Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Br)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:23][N:24]2[CH3:27])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:31]3[CH2:30][CH2:29][CH:28]([C:22]4[C:21]5[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=5)[N:24]([CH3:27])[N:23]=4)[CH2:33][CH2:32]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cn1nc(C2CCNCC2)c2ccc(F)cc21
Reactant: CC(=O)N1CCc2c(sc(C)c2CCBr)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(c3nn(C)c4cc(F)ccc34)CC2)C1
Temperature: 90 °C
Reaction time: 22 h
Yield: 60.8 %

Procedure:
A mixture of 590 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 580 mg of 4-(6-fluoro-1-methyl- 1H-indazol-3-yl) piperidine, 780 mg of potassium carbonate and 415 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90° C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 540 mg of 6-acetyl-3-(2-(4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 213°-216° C. as oxalate thereof.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[NH:4][C:3]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].[F:26][C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=1[CH2:29]Br>CN1C(=O)CCC1.CO>[F:26][C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][C:28]=1[CH2:29][N:4]1[C:5]2[C:6](=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=2)[N:2]([CH3:1])[C:3]1=[O:19]
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Reactant: Fc1ccc(C(F)(F)F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)n(Cc2cc(C(F)(F)F)ccc2F)c2ccc(-c3ccccc3C#N)nc21
Temperature: 90 °C

Procedure:
2-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)benzonitrile (4-1) (30 mg, 0.12 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added to a microwave vial and suspended in NMP (0.5 mL) under nitrogen. 2-Fluoro-5-(trifluoromethyl)benzyl bromide (47 mg, 0.18 mmol) was added to the suspension and then heated at 90° C. overnight. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce 2-{1-[2-fluoro-5-(trifluoromethyl)benzyl]-3-methyl-2-oxo-2,3-dihydro 1H-imidazo[4,5-b]pyridin-5-yl}benzonitrile (6-1). HRMS (M+H)+: observed=427.1179, calculated=427.1177.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[NH:22])[NH2:21])[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(O)C>[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[NH:21])[NH2:22])[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[NH:34])[NH2:3]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N=C(N)c1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N′-(1-amidinopiperidin-4-yl)cycloheptylurea (0.03 g, 0.075 mmol) in anhydrous ethanol (5 ml) for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to give a viscous residue which was dissolved in anhydrous ethanol and ammonium carbonate (0.06 g, 0.63 mmol) was added. The reaction was stirred over night at ambient temperature and then concentrated in vacuo. The crude product appeared to be about 1:2 ratio of the desired product to starting material. Pure N-(3-amidinophenyl)-N′-(1-amidinopiperidin-4-yl)cycloheptylurea was isolated by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 20 min, to give two major fractions: N-(3-amidinophenyl)-N′-(1-amidinopiperidin-4-yl)cycloheptylurea, the desired product eluted at 13.3 minutes, (8.2 mg); LRMS (M+2H)+2 m/z 179.8; HRMS calc. 358.2355, found 358.2349; 1H NMR (DMSO-d6): 9.25(s, 2H), 9.0(s, 2H), 7.55-7.4(m, 4H), 7.32(s, 4H), 3.95(m, 3H), 3.65(m, 2H), 3.25(m, 2H), 3.07(m, 2H), 1.8-1.6(m, 8H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][CH:16]=3)=[CH:10][C:2]1=2.[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].C(N(CC)CC)C>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([C:24]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[N:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=4)=[CH:10][C:2]2=3)=[O:25])[CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31]
Reactant: CN(C)c1cccc(-c2cnc3c(c2)NCCO3)c1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc(N(C)C)c4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
By the same method as in the step d) of Example 2, [3-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-phenyl]-dimethyl-amine (102 mg, 0.39 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (197 mg, 0.59 mmol) and triethylamine (286 μl, 1.99 mmol) were dissolved in dichloromethane (5 ml) and then stirred at room temperature for 3 hours to obtain the target compound 48, i.e., (3,5-dibromo-4-methoxy-phenyl)-[7-(3-dimethylamino-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone, as white solid (135 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([C@@H:11]2[C@@H:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[NH:12]2)=[O:10])=[CH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([CH:11]2[CH:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[O:10])=[CH:19][CH:20]=1
Reactant: OB(O)c1ccccn1
Reactant: C=CC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccc(OC)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1C(=O)N(c2ccccn2)C1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.8 %

