Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:15](C)[N:14]=[C:13]([CH2:17][OH:18])[N:12]=1)=O.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH4-].[Na+]>C(O)C>[C:23]1([CH2:22][NH:29][CH2:1][C:3]2[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=2)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]2[NH:15][N:14]=[C:13]([CH2:17][OH:18])[N:12]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: Cn1nc(CO)nc1NCCCOc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1n[nH]c(NCCCOc2cccc(CNCc3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-[[3-(3-formylphenoxy)propyl]amino]-1-methyl-1H-1,2,4-triazole-3-methanol (532 mg) in ethanol (15 ml) was treated with benzylamine (5 ml) and stirred at room temperature for 1.5 h. The solution was treated with sodium borohydride (500 mg) and stirred at room temperature for 16 h. The mixture was evaporated, and the residue partitioned between 2N hydrochloric acid and ethyl acetate. The aqueous layer was washed with ethyl acetate, neutralised with potassium carbonate, and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo to yield an oil. This oil was chromatographed on silica gel, using a mixture of methanol-ethyl acetate (1:1) to give the title compound as an oil (315 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([OH:1])[CH:3]=2)[CH:27]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NCc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.476 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture is stirred for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a brown gum. Recrystallization from methanol gave the product (500 mg), mp 134-135° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1CC1(NC(=O)C1CC(O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Compound 21a (11.8 g, 32.0 mmol) and pyridine (27 ml, 305 mmol) were dissolved in DCM (200 ml) and cooled to 0° C., 4-nitrobenzoyl chloride (6.6 g, 35.6 mmol) was added and the solution was stirred at room temperature overnight. The reaction mixture was washed with NaHCO3 (aq), aqueous citric acid and brine, dried over MgSO4 and evaporated on silica. The crude product was purified by column chromatography on silica (EtOAc/n-Heptane: 50:50) to give 11.84 g, 72% of the title compound.
Reaction SMILES: [NH4+].[OH-].CS(O)(=O)=[O:5].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([C:22]([NH:24][C@H:25]([CH3:42])[C@:26]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:27][N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[O:23])=[C:19]([CH3:21])[N:20]=2)=[CH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([C:22]([NH:24][C@H:25]([CH3:42])[C@:26]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:27][N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[O:23])=[C:19]([CH3:21])[N:20]=2)=[CH:12][CH:11]=1)(=[O:5])[NH2:9]
Reactant: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)N[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(N)=O)cc2)sc1C(=O)N[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
To a solution of NH4OH in a H2O--THF mixture was added (1R,2R)-2-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-methyl thiazole-5-carboxamide methanesulfonate (0.5 g, 0.84 mmol, obtained in example 31). The mixture was refluxed for 2 days, then was concentrated and the aqueous residue was extracted with CHCl3. The organic layer was separated, dried over Na2SO4, filtered and the filtrate was concentrated to a solid (0.53 g). This was purified by flash chromatography to give the title compound as a white solid: 133°-135° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 7.98 (d, J=8.3, 2H, arom), 7.87 (d, J=8.3, 2H, arom), 7.81 (s, 1H, triazole), 7.71 (s, 1H, triazole), 7.40 (dt, Jd =6.5, Jt =8.8, 1H, arom), 6.8-6.6 (m, 2H, ) arom), 6.57 (br d, J=9.5, 1H, NH), 6.27 (br s, 2H, NH2), 5.63 (s, 1H, OH), 5.05 (d, J=14.5, 1H, TrCH(H)), 4.98 (br quint, J=7, 1H, CHMe), 4.57 (d, J=14.5, 1H, TrCH(H)), 2.81 (s, 3H, Me-thiazole), 1.05 (d, J=6.8, 3H, MeCH); MS 288 and 289 (ethylaminoacyl group, C14H15N3O2S), 245 (acyl group, C12H9N2O2S), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =-74.5° (c 1, MeOH). Analysis calculated for C24H22F2N6O3S: C 56.24; H 4.33; N 16.40; S 6.26. Found: C 55.90; H 4.64; N 15.29; S 5.62.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:15]1([CH2:20][C:21]([N:23]2[CH2:27][C@H:26]([OH:28])[CH2:25][C@H:24]2[C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:34][CH:33]=2)=[O:30])=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1.[C:46]1(O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:15]1([CH2:20][C:21]([N:23]2[CH2:27][C@H:26]([O:28][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:25][C@H:24]2[C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[CH:36][CH:37]=2)=[O:30])=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: Oc1ccccc1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](O)CN1C(=O)Cn1cncn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Oc2ccccc2)CN1C(=O)Cn1cncn1
Temperature: 60 °C
Yield: 2.2 %

