Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH:7]=[CH:8]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH:7]2[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2](=[O:1])[CH2:8]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(COC2CCN(C(=O)OC(C)(C)C)CC(=O)C2)cc1
Yield: 60.1 %

Procedure:
A solution of (Z)-tert-Butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (2 g, 9.48 mmol), (4-methoxyphenyl)methanol (6.55 g, 47.4 mmol) and DBU (0.14 mL, 0.95 mmol) in acetonitrile (10 mL) was heated at 60° C. for 23 hr. The solvents were removed under reduced pressure. Purification by silica gel column chromatography (0-40% EtOAc/isohexane) gave tert-butyl 5-(4-methoxybenzyloxy)-3-oxoazepane-1-carboxylate as a clear oil (1.99 g). To a solution of this oil (1.33 g, 3.8 mmol) in water/THF (20 mL/20 mL) was added NaBH4 and the mixture was stirred for 1.5 h. The THF was removed under reduced pressure and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 3-hydroxy-5-(4-methoxybenzyloxy)azepane-1-carboxylate (1.30 g) as a clear oil. This oil (1.15 g, 3.28 mmol) was dissolved in DCM (20 mL) and deoxo-Fluor® was added (50% in THF, 5.93 mL, 16.4 mmol). The mixture was stirred at room temperature for 18 hr, diluted with DCM (30 mL), cooled in an ice/water bath and quenched by dropwise addition of saturated aqueous NaHCO3 solution (50 mL). The resulting mixture was stirred for 10 min. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave tert-butyl 3-fluoro-5-(4-methoxybenzyloxy)azepane-1-carboxylate (746 mg, 39% over three steps) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.36-7.30 (m, 2H), 6.95 (d, J=8.2 Hz, 2H), 5.19-4.64 (m, 1H), 4.65-4.43 (m, 2H), 4.06-3.20 (m, 8H), 2.35-1.67 (m, 4H), 1.55-1.50 (m, 9H).
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26].[I-].[K+]>CC(C)=O>[C:25]([CH:24]=[CH:23][CH2:22][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:14])[CH3:13])=[CH:11][CH:10]=1)([O:27][CH3:28])=[O:26]
Reactant: COC(=O)/C=C/CBr
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C=CCOc1ccc(CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 4-hydroxyphenylpropan-2-one ethylene ketal (3.0 g) and potassium carbonate (2.13 g) in acetone (50 ml) was treated with methyl 4-bromocrotonate (2.77 g) and a trace of potassium iodide. After heating under reflux for 12 hours, the solution was filtered, the solvent evaporated and the residue dissolved in methanol (50 ml) and 2.5 N hydrochloric acid (25 ml). The solution was stirred at ambient temperature for 2 hours, the solvent evaporated, the residue extracted with ether, washed with 2 N sodium hydroxide, water and dried (MgSO4). Removal of the solvent gave the title compound as an oil (2.3 g).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[NH:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>CC[O-].[Na+]>[CH2:9]([C:6]1[CH:5]=[N:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[N:17][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: N=C(N)c1ccc(-c2ccc(Br)cc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCCc1cnc(-c2ccc(-c3ccc(Br)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.42 G. of the thus-obtained crude 2-n-pentyl-3-ethoxyacrolein are dissolved in a sodium ethylate solution (obtained from 580 mg. of sodium in 40 ml. of ethanol) and treated with 2.6 g. of the aforementioned 4'-bromo-4-biphenylamidine hydrochloride. The mixture is stirred at room temperature for 3 days. After some of the solvent has been distilled off, water is added and the mixture is extracted with chloroform in the usual manner. Upon crystallization from ethanol, there is obtained 5-n-pentyl-2-(4'-bromo-4-biphenylyl)-pyrimidine in the form of needles, having a melting point of 137° C. and a clearing point of 197° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C>ClCCCl>[CH2:33]([N:16]([CH3:15])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:31][CH:32]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: CNCCc1ccc(Oc2ccc(O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(CCc1ccc(Oc2ccc(O)cc2)cc1)Cc1ccccc1
Yield: 58 %

