Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.S(Cl)(Cl)=O.[CH2:17](Cl)Cl.O>CO>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: ClCCl
Reactant: Cc1cc(C(=O)O)c(O)cc1Br
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(C)c(Br)cc1O
Temperature: 50 °C

Procedure:
To a solution of 4-bromo-2-hydroxy-5-methylbenzoic acid (may be prepared as described in Description 13; 1.47 g, 6.36 mmol) in methanol (15 ml) was added thionyl chloride (0.93 ml, 12.72 mmol). The reaction was heated at 50° C. for 72 hours, then DCM (20 ml) and water (10 ml) were added. The organic layer was separated and washed with saturated NaHCO3 solution (10 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a white solid. 1.2 g.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([NH2:14])[C:7]=2[N:15]=1.Cl.[O:21]([NH2:23])[CH3:22].C(N(CC)CC)C.O>CN(C=O)C>[CH2:16]([N:5]1[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([NH2:14])[C:7]=2[N:15]=[C:4]1[CH2:3][NH:23][O:21][CH3:22])[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1nc(N)c2nc(CCl)n(CC(C)C)c2c1C
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CONCc1nc2c(N)nc(C)c(C)c2n1CC(C)C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
2-(chloromethyl)-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine hydrochloride (1.53 g, 5.05 mmol) was dissolved in 10 mL of DMF in a pressure tube under a nitrogen atmosphere. Methoxylamine hydrochloride (1.27 g, 15.15 mmol) and triethylamine (4.22 mL, 30.3 mmol) were added, the tube was sealed and the contents heated to 50° C. for two hours, then to 60° C. for five hours. The mixture was then stored in the refrigerator over the weekend. The contents were poured into water (60 mL) and stirred for 20 minutes. The solution was extracted with chloroform (3×70 mL) and the organics were washed with water (4×40 mL) and brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by HPFC eluting with a gradient of 0-30% CMA (80/18/2 v/v/v chloroform/methanol/concentrated ammonium hydroxide) in chloroform and then recrystallized from acetonitrile to provide 1-isobutyl-2-[(methoxyamino)methyl]-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 154.0-156.0° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([NH2:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CN(C)C=O.C(O)C.[Pd]>[N:1]1([CH2:6][C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1cc(Cn2ccnc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ccc(Cn2ccnc2)cc1N
Yield: 120.3 %

