Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][NH:12][CH2:11]1>O>[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][N:12]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:11]1
Reactant: CC1CNCC(C)C1
Reactant: Nc1cccc(F)n1
Solvent: O
Product: CC1CC(C)CN(c2cccc(N)n2)C1
Temperature: 205 °C
Yield: 83 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and 3,5-dimethylpiperidine (0.61 g, 5.35 mmol) in water (0.2 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200-300 mesh, ethyl acetate:petroleum ether=1:8) to afford 6-(3,5-dimethylpiperidin-1-yl)pyridin-2-amine (0.76 g, 83%) as a yellow oil. LC-MS: [M+1]+=206, tR=1.240 min.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([CH:18]=[O:19])=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[CH:6][C:5]=1[CH3:20].[Cl-].[NH4+]>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[CH2:18][OH:19])=[CH:6][C:5]=1[CH3:20]
Reactant: Cc1cc(C)c(C=O)c(-c2ccc(F)c(C)c2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(C)c(CO)c(-c2ccc(F)c(C)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (0.45 g, 12 mmoles) was added to a stirred suspension of 4'-fluoro-3,3',5-trimethyl-1,1'-biphenyl-2-carboxaldehyde (2.9 g, 12 mmoles) in ethanol (20 ml) which was cooled in an ice-water bath. After 5 minutes the cooling bath was removed and the reaction mixture was stirred at ambient temperature for one hour. The solution was cooled to 0° C. and excess ammonium chloride (2.67 g, 50 mmoles) was added and the mixture was partitioned between ether (150 ml) and water (50 ml). The water was separated and extracted with ether (50 ml). The combined ether extracts were washed with water (2×50 ml) dried (MgSO4), filtered, and the solvent evaporated in vacuo to leave the title compound, a gum which crystallized on standing, to give 2.77 g, m.p. 74°-75° C. A sublimed sample had m.p. 102°-103° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:11]>C1COCC1>[NH2:11][C:6]1[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N#Cc1c(Cl)ncnc1Cl
Reactant: N
Solvent: C1CCOC1
Product: N#Cc1c(N)ncnc1Cl
Reaction time: 0.83 h

Procedure:
The white solid, 4,6-dichloropyrimidine-5-carbonitrile (5.82 g, 33.5 mmol) was dissolved in THF (66.9 mL) in a 500 mL round-bottom flask and to the mixture was bubbled through ammonia gas (0.570 g, 33.5 mmol) for 3 min in 10 min intervals with stirring. After 50 min, a white precipitate (ammmonium chloride) was filtered and the solid was washed with THF (100 mL). To the filtrate was added silica gel and concd under reduced pressure. The mixture was purified by silica gel column chromatography on a 120 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 27 min and then 100% isocratic of EtOAc in hexane for 20 min as eluent to give 4-amino-6-chloropyrimidine-5-carbonitrile as an off-white solid. The off-white solid was suspended in EtOAc-hexane (1:1, 20 mL), filtered, washed with EtOAc-hexane (1:1, 30 mL), and dried to give 4-amino-6-chloropyrimidine-5-carbonitrile as a white solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 7.91-8.77 (3 H, m); Mass Spectrum (ESI) m/e=154.9 (M+1).
Reaction SMILES: [C:1]1([S:7][CH:8]=[CH:9][C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](OC1C=CC(C2C=CC=CC=2)=CC=1)(=O)C#C.C1C=CC(CS)=CC=1>>[CH2:1]([S:7][CH:8]=[CH:9][C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:11])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:25]=1
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(C=CSc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Agent: SCc1ccccc1
Product: O=C(C=CSCc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Yield: 91 %

Procedure:
The compound 5 was prepared according to the method described for compound 4 employing compound 1 (200 mg, 0.89 mmol) and benzylthiol (112 mg, 0.89 mmol) to give white solid compound 5 (284 mg, 91%). 1H NMR (300 MHz, CDCl3) δ 4.10 (s, 2H), 6.02 (d, J=15.1 Hz, 1H), 7.18 (d, J=8.3 Hz, 2H), 7.39 (m, 8H), 7.57 (t, J=5.9 Hz, 4H), 7.94 (d, J=15.1 Hz, 1H). HRMS ESI (m/z): Calculated for C22H18O2S ([M+H]+): 347.1028. found: 347.1101.
Reaction SMILES: [CH3:1][C:2]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[N:3]O>[Pt].C(O)(=O)C>[CH3:1][CH:2]([NH2:3])[C:5]12[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2
Reactant: CC(=NO)C12CC3CC(CC(C3)C1)C2
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(N)C12CC3CC(CC(C3)C1)C2
Reaction time: 8 h
Yield: 96 %