Procedure:
Sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added to a solution of 4-[4-(2-Methylamino-ethyl)-phenoxy]-phenol (75 mg, 0.31 mmol), benzaldehyde (34 mg, 0.32 mmol), acetic acid (19 mg, 0.32 mmol), and 1,2-dichloroethane (5 mL). Stirred the reaction at room temperature overnight, quenched with a pH=10 buffer, then extracted with dichloromethane (3×25 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (100 mg). The crude product is purified by flash column chromatography on silica gel eluting with ethanol in dichloromethane to yield 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol, (60 mg): m/z=334.01(M+1); HPLC=97% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. 1H NMR (CDCl3, 300.00 MHz): 7.42-7.28 (m, 7H), 7.11-7.05 (m, 2H), 6.97-6.79 (m, 4H), 3.63 (s, 2H), 2.86-2.78 (m, 2H), 2.71-2.63 (m, 2H), 2.33 (s, 3H),
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[C:19]([NH:22][C:23]1[S:24][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:26][N:27]=1)(=[O:21])[CH3:20]>>[C:19]([NH:22][C:23]1[S:24][C:25]([S:28]([NH:1][CH2:2][C:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])([OH:10])[CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)(=[O:29])=[O:30])=[CH:26][N:27]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: CC(=O)Nc1ncc(S(=O)(=O)NCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)s1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-acetamido-5-thiazolesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.N1CCCCC1>CO>[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1/[CH:16]=[C:3]1\[C:2](=[O:10])[NH:1][C:9]2[C:4]\1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C/c1ccc[nH]1
Yield: 96.1 %

Procedure:
A mixture of oxindole (137 mg, 1.03 mmol), pyrrole-2-carboxaldehyde (115.1 mg, 1.21 mmol) and piperidine (40 μL, 0.404 mmol) in 2.0 mL MeOH was heated at reflux for 3 h. The mixture was cooled in an ice bath and the solid which formed was collected by filtration to give the title compounds (208 mg, 96%) as a yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][N:31]=1>>[CH3:36][C:35]1[C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:25])([F:27])[F:26])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cccnc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 2-bromo-3-methylpyridine
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:7][CH2:6][C:5]1=[O:23])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N+:7]([O-:32])[CH2:6][C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)CN=C(c2ccccc2F)c2cc(Cl)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C=CCN1C(=O)C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6.4 g of 1-allyl-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 50 ml of chloroform are treated with 7 g of m-chloroperbenzoic acid and stirred for 16 hours at room temperature. Then the chloroform solution is washed with 1 N sodium bisulfite solution, with 2 N sodium hydroxide and with water. The organic phase is dried over calcium chloride, filtered and concentrated. The residue is recrystallized from ethanol and there is obtained 1-allyl-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide of melting point 183°C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH2:11][CH2:12][N:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:16](=[O:26])[C:15]([C:27]([OH:29])=O)=[CH:14]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[C:65]([NH2:71])=[N:66][CH:67]=[C:68]([Br:70])[CH:69]=2)=[CH:60][CH:59]=1>CN(C=O)C.O>[NH2:71][C:65]1[C:64]([C:61]2[CH:60]=[CH:59][C:58]([NH:57][C:27]([C:15]3[C:16](=[O:26])[C:17]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[CH:18][N:13]([CH2:12][CH2:11][F:10])[CH:14]=3)=[O:29])=[CH:63][CH:62]=2)=[CH:69][C:68]([Br:70])=[CH:67][N:66]=1
Reactant: O=C(O)c1cn(CCF)cc(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CCF)cc(-c3ccc(F)cc3)c2=O)cc1
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
DIPEA (114 μl) was added to a solution of the compound obtained in Step 2 of Example 8 (91 mg) and COMU (181 mg) in DMF (2.0 ml) at room temperature, and the mixture was stirred for 20 minutes. The compound obtained in Step 1 of Example 1 (95 mg) was added at room temperature. The mixture was stirred for six hours, followed by the addition of water. After extraction with ethyl acetate, the organic layer was washed with brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->30:1 (v/v)] to give 139 mg of the title compound as a solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)/[CH:7]=[CH:8]/[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[C:21]1(=[O:25])[O:24][CH2:23][CH2:22]1>CN(C)C=O>[C:21]([CH2:22][CH2:23][O:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)/[CH:7]=[CH:8]/[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)([OH:25])=[O:24]
Reactant: Oc1cccc(/C=C/c2nc3ccccc3s2)c1
Reactant: O=C1CCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCOc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To 3 ml of dimethylformamide were added 47 mg of 60% sodium hydride and 300 mg of 2-(trans-3-hydroxystyryl)benzothiazole, and the mixture was stirred at room temperature for 30 minutes. Then, 74 μl of β-propiolactone was added and the mixture was further stirred for 4.5 hours. The acidic portion was extracted in a conventional manner with chloroform, and after drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the crude crystals were washed with ethyl ether, followed by drying under reduced pressure to give 118 mg (yield 31%) of the title compound.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][N:12]2[N:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13]2)=[CH:8][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][N:12]2[N:16]=[C:15]([NH2:17])[CH:14]=[N:13]2)=[CH:8][CH:7]=1
Reactant: COCc1ccc(Cn2ncc([N+](=O)[O-])n2)s1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCc1ccc(Cn2ncc(N)n2)s1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-((5-(methoxymethyl)thiophen-2-yl)methyl)-4-nitro-2H-1,2,3-triazole (169 mg, 0.67 mmol), iron powder (131 mg, 2.33 mmol) and NH4Cl (215 mg, 3.99 mmol) in a mixture of EtOH (4.6 mL) and water (2.4 mL) was stirred at 50° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 3N NaOH (5 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (3×15 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.58 min, [M+H]+=225.18.
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[CH2:23]([C:25]1[N:26]=[N:27][NH:28][N:29]=1)[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@@H:9]2[CH2:10][C@H:6]([N:27]3[N:28]=[N:29][C:25]([CH2:23][CH3:24])=[N:26]3)[CH:7]=[CH:8]2)=[C:16]([Cl:20])[N:15]=1
Reactant: CCc1nn[nH]n1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1
Reaction time: 0.08 h