Procedure:
Potassium carbonate (1.18 g, 8.54 mmol) was added to a stirred solution of 4-(bromomethyl)-2-fluoro-1-nitrobenzene (2.0 g, 8.55 mmol) and imidazole (584 mg, 8.58 mmol) in acetonitrile (40 mL), the mixture stirred at room temperature for 3.5 h, the solvent removed under reduced pressure, and the residue partitioned between water and EA. The aqueous layer was extracted three times with EA, then the combined EA layers were extracted three times with 1M hydrochloric acid. The pH of the combined aqueous layers was adjusted to 8 with 5M aqueous sodium hydroxide, and the resulting milky solution was extracted three times with EA. The EA layers were combined, washed with brine, and dried over magnesium sulfate. Filtration and concentration gave 1-(3-fluoro-4-nitrobenzyl)-1H-imidazole (914 mg), which contained about 15% of a bis-alkylated imidazole byproduct. 1-(3-Fluoro-4-nitrobenzyl)-1H-imidazole (914 mg) was treated with an ethanolic ammonia solution (2M NH3, 55 mL) in a sealed tube heated to 80° C. for 2 days. After cooling, the solvent was removed to give 5-[(1H-imidazol-1-yl)methyl]-2-nitrobenzeneamine (1.0 g) as an orange solid. 5-[(1H-Imidazol-1-yl)methyl]-2-nitrobenzeneamine (1.0 g, 4.77 mmol) was dissolved in a 10% solution of dimethylformamide in ethanol (44 mL), and 10% palladium on carbon (130 mg, 0.12 mmol) was added. The solution was degassed and stirred under a hydrogen atmosphere using a balloon for 1 day. Following degassing, the solution was diluted with MeOH and filtered through diatomaceous earth, giving 4-[(1H-imidazol-1-yl)methyl]benzene-1,2-diamine (1.08 g) as a brown oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](N(C)OC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br.C1COCC1.C1(C)C=CC=CC=1>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:15])[CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A solution of 47.32 g 1-benzyl-N-methyl-N-methoxy-piperidine-4-carboxamide in 1.5 L anhydrous ether in a 2-L 3-neck round-bottom flask fitted with a nitrogen bubbler, an overhead stirrer, and an addition funnel was cooled with an ice-acetone bath, and was treated with 270 mL of a 1.53M solution of methylmagnesium bromide in 1:3 THF:toluene with stirring over 70 minutes. After stirring in an ice bath for additional two hours, the mixture was quenched with 15 mL EtOAc, stirred for 10 minutes, and then poured into 2 L of ice water. After adjusting the pH to 8˜9, the layers were separated. The mixture was extracted with 4×250 mL ether, the combined ether solution was washed with 300 mL each of water and saturated brine, and then dried over Na2SO4. Removal of solvent under reduced pressure gave 40.68 g of crude product. This material was purified by flash chromatography on silica gel eluting with 25%˜40% EtOAc in hexanes with 1% Et3N to give 39.533 g of the title compound as a yellowish liquid. RF: 0.20 (20% EtOAc in hexanes with 1% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.32˜7.35 (m, 4H), 7.25˜7.30 (m, 1H), 3.53 (s, 2H), 2.91˜2.95 (m, 2H), 2.28˜2.34 (m, 1H), 2.16 (s, 3H), 2.01˜2.07 (m, 2H), 1.83˜1.88 (m, 2H), 1.66˜1.74 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[N+:2]=[N-:3].OC(C1C([O-])=C(O)C(=O)O1)CO.[Na+].[C:22]([C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38]3[N:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][N:39]=3)[CH:33]=[C:34]([CH3:36])[CH:35]=2)=[CH:26][CH:25]=1)#[CH:23]>C(O)C.O.CN(C=O)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:36][C:34]1[CH:35]=[C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:22]3[N:3]=[N:2][N:1]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH:23]=3)=[N:29][CH:28]=2)[CH:31]=[C:32]([NH:37][C:38]2[N:43]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:41]=[CH:40][N:39]=2)[CH:33]=1
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: C#Cc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [Cu+2]
Agent: O=C1OC(C(O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(-c2ccc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)cn2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl azidoacetate (160 mg, 0.452 mmol), sodium 2-(1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (130 mg, 0.656 mmol), copper sulfate (0.100 mL, 0.100 mmol) in ethanol (2.00 mL) and water (0.500 mL) was added to a solution of N-[3-(6-ethynylpyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.869 mmol) in DMF (0.500 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford methyl {4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-1H-1,2,3-triazol-1-yl}acetate. MS APCI C22H19F3N7O2 [M+H]+ 470. found 470. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.89-8.86 (m, 1H), 8.84 (d, J=5.1 Hz, 1H), 8.66 (s, 2H), 8.05-7.98 (m, 1H), 7.58 (s, 1H), 7.28 (d, J=5.1 Hz, 1H), 7.26 (s, 1H), 5.50 (s, 2H), 3.72 (d, J=14.9 Hz, 3H), 2.37 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][OH:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][O:40][C:49](=[O:56])[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccccc3)c3ccccc3)[C@H]2SC1
Reaction time: 1 h

Procedure:
To a solution of diphenylmethyl 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylate (1.0 g) and pyridine (1.5 ml.) in ethyl acetate (30 ml.) was added benzoyl chloride (1.5 ml.) and the mixture allowed to stand for one hour at room temperature. The solution was then washed with 2N-hydrochloric acid (50 ml.) and saturated brine, dried (sodium sulphate) and concentrated to ca. 5 ml. The concentrate was added dropwise to petroleum (b.p 40°-60°; 350 ml.) and the precipitated solid filtered, washed with petroleum and dried, yielding the title ester as a yellow solid (1.0 g; 85%), [α]D + 6.4° (c 0.94, DMSO), λmax. (EtOH) 259 nm (ε 26,700), νmax. (CHBr3) 1780 (β-lactam), 1640 and 1522 cm.-1 (CONH), τ (DMSO-d6) values include -0.27 (doublet J 8 Hz; NH), 1.8 - 2.8 (multiplet; aromatic protons), 8.01 (singlet; OCOCH3).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[C:11]([F:17])=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:10]1[C:11]([F:17])=[N:12][CH:13]=[C:14]([CH2:16][Br:1])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(F)c(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ncc(CBr)cc1Br
Yield: 22.3 %

Procedure:
N-Bromosuccinimide (4.732 g, 26.59 mmol) and benzoyl peroxide (0.1356 g, 0.5598 mmol) were added to a solution of 3-bromo-2-fluoro-5-methylpyridine (Matrix Innovation Inc., Montreal, Quebec, Canada 5.318 g, 27.99 mmol) in CCl4 (50 mL), and the mixture was heated at gentle reflux under a N2 atmosphere for 16 h. The mixture was filtered, washing with CCl4, and the residue concentrated and purified by flash chromatography on silica (1% to 1.5% EtOAc/hexane) to give 3-bromo-5-(bromomethyl)-2-fluoropyridine (1.593 g, 21.17% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H); 8.03 (dd, J=8.02, 2.15 Hz, 1H); 4.43 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −65.17 (br. s., 1F). Sample did not ionize well in ESI+ mode.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[O:13][CH3:14].C(O)(=[O:17])C>C(OC(=O)C)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]2[C:6](=[O:12])[O:11][C:7](=[O:17])[NH:8][C:9]=2[CH:10]=1
Reactant: COc1cc2c(cc1Cl)NC(=O)C2=O
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2c(=O)oc(=O)[nH]c2cc1Cl