Procedure:
Into a Parr hydrogenation flask were placed 8.0 g of 1-adamantyl methyl ketoxime, 200 ml of glacial acetic acid, and 2.8 g of 5% Pt/C. Hydrogenation was continued overnight at 39 psia (270 KPa) and at ambient temperature. The catalyst was removed by filtration and the acetic acid solution was concentrated to one-third of the original volume by vacuum distillation. Water, 200 ml, was added to this conc. acetic acid solution and it was made basic with sodium hydroxide to give a milky solution. The milky solution was extracted three times with 100 ml of methylene chloride. The combined methylene chloride layer was dried over magnesium sulfate which was removed by filtration. The methylene chloride solution was distilled under vacuum to give 7.1 g of clear liquid rimantadine free base (96% yield).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:20]2)=[CH:16][CH:15]=1.[CH3:39][C:40]1[O:44][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:42][C:41]=1[CH2:51][CH2:52]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.C1(C)C=CC=CC=1>[CH3:39][C:40]1[O:44][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[N:42][C:41]=1[CH2:51][CH2:52][O:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A toluene solution (5.66 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (2.84 g), 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (2.48 g), triphenylphosphine (3.31 g) and tetrahydrofuran (25 ml) at room temperature. After the above solution was stirred at room temperature for 2 hours, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). A mixture of the oily substance obtained, 1N aqueous sodium hydroxide solution (15 ml), tetrahydrofuran (15 ml) and ethanol (15 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was acidified by adding 1N hydrochloric acid. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (2.72 g, yield: 57%). This was recrystallized from ethanol-water. Melting point: 147–148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10]12[O:15][CH:11]1[CH2:12][CH2:13][CH2:14]2>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][C@@H:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[OH:15]
Reactant: C1CC2OC2C1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O[C@@H]1CCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Yield: 44 %

Procedure:
A solution of 50.0 g. (0.31 mole) of 3,4-dichloroaniline in 100 ml. of cyclopentene oxide is refluxed for 7 days. The solution is evaporated and the residue triturated with 250 ml. of petroleum ether (b.p. 30°-60° C.) five times to remove unreacted 3,4-dichloroaniline. The residue is treated with excess ethereal hydrogen chloride and the resulting crude hydrochloride salt is recrystallized twice from a methanol/ethyl ether mixture to give trans-2-(3,4-dichloroanilino)cyclopentanol, 38.7 g. (44% yield), m.p. 167°-168° C. The ultraviolet, infrared and nuclear magnetic resonance spectra are consistent with the structure of this product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[C:9](I)[CH:8]=[C:7]([Br:12])[CH:6]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[C:9]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH:8]=[C:7]([Br:12])[CH:6]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)Nc1cc(Br)cc(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)Nc1cc(Br)cc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
(3-Bromo-5-iodo-phenyl)-carbamic acid methyl ester (0.22 g, 0.62 mmol), 3-pyridylboronic acid (0.11 g, 0.93 mmol), and Pd(dppf)Cl2.CH2Cl2 complex (0.051 g, 0.062 mmol) were dissolved in dioxane (6 mL). Aqueous 2 M potassium carbonate (0.26 g, 1.9 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was then heated to 60° C. for 24 hrs. The reaction mixture was filtered through Celite® and the solvent was removed. The product was chromatographed to give 0.073 g (38% yield) of (3-bromo-5-pyridin-3-yl-phenyl)-carbamic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:37][Si](C)(C)C)(C)C.[Li+].N>C1COCC1.CO.ClCCl.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]>[O:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH2:37])[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Brc1ccc2[nH]cc(CCCN3CCOCC3)c2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2[nH]cc(CCCN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an argon purged vial fitted with a magnetic stirbar was charged a solution of compound 179 (407 mg, 1.26 mmol) in anhydrous THF (8 mL). The orange solution was treated with solid Pd2(dba)3 (58 mg, 0.063 mmol) which resulted in a dark red reaction mixture. Tri-t-butyl phosphine solution (10%, 0.37 mL, 0.13 mmol) was added and the reaction was stirred at room temperature for 5 minutes. A 1M solution of lithium bis(trimethylsily)amide in THF (3.78 mL, 3.78 mmol) was added, and the yellow-brown solution placed in a metal heating block and heated to reflux. The reaction was stirred at this temperature for 16 hours. TLC (10% 2M ammonia in methanol, 90% dichloromethane) revealed all starting material had reacted. The reaction was cooled to room temperature and quenched with 1M aqueous hydrogen chloride (15 mL). The acidic reaction was extracted with ethyl acetate (3×10 mL). The aqueous phase was basified with 3N sodium hydroxide (8 mL) and partitioned into ethyl acetate (3×10 mL). The organics were washed with brine, dried over magnesium sulfate, and treated with charcoal. Filtration through celite, concentration and further drying under high vacuum afforded a dark yellow oil. Purification of the product was performed using silica gel column chromatography (5-10% 2M ammonia in methanol, 95-90% dichloromethane) Yield: 102 mg of brown oil, compound 180 (31.2%). 1H NMR (CDCl3) δ 7.72 (br s, NH), 7.17-7.14 (d, 1H, J=8.4 Hz), 6.92-6.89 (dd, 2H, J=2.1, 4.5 Hz), 6.67-6.64 (dd, J=2.1, 8.4 Hz, 1H), 3.77-3.74 (t, J=4.5 Hz, 4H), 2.74-2.69 (t, J=7.5, 2H), 2.49-2.43 (m, 6H), 1.97-1.89 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].C(=O)([O-])[O-].[K+].[K+].[C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[N:12]>C(O)(C)C>[Cl:4][CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][CH:13]([C:11]#[N:12])[CH2:14][CH2:15]1
Reactant: N#CC1CCNCC1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: N#CC1CCN(CCCl)CC1