Procedure:
Carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AC) (3 g, 8.75 mmol), 5-Ethyl-2H-tetrazole (0.94 g. 9.62 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.40 g, 0.44 mmol) and triphenylphosphine (0.35 g, 1.32 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (40 mL) is added and the reaction mixture is stirred gently for 5 minutes. Triethylamine (20 mL) is added and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue was taken up in methanol (50 mL) and the solid was filtered off-product. 1H nmr (CDCl3, 400 MHz); 8.55 (s, 1H), 6.35 (m, 1H), 6.25 (m, 1H), 6.05 (m, 1H), 5.90 (m, 1H), 3.45 (m, 1H), 2.85 (q, 2H), 2.30 (m, 1H), 1.30 (t, 3H), MS (ES+) m/e 351 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH:13]([NH:16][C:17]([C@H:19]1[CH2:23][CH2:22][CH:21]([CH3:24])[NH:20]1)=[O:18])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:20]1[CH:21]([CH3:24])[CH2:22][CH2:23][C@@H:19]1[C:17]([NH:16][CH:13]([CH3:15])[CH3:14])=[O:18])=[N:7][N:6]=[CH:5]2
Reactant: CC(C)NC(=O)[C@H]1CCC(C)N1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)[C@H]1CCC(C)N1c1nncc2cc(Br)ccc12
Temperature: 200 °C

Procedure:
6-Bromo-1-chlorophthalazine (215 mg, 881 μmol), (R)-N-isopropyl-5-methylpyrrolidine-2-carboxamide (150 mg, 881 μmol), and cesium carbonate (1435 mg, 4405 μmol) were added to acetonitrile (4.4 mL) and heated in the microwave oven for 80 min at 200° C. The reaction was diluted with 75 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3× with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give crude. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 377(M+H)+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[N:21][C:22]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([O:36][CH3:37])=[O:35])[CH:32]=3)[C:27]([S:38][CH3:39])=[CH:26]2)=[N:23][CH:24]=1>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[N:21][C:22]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([O:36][CH3:37])=[O:35])[CH:32]=3)[C:27]([S:38]([CH3:39])=[O:6])=[CH:26]2)=[N:23][CH:24]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.98 g, 4.38 mmol) in dichloromethane (5 mL) was added dropwise to an ice-cooled solution of 51c) (2.3 g, 5.85 mmol) in dichloromethane (25 mL). The resulting mixture was stirred at room temperature for 2 h, then diluted with dichloromethane (50 mL), and successively washed with saturated sodium hydrogen carbonate solution (2×50 mL) and brine (1×50 mL). The organic phase was dried over sodium sulfate and evaporated to obtain the crude product that was purified by column chromatography [100-200 mesh silica; 2% methanol in dichloromethane]. White solid. Yield: 2.2 g (92% of theory). HPLC-MS (method 5): Rt=3.38 min; m/z [M+H]+=410
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:3]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+]>>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:26])[CH2:17][CH2:16]2)[CH2:3]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC1(C)CN(CC2CCNCC2)c2cc([N+](=O)[O-])ccc21
Agent: C=O
Agent: [Na+]
Product: CN1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-1-piperidin-4-ylmethyl-6-nitro-2,3-dihydro-1H-indole was treated with an excess of formaldehyde and NaBH(OAc)3 and stirred overnight at RT. The reaction was quenched with MeOH and concentrated in vacuo. The residue was partitioned between EtOAc and 1N NaOH. The organic layer was removed, washed with brine, dried (Na2SO4), filtered and concentrated to provide the compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[OH:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C=O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2O)C1
Reaction time: 15 h