Procedure:
Chromium trioxide (4.7 g) was added in small portions to a stirred suspension of 6-chloro-5-methoxyisatin (5.9 g) in glacial acetic acid (22 ml) and acetic anhydride (22 ml) at 80°. Some spontaneous ignition of the chromium trioxide was observed where this reagent became exposed to the air in the stirring vortex. The mixture was cooled and diluted with water (100 ml). The solid product was recrystallised from industrial methylated spirit to give the novel compound 7-chloro-6-methoxy-1H-3,1-benzoxazine-2,4-dione containing some unreacted starting material.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([NH:20][C:2]2[C:3]3[CH:13]=[CH:12][NH:11][C:4]=3[N:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1Cl
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.182 g, 0.921 mmol) in DMF (5 mL) was added cyclohexylamine (0.55 g, 5.5 mmol). The reaction mixture was stirred at ambient temperature for about 2 h. The solvent was removed under reduced pressure and EtOAc (100 mL) and water (20 mL) were added. The layers were separated and the organic layer was washed with water (3×25 mL) and brine (20 mL), dried over anhydrous MgSO4, filtered, and concd to give N-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (0.20, 57%) as a brown residue: LC/MS (Table 1, Method c) Rt=1.53 min; MS m/z 261 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[F:16][C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH:18]=1>CCO>[F:16][C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:19][CH:18]=1
Reactant: NCC1CC=C(F)CC1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CC=C(F)CC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)acetamide (460 mg, 2.32 mmol) and [(4-fluorocyclohex-3-en-1-yl)methyl]amine hydrochloride (350 mg, 2.11 mmol) were stirred in 20 mL of EtOH containing TEA (0.735 mL, 5.28 mmol) at 75° C. for 48 h. The solvent was concentrated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel using hexanes/acetone (2:1) as eluent. Yield: 553 mg (85%). 1H NMR (400 MHz, CDCl3) δ 1.51-1.61 (m, 1 H), 1.84-1.93 (m, 1 H), 1.96-2.03 (m, 2 H), 2.16-2.18 (m, 3 H), 2.22-2.32 (m, 3 H), 3.26 (td, J=6.05, 2.93 Hz, 2 H), 5.19 (dt, J=16.45, 2.61 Hz, 1 H), 6.84 (d, J=9.37 Hz, 1 H), 7.21 (s, 1 H), 7.79 (dd, J=9.18, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[OH-].[K+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: ClC1=NN(c2cccnc2)CC1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
3-(3-Chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (362 mg, 2.0 mol) was introduced into a 25 mL vial. Potassium hydroxide solution (658 mg, 85% pure) in water (H2O) (4.0 mL) was added and the mixture was heated to 60° C. Potassium ferricyanide solution (656 mg in 1.0 mL water) was added over 15 minutes leading to brown mixture. The mixture was stirred at 62° C. for another 15 minutes. Potassium persulfate solution (270 mg, 1.0 mmol, 0.5 eq.) in water (1.0 mL) was added in one portion. The mixture was stirred at 60° C. and monitored by LC. Additional two portions of potassium persulfate solution (270 mg, 1.0 mmol, 0.5 eq.) in water (1.0 mL) was added at 1.5 hours and at 2.5 hours. The reaction mixture was stirred for a total 4.5 hours and LC indicated 88.0% conversion. The mixture was then stirred at 75° C. for 1.5 hours and LC indicated >90% conversion. After filtration, the filter cake was washed with water (10 mL) affording crude product as a pale brown solid. The crude product was then washed with acetonitrile (2×15 mL). The organic filtrate was dried and concentrated to afford desired product as light brown solid (328 mg, 91.6%, 94.0% pure by LC).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][N:16]=[N+]=[N-])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][NH2:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C[C@H](CCCN=[N+]=[N-])N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCCN)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-azidobutyl]benzene-sulfonamide (0.394 g, 0.949 mmol) in THF (10 mL) was added lithium aluminum hydride (1.90 mL, 1 M in THF) at 0° C. under nitrogen atmosphere. The resulting mixture was allowed to stir at 0° C. for 1 h and subsequently treated by successive dropwise addition of 0.072 mL of water, 0.072 mL of 15% sodium hydroxide solution, and 0.216 mL of water. The mixture was filtered and concentrated under reduced pressure. Silica gel chromatography (3:10 ethyl acetate:hexanes) of the concentrate afforded 0.329 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-aminobutyl]benzenesulfonamide as a light brown oil in 89% yield.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])=[CH:12]2)=[CH:3][CH:2]=1.[Mg+2].[Cl-].[Cl-].C1N=C(N)C2N=CN([C@@H]3[O:42][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O[C@H]3O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1>C(#N)C>[OH:42][C:2]1[CH:3]=[C:4]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])=[CH:12]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: N=C(N)NC(=O)c1cn(-c2ccnc3ccccc23)c2ncccc12
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C(O)[C@H]1O[C@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: N=C(N)NC(=O)c1cn(-c2cc(O)nc3ccccc23)c2ncccc12
Reaction time: 2 h