Procedure:
1-Bromo-2-chloroethane (2.6 ml) and potassium carbonate (6.6 g) were added to a solution of 4-cyanopiperidine (2.63 g) in isopropanol (50 ml), followed by refluxing for 10 hours. The reaction mixture was concentrated under reduced pressure. After adding a 50% aqueous solution of potassium carbonate to the residue, the resulting mixture was extracted with diethyl ether. The extract was washed with saturated saline, followed by an addition of anhydrous potassium carbonate to dry the diethyl ether solution. The thus-dried diethyl ether solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: methanol-chloroform) to obtain 0.31 g of the desired product in an oily form.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15]([OH:22])=[C:16]([C:19](=O)[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]>CO>[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15](=[O:22])[C:16](=[C:19]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccccc2N)C(=O)OC1=O

Procedure:
o-Phenylenediamine (2.1 g., 0.02 m.) is added to a hot solution of 4.2 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol and the resulting mixture is refluxed for 2 hours. The reaction mixture is cooled and filtered to yield 5-acetyl-3-[1-(o-aminophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 179° -181° C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][NH:28][CH2:27][CH2:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCCCCCC(=O)NOCc1ccccc1)CC2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.3 g, 1.3 mmol) was reacted with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.43 g, 1.3 mmol) in the presence of potassium carbonate (0.18 g, 1.4 mmol) and DMF as solvent to give 8-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.28 g, 49%; purified by column chromatography using silica gel and ethyl acetate: methanol 9:1 as an eluent). MS (M+H+)=441.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-chloro-9H-purin-2-ylamine (20 g, 0.12 moles) in DMF (200 mL) at −11° C. was added NaH (5.7 g, 0.14 moles, 60%) portionwise over 1 h. The mixture as stirred for 1 h, then 2-iodopropane (14.2 mL, 0.14 moles) was added dropwise. The solution was warmed to rt, stirred for 18 h, quenched with sat'd NH4Cl, and extracted with EtOAc. The combined extracts, were washed with water, sat'd NaCl, then dried over MgSO4 and filtered. Concentration yielded an oil which was purified by silica gel chromatography (60% EtOAc/Hexane) to a white solid (13.4 g, 54%): MS [M+H]+ 212; m.p. 135–136° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:20]=[C:19]3[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][N:28]5[N:31]=[CH:32][C:33]([CH:34]=[O:35])=[C:27]5[CH:26]=4)[N:22]=[N:23][C:18]3=[N:17][CH:16]=2)[CH:12]=[N:11]1.OCC1C=NN2C=CC(CN3C4=NC(C5C=NN(CCO)C=5)=CN=C4N=N3)=CC=12>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:20]=[C:19]3[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][N:28]5[N:31]=[CH:32][C:33]([CH2:34][OH:35])=[C:27]5[CH:26]=4)[N:22]=[N:23][C:18]3=[N:17][CH:16]=2)[CH:12]=[N:11]1
Reactant: O=Cc1cnn2ccc(Cn3nnc4ncc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc12
Agent: OCCn1cc(-c2cnc3nnn(Cc4ccn5ncc(CO)c5c4)c3n2)cn1
Product: OCc1cnn2ccc(Cn3nnc4ncc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc12

Procedure:
The title compound (Intermediate 322-d) was prepared from 322-c according to the procedure of Compound 313. MS (m/z): 476.1 (M+H)+.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([O:20][C@@H]2O[C@H](CO)[C@H](O)[C@H]2O)[C@@H:3]([OH:30])[C@@H:2]1[NH2:31].Cl>CO>[CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([OH:20])[C@@H:3]([OH:30])[C@@H:2]1[NH2:31]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H]3O)[C@@H](O)[C@H](N)C[C@@H]2N)[C@H](N)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Product: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](N)C[C@@H]2N)[C@H](N)[C@@H](O)[C@@H]1O