Procedure:
Diisopropylazodicarboxylate (0.111 mL, 0.551 mmol) was added to a flask charged with (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide (233 mg, 0.551 mmol), prepared as in Reference 11, phenol (52 mg, 0.55 mmol), triphenylphosphine (145 mg, 0.551 mmol) and THF (3 mL). The reaction mixture was heated at 60° C. for 30 minutes and then concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 259, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-phenoxypyrrolidine-2-carboxamide (15 mg, 0.012 mmol, 5% yield), as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.17 (s, 1H), 8.45 (s, 1H), 7.94 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.37-7.32 (m, 2H), 7.21-7.17 (m, 2H), 7.04-6.95 (m, 7H). MS (EI) for C27H24FN5O4. found 502.3 (MH+).
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]([OH:8])[CH2:10][CH:11]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC1COc1ccccc1CCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](O)CC1COc1ccccc1CCc1ccccc1
Yield: 97.5 %

Procedure:
A solution of 390 mg of (4R)-4-benzyloxy-1-t-butoxycarbonyl-2-[2-(2-phenylethyl)phenoxymethyl]pyrrolidine [prepared as described in step (a) above] in 25 ml of ethanol was stirred at 60° C. for 5 hours in an atmosphere of hydrogen at atmospheric pressure and in the presence of 100 mg of 5% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 310 mg (yield 97%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:26][CH:27]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2C)nc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCc1cnc(N(CCc2ccc(O)c(C)c2C)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-2,3-dimethylphenyl)ethyl]pyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])C.O>[OH-].[Na+]>[CH2:1]([CH:3]1[N:4]2[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12]1)[C:16](=[O:15])[C:17]([C:18]([OH:20])=[O:19])=[CH:23]2)[CH3:2]
Reactant: CCC1CCc2ccccc2N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1CCc2cccc3c(=O)c(C(=O)O)cn1c23
Temperature: 127.5 °C

Procedure:
Following the procedure set forth in Example 1, 2-ethyltetrahydroquinoline is mixed with diethyl ethoxymethylenemalonate and heated to 125 to 130° C. for 2 hours. Polyphosphoric acid is added, and the mixture is heated at 115° C. for one hour. The mixture is poured into water, neutralized with 40 percent sodium hydroxide, and the product is isolated and saponified in 10 percent sodium hydroxide solution. The solution is neutralized, and the solid product, 6,7-dihydro-5-ethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, is isolated by filtration.
Reaction SMILES: [OH-].[K+].[C:3]1([CH:9]=[CH:10][C:11](=O)[CH:12]([OH:26])[CH2:13][C:14](=[O:25])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.O.C(O)(=O)C(O)=O>C(Cl)(Cl)Cl>[OH:26][CH:12]1[CH2:13][C:14](=[O:25])[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:11]1[CH:10]=[CH:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCCCCCCC(=O)CC(O)C(=O)C=Cc1ccccc1
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O

Procedure:
To 3000 parts by volume of an aqueous solution containing 6.7 parts of potassium hydroxide is added, with stirring at 21°-23° over a period of about 2 1/4 hours, a solution of 10.4 parts of dl- 14-phenyl-9,12-dioxo-11-hydroxytetradec-13-enoic acid in 187 parts of chloroform. After completion of the addition, the reaction mixture is stirred for an additional 2 hours, then is made acidic by adding 10 parts of oxalic acid dihydrate. The acidic mixture is extracted with chloroform and the organic layer is washed with dilute aqueous sodium chloride, then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue is recrystallized first from benzene, then from chloroform-ether to yield dl- 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid, which displays a melting point at about 118°. This compound displays an ultraviolet absorption maximum at about 325 millimicrons with a molecular extinction coefficient of about 36,400.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12](=[O:16])[O:13][CH2:14]I.[C:17]([OH:20])(=[O:19])[CH3:18]>C([O-])(=O)C.[Ag+]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12]([O:13][CH2:14][O:20][C:17](=[O:19])[CH3:18])=[O:16]
Reactant: N#Cc1cc(Br)c(OC(=O)OCI)c(Br)c1
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: CC(=O)OCOC(=O)Oc1c(Br)cc(C#N)cc1Br
Reaction time: 3 h