Procedure:
4.8 mg of N-(1-quinolin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-guanidine were dissolved using 150 ml of an aqueous solution containing 381 mg MgCl2, 1.3 mM NADPH (Dihydronicotinamide adenine dinucleotide phosphate, Calbiochem product number: 481973; Shen, A. L., et al. 1989. J. Biol. Chem. 264, 7584; Yamano, S., et al. 1989. Mol. Pharmacol. 36, 83.), 300 mg of human S9 fraction and 2.5 mM UDPGA (Uridine 5′-diphosphoglucuronic acid trisodium salt, Sigma catalog number U6751). The mixture was incubated for 120 minutes at 37° C. Then, 40 ml of acetonitrile were added, proteins centrifuged and decanted. This solution was concentrated to 100 ml and chromatographed using the system described below. The solvents were removed under reduced pressure to yield 0.9 mg of N-[1-(2-hydroxy-quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-guanidine as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([O:15][S:27]([CH3:26])(=[O:29])=[O:28])[C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(O)CCN1c1cccc(OC(F)(F)F)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Temperature: 25 °C

Procedure:
A stirred solution of 1-(3-trifluoromethoxyphenyl)-3-hydroxy-2-pyrrolidone (19.42 g) in dichloromethane (250 ml) was cooled in an ice bath and treated with triethylamine (11.32 ml). Methanesulfonyl chloride (6.05 ml) was added dropwise via a syringe, and the mixture stirred with cooling for a further 1 hour after which it was allowed to warm to room temperature. After stirring for 2 hours at room temperature methanesulfonyl chloride (0.5 ml) and triethylamine (1.0 ml) were added and the mixture was stirred for a further 2 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane extracts were washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure to give the crude sub-title compound (23.0 g), which was used without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 80 °C
Yield: 29.1 %

Procedure:
A mixture of 6-bromo-3-pyridinol (7 g, 40 mmol), [4-(methylsulfonyl)phenyl]boronic acid (8 g, 40 mmol), 2M Na2CO3 (30 mL), PdCl2(PPh3)2 (1 g) and DME (60 mL) under N2 was heated at 80° C. overnight. The reaction was allowed to cool to room temperature and was diluted with EtOAc and water. The resulting precipitate was filtered off and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The aqueous phase was also concentrated. Each of the residues was recrystallized from MeOH. The solid material from the organic phase recrystallization and the mother liquors from both aqueous and organic recrystallizations were combined, concentrated and purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (2.9 g, 29%) as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:19]2[N:20]=[C:21]([CH2:26][CH3:27])[C:22]([N+:23]([O-])=O)=[C:18]2[CH:17]=[CH:16][CH:15]=1.C(O)C.O>[Zn].C(O)(=O)C>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH2:9][O:10][CH3:11])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:14]1[N:19]2[N:20]=[C:21]([CH2:26][CH3:27])[C:22]([NH2:23])=[C:18]2[CH:17]=[CH:16][CH:15]=1
Reactant: CCc1nn2c(-c3c(OC)cc(COC)cc3OC)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCc1nn2c(-c3c(OC)cc(COC)cc3OC)cccc2c1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A suspension of 7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (0.7 g) in a mixed solvent of ethanol (35 mL), water (18 mL) and acetic acid (3.5 mL) was added zinc powder (0.7 g) at room temperature, and the reaction mixture was heated and stirred for 30 minutes at 60° C. The reaction mixture was filtered through celite to remove insoluble residue, water was added to the filtrate and extraction was performed with ethyl acetate. The obtained organic extract was washed with brine, saturated aqueous sodium bicarbonate and then brine and dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (0.48 g) was obtained as a yellow oil from the n-hexane:ethyl acetate (4:1) fraction.