Procedure:
When xylostasin is subjected to methanolysis with 0.4N HCl in methanol at 22°C for 6 days, methyl D-xyloside and neamine are produced and, when xylostasin is hydrolyzed with 0.5N sulfuric acid at 90°C for 6 hours, D-xylose and neamine are detected in the hydrolyzate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])O[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1.[CH3:18][NH2:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])[N:19]([CH3:18])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: CN
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2o1
Product: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2n1C
Temperature: 40 °C

Procedure:
A mixture of the product from step (i) (3.33 g), and 40% w/v aqueous methylamine solution was heated at 40° C. for 4 h. The solid was filtered and washed with water then dried under vacuum to give the subtitled product as a cream powder.
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([C:15]([NH:17][C:18]2[CH:37]=[CH:36][C:21]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[CH:20][CH:19]=2)=[O:16])[CH2:12]1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].O1CCCC1>[NH:11]1[CH2:14][CH:13]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]3)=[CH:36][CH:37]=2)=[O:16])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CN(C(=O)OCc4ccccc4)C3)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-(4-(1-(benzyloxycarbonyl)azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate (50 mg, 0.098 mmol) and tetrahydrofuran (5 ml) were added to 20% wet palladium hydroxide on carbon (10 mg, 0.071 mmol) in a 50 ml pressure bottle and the mixture was stirred for 16 hours at 30 psi and room temperature. The mixture was filtered through a nylon membrane and the filtrate was concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:19])([F:20])[F:18])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:33]=[N:34][CH:35]=1
Reactant: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncc(F)c1
Product: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 205.1) and (5-fluoropyridin-3-yl)boronic acid to afford a yellow wax which slowly crystallized upon drying. UPLC-MS (Condition 3) tR=1.12 min, m/z=497.3 [M+H]+, m/z=495.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.79 (m, 1H) 1.84 (qd, J=8.43, 4.33 Hz, 1H) 2.88 (d, J=11.42 Hz, 1H) 3.18-3.29 (m, 2H) 3.34-3.47 (m, 1H) 4.14-4.27 (m, 1H) 4.88 (d, J=3.39 Hz, 1H) 7.67 (dd, J=8.66, 2.01 Hz, 1H) 7.75 (t, J=8.41 Hz, 1H) 7.84 (dt, J=9.72, 2.10 Hz, 1H) 7.97 (dd, J=11.73, 2.07 Hz, 1H) 8.07 (d, J=2.38 Hz, 1H) 8.48-8.54 (m, 1H) 8.60 (d, J=2.76 Hz, 1H) 8.79 (d, J=2.26 Hz, 1H) 10.45 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.CC1C=CC(S(O[CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]2)(=O)=O)=CC=1>>[NH2:20][C:16]1[C:15]2[N:21]=[C:12]([S:11][C:3]3[C:2]([Br:1])=[CH:10][C:6]4[O:7][CH2:8][O:9][C:5]=4[CH:4]=3)[N:13]([CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]3)[C:14]=2[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Reactant: CC(=O)N1CCC(CCOS(=O)(=O)c2ccc(C)cc2)CC1
Product: CC(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)nccc32)CC1

Procedure:
The title compound was prepared by a similar procedure described for step 7 of example 1 using 2-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-1H-imidazo[4,5-c]pyridin-4-amine and 2-(1-acetylpiperidin-4-yl)ethyl 4-methylbenzenesulfonate. 1H NMR (DMSO-d6) δ; 7.70 (d, J=6.0 Hz, 1H), 7.38 (s, 1H), 6.79 (d, J=6.0 Hz, 1H), 6.66 (s, 1H), 6.42 (s, 2H), 6.07 (s, 2H), 4.30 (brd, J=13.2 Hz, 1H), 4.20 (t, J=7.2 Hz, 2H), 3.74 (brd, J=13.2 Hz, 1H), 2.89 (t, J=13.6 Hz, 1H), 2.40 (t, J=13.6 Hz, 1H), 1.96 (s, 3H), 1.66 (m, 2H), 1.56-1.51 (m, 2H), 1.43 (m, 1H), 1.08 (m, 1H), 0.94 (m, 1H); LC-MS [M+H]+ 518.09.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:3]=1.[H-].[Na+].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH:5]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:25]=2)[N:3]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCc1ccc2cc(-c3ccc(O)cc3)nc(F)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cc3ccc(CCCCCCCC)cc3c(F)n2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1-fluoro-3-(4-hydroxyphenyl)-7-octylisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1-fluoro-3-[4-(octyloxy)phenyl]-7-octylisoquinoline.