Procedure:
To a CH2Cl2 (280 mL) solution of the title compound of Step B (24.7 g, 69.4 mmol) was added m-CPBA (77 wt %, 23.3 g, 104 mmol). After 15 h, 10% Na2S2O5 was added and the solution allowed to stir until the aqueous was Kl paper negative and extracted with CH2Cl2 (2×). The combined organic layers were washed with saturated NaHCO3 (aq.), concentrated and treated with MeOH (220 mL) and 1N NaOH (220 mL). After 15 h, the reaction was partially concentrated to remove the MeOH and acidified with 1M KHSO4 (220 mL) then extracted with CH2Cl2 (2×). The combined organic layers were washed with brine and dried to give a brown solid that was triturated with EtOAc/hexanes giving 17.6 g (74% yield) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3): 7.03 (dd, J=8.5, 2.1 Hz), 1H), 6.84 (d, J=8.5 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 4.93-4.89 (m, 1H), 4.34 (dd, J=10.1, 6.8 Hz, 1H), 4.03 (dd, J=9.9, 3.7 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:23]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[N+:24]=[N-:25]
Reactant: CCOC(=O)c1ccc(N2CCC(OS(C)(=O)=O)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCC(N=[N+]=[N-])CC2)cc1
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of ethyl 4-(4-(methylsulfonyloxy)piperidin-1-yl)benzoate (10.5 g, 32.1 mmol) in DMF (50 mL) was added sodium azide (4.17 g, 64.2 mmol). The mixture was heated at 80° C. for 5 hours, cooled to room temperature, diluted with brine (300 mL), and extracted with ethyl acetate (400 mL). The organic phase was washed with brine (2×300 mL), dried over anhydrous MgSO4, filtered, and concentrated, to afford ethyl 4-(4-azidopiperidin-1-yl)benzoate as a yellow solid (7.62 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[O:11][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1cccc(O)c1O
Reactant: ClCc1ccccc1
Product: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1

Procedure:
In one embodiment, the compounds can be prepared as shown in Scheme II. A dihydroxy benzoic acid methyl ester is reacted with benzyl chloride, to produce a Bis-benzyloxy benzoic acid methyl ester (1). The Bis-benzyloxy benzoic acid methyl ester can then be heated with LiOH to give a Bis-benzyloxy benzoic acid (2). The Bis-benzyloxy benzoic acid (2) is then reacted with an aminophenyl to produce a phenyl-benzamide (3). The phenyl-benzamide (3) is then reacted with hydrazine to give a triazol (4). The hydroxy groups can then be unprotecxted in the presence of palladium on charcoal to give the final product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=1)[C:22]#[N:23].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:19]2[CH:20]=[C:21]([C:22]#[N:23])[CH:24]=[CH:25][N:26]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cc(C#N)ccn2)cc1
Temperature: 137.5 °C
Yield: 73.3 %

Procedure:
[2-(4-Hydroxyphenyl)-ethyl]-carbamic acid tert-butyl ester (5.31 g, 22.4 mmol) and 2-chloroisonicotinonitrile (3.27 g, 22.4 mmol) were dissolved with magnetic stirring in dimethyl sulfoxide (DMSO; 50 mL) in a 250 mL round bottom flask equipped with a reflux condenser and a dry nitrogen line at 25° C. To the solution was added K2CO3 (6.0 g, 43.5 mmol), and the reaction mixture was slowly heated to 135-140° C. over 1 h. The reaction was filtered, concentrated in vacuo, and diluted with H2O (500 mL). The precipitate which formed was collected by suction filtration, dissolved in CH2Cl2 and treated with decolorizing carbon. The mixture was filtered and concentrated in vacuo to afford {2-[4-(4-cyanopyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (5.57 g) as a beige solid: mp 92-96° C.; 1H-NMR (CDCl3) δ 8.32 (d, J=5.3 Hz, 1H), 7.26 (m, 2H), 7.20 (dd, J=5.1, 0.8 Hz, 1H), 7.16 (m, 1H), 7.10-7.04 (m, 3H), 3.40 (br m, 2H), 2.83 (m, 2H), 1.45 (s, 9H); ESIMS m/z 284.2 ([M−C4H8+H]+). This material was used without further purification in the next step.