Procedure:
A solution of carbonic acid iodomethyl ester 2,6-dibromo-4-cyanophenyl ester (0.30 g, 0.65 mmol) in acetic acid (6.5 mL) was added silver acetate (0.33 g, 1.95 mmol). The mixture was stirred for 3 h. The slurry was concentrated to solids and washed with ether. The ether was concentrated to afford the desired product as white solids (240 mg). 1H-NMR (300 MHz, CDCl3) δ (ppm): 2.19 (s, 3H), 5.90 (s, 2H), 7.89 (s, 2H).). 13C-NMR (300 MHz, CDCl3) δ (ppm): 21.0, 83.3, 113.7, 115.7, 119.1, 136.4, 149.9, 169.4, 183.7. Mp=84-86° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[H-].[Na+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[OH-].[Na+]>CN1CCCN(C)C1=O.C(OCC)(=O)C>[CH3:21][C:15]([O:11][C:5]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
A solution of 2-nitro-4-methylphenol (11.48 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (50 ml) was cooled at 5° C. and treated with portions of sodium hydride (55% w/w dispersion in mineral oil, 3.27 g). The mixture was stirred at room temperature for 2 hours, then cooled to 5° C. and treated with ethyl 2-bromo-2-methylpropionate (13.15 g). The mixture was heated at about 100° C. for 18 hours, then cooled to room temperature and poured into a mixture of aqueous sodium hydroxide solution (1M) and ethyl acetate. The organic solution was separated and washed twice with 1M sodium hydroxide solution, then dried (MgSO4) and concentrated. The resulting oil was purified by flash column chromatography, eluting with a mixture of ethyl acetate and hexane, (increasing from 5:95 v/v to 10:90 v/v), to give ethyl 2-methyl-2-(2-nitro-4-methylphenoxy)propionate (4.48 g) as an oil; NMR: 1.25 (3H, t), 1.60(6H, s), 2.35(3H, s), 4.25(2H, q) and 6.8-7.6(3H, m).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[F:25][B-](F)(F)F.F[B-](F)(F)F.F[N+]1C=CC=CC=1C1C=CC=C[N+]=1F.[Na]>C(#N)C>[F:25][C:12]1[CH:13]=[C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:3][CH:2]2[OH:1])[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: F[B-](F)(F)F
Agent: F[n+]1ccccc1-c1cccc[n+]1F
Agent: [Na]
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(O)c(F)c2)C(O)C1

Procedure:
A solution of 0.581 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate in 5 ml of acetonitrile is admixed with 0.320 g of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) and the suspension is subsequently heated at reflux over 15 hours. The reaction mixture is poured onto 10 ml of saturated aqueous sodium thiosulpphate solution and the mixture is extracted with 2×50 ml of ethyl acetate. The combined organic phases are washed with 10 ml each of 0.5 M HCl and brine, dried over sodium sulphate and concentrated. The title compound is obtained as a colourless solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (2:1 EtOAc-heptane); Rt=3.80.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:16])[C@@H:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:14][O:13][CH2:12][O:11][C:10]=2[CH:15]=1)[OH:5].CCN(C(C)C)C(C)C.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>C1COCC1>[O:11]1[C:10]2[CH:15]=[C:6]([C@H:4]3[O:5][C:31](=[O:32])[NH:2][C@H:3]3[CH3:16])[CH:7]=[CH:8][C:9]=2[CH2:14][O:13][CH2:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](N)[C@H](O)c1ccc2c(c1)OCOC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1NC(=O)O[C@@H]1c1ccc2c(c1)OCOC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propan-1-ol hydrochloride (I3b) (120 mg, 0.49 mmol), DIEA (0.100 mL, 0.59 mmol) and CDI (90 mg, 0.56 mmol) in THF (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated by evaporation, the residual material was partitioned between EtOAc and water, the organic phase was washed with 10% NaHSO4, dried over MgSO4, filtered and evaporated. The crude product was analysed by LC/MS and was considered pure enough for further analysis by NMR. Yield 66 mg (57%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:3]=1.[Cl:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:15][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(-c2ccc(F)cc2)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2cccc(CCl)n2)cc1

