:9]([CH3:18])[C:10]([CH3:17])=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)n(C)c1C(C=O)C(=O)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C(=CN)c1c(C(=O)OC)cc(C)n1C
Yield: 96.9 %

Procedure:
A mixture of methyl 2-[1-formyl-2-(methyloxy)-2-oxoethyl]-1,5-dimethyl-1H-pyrrole-3-carboxylate (2.59 g), ammonium acetate (4.0 g) and methanol (50 ml) was heated under reflux for 4 hours. After cooling the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with 2 further portions of ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to afford the title compound 2.5 g, as a tautomeric mixture.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].B.C1COCC1>C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:11]=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(CO)c1
Reaction time: 12 h
Yield: 90.2 %

Procedure:
A solution of 3-(methylsulfonyl)benzoic acid (1.0 g, 5.0 mmol) in anhydrous THF (25 mL) was treated with BH3.THF (1 M solution, 7.5 mL) at room temperature. The reaction was stirred for 12 hours before it was quenched by slow addition of MeOH. The solvent was removed and the residue was purified by flash column chromatography (0–5% MeOH in CH2Cl2) to give the product (0.84 g, 90% yield). 1H NMR (300 MHz, CDCl3) δ: 3.06 (s, 3 H), 4.81 (d, J=6.0 Hz, 2 H), 7.54–7.59 (m, 1 H), 7.65–7.68 (m, 1 H), 7.85–7.88 (m, 1 H), 7.96 (s, 1 H).
Reaction SMILES: [ClH:1].Cl.[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[CH2:36](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:30][CH2:31][N:32]([CH3:36])[CH2:33][CH2:34]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCCCC2)ccc1OC1CCCCC1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1

Procedure:
To a solution of 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.079 mmol, 0.04 g) and aqueous formaldehyde (37%, 0.39 mmol, 0.035 mL) in dry DCM (1 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.47 mmol, 0.20 g). The mixture was shaken for 2 hours. The reaction was placed directly onto a 4 g SiO2 cartridge and the column was eluted with 4-6% (2N NH3 in MeOH) in DCM to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.04 g). LCMS: m/z 451 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.63-7.79 (1 H, m), 7.38-7.43 (2 H, m), 7.10-7.14 (2 H, m), 5.33-5.57 (1 H, m), 4.40-4.51 (1 H, m), 3.66-3.69 (1 H, m), 3.11-3.54 (3 H, m), 2.94 (3 H, s), 2.37-2.62 (2 H, m), 2.20-2.30 (1 H, m), 1.20-2.17 (22 H, m).