Procedure:
0.60 g (3.2 mmol) of the product of step 2 was dissolved in 50 mL of carbon tetrachloride, along with 0.54 g (3.5 mmol) of N-chloro succinimide and a catalytic amount of benzoyl peroxide. After refluxing for 20 hr, the solution was concentrated and filtered through a plug of silica gel eluting with 20% ethyl acetate:hexane. The resulting oil was contaminated with ˜10% of unreacted starting material and was used in the next step without further purification. NMR (200 MHz, CDCl3) δ 7.96 (m, 2H, ArH), 7.63 (m, 1H, ArH), 7.43 (m, 1H, ArH), 7.17 (m, 3H, ArH), 4.72 (s, 2H, CH2Cl).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:21])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>C(OCC)(=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:2]2[N:3]=[C:4]([O:11][C:12]3[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[CH3:21])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2ccsc12
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccsc12
Temperature: 90 °C
Reaction time: 15 h
Yield: 34 %

Procedure:
To a solution of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (187 mg, 0.6 mmol), TFA (0.37 mL, 4.8 mmol) in TFE (3 mL) was added 4-aminobenzonitrile (283 mg, 2.4 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. Reaction mixture was diluted with ethyl acetate (5 mL) and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC afforded the product as a white solid (81 mg, 34%):
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].F[C:24](F)(F)[C:25](O)=O.COC1N=C2C(N=1)=C(N)NC(O[C@@H](C)CCCC)=N2.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH2:21][CH2:24][CH3:25])=[N:10][C:11]=2[NH2:17]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: CCCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Agent: ClCCCCBr
Product: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from 8-(methyloxy)-2-{[(1S)-1-methylpentyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](=[N:11][OH:12])[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[NH2:1][C:2]1[C:3]([C:9](=[NH:10])[NH:11][O:12][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=NO)c1nc(Br)cnc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N=C(NOC(=O)c1ccccc1)c1nc(Br)cnc1N
Reaction time: 1 h
Yield: 69.1 %

Procedure:
3-amino-6-bromo-N′-hydroxypyrazine-2-carboximidamide (890 mg, 3.836 mmol) was suspended in dichloromethane (11.56 mL) and treated with triethylamine (427.0 mg, 588.2 μL, 4.220 mmol) followed by benzoyl chloride (593.2 mg, 489.8 μL, 4.220 mmol) The reaction mixture was allowed to stir for 1 hour and concentrated in vacuo. The resultant residue was triturated with methanol to give the desired product as a pale beige solid (891 mg, 69% Yield). 1H NMR (400.0 MHz, DMSO) d 7.55 (2H, m), 7.65 (1H, m), 7.90 (2H, br s), 8.28 (2H, m), 8.33 (1H, s); MS (ES+) 337.87
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCOCC2)CC1
Yield: 100 %

Procedure:
A mixture of 2.00 g (10.0 mmol) of 1-t-butoxycarbonyl-4-piperidone, 35 ml of benzene and 1.05 g (12.1 mmol) of morpholine was refluxed and the formed water was removed by using a Dehn-Stark dehydrating tube. After completion of distillation of water, the reaction mixture was concentrated under reduced pressure to obtain 2.69 g (10.0 mmol) of 1-t-butoxycarbonyl-4-morpholino-1,2,5,6-tetrahydropyridine as yellowish solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[C:60]1[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=1>CN(C=O)C>[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[C:60]1[CH:61]=[C:62]([NH:66][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=1
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5ccccc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 87.2 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.068 mmol) and HATU (0.029 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-naphthalen-2-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.025 g of product in 86% yield: LCMS (ESI) m/z 422 (MH+).