Procedure:
A mixture of β-lactam 59 (60 mg, 0.22 mmol), Pyridin-2-boronic acid (81 mg, 0.66 mmol), copper acetate (120 mg, 0.66 mmol), triethylamine (0.153 mL, 1.1 mmol) and activated 4A molecular sieves (270 mg) in dichloromethane (5 mL) was stirred at room temperature for 2 days. The reaction mixture was filtered through celite and the filtrate was concentrated. Preparative TLC (20% EtOAc/Hexanes) of the residue gave the desired product 80 (19.2 mg, 24.8%) 1HNMR (300 MHz, CDCl3): 2.60 (m, 2H), 3.49 (m, 1H), 3.81 (s, 3H), 4.41 (d, J=2.61 Hz, 1H), 5.11-5.21 (m, 4H), 5.82 (m, 1H), 6.85 (d, J=8.7 Hz, 2H), 7.01 (m, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.66-7.72 (m, 2H); 8.19 (d, J=4.7 Hz, 1H) Anal. C20H20N2O4, Mol. Wt.: 352.38. Found: ESI-MS: 352.9 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.C1(C)C=CC(S(O)=O)=CC=1.[Na].[C-:22]#[N:23].[K+]>CS(C)=O.O>[NH:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([C:22]#[N:23])[C:3]=2[CH:10]=[N:9]1
Reactant: [C-]#N
Reactant: Ic1ccnc2[nH]ncc12
Agent: Cc1ccc(S(=O)O)cc1
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccnc2[nH]ncc12
Temperature: 100 °C

Procedure:
4-Iodo-1H-pyrazolo[3,4-b]pyridine (802 mg, 3.27 mmol) was dissolved in DMSO (10 mL) then added p-toluenesulfinic acid, sodium salt (583 mg, 3.27 mmol) and KCN (319 mg, 4.90 mmol). The reaction was heated at 100° C. for 18 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4 to yield 1H-pyrazolo[3,4-b]pyridine-4-carbonitrile as a light orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:25][C:26]3[N:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:25][C:26]3[N:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc([N+](=O)[O-])ccc23)n(C(C)(C)C)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc(N)ccc23)n(C(C)(C)C)n1
Yield: 66.7 %

Procedure:
2.00 g of 7-Nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one were hydrogenated over palladium on charcoal in methanol/THF 1:1 at room temperature. After completion of the reaction the catalyst was filtered off and the filtrate evaporated. The residue was dissolved in 50 ml dichloromethane and extracted three times with a 3:1 mixture of water/conc. HCl. The combined aqueous phases were brought to pH 8 by addition of sodium bicarbonate and extracted with dichloromethane. Removal of the solvent yielded 1.25 g of the title product.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(CN)O.O>COCC(O)CC>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: CCC(O)COC
Solvent: NCCO
Solvent: O
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) is placed in mixture of 1-methoxy-2-butanol (13.0 g) and ethanolamine (1.3 g, 21.3 mmol, 1.65 equiv) is heated at 110 to 114° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at 15 to 25° C. in a mixture of ethanolamine (9.6 g, 157.2 mol, 12.2 equiv) and 1-methoxy-2-butanol (0.8 g) and the solution added in portions to the Thebaine mixture over 1 h 10 min. The reaction mixture is held at 110 to 114° C. for 1 h then cooled to 15 to 25° C. and water (24 g) added while maintaining the batch temperature at ≦30° C. The resulting slurry (pH 11.0) is stirred, further cooled to 0 to 5° C. and then filtered. The product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.87 g, 96.0% yield; 98.3 area % purity by HPLC).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:9]=2[CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:5]=[CH:4][CH:3]=1.[CH3:35][NH:36][CH3:37]>CN1CCCC1=O>[CH3:35][N:36]([CH3:37])[C:2]1[N:7]=[C:6]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:9]=2[CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2cccc(Br)n2)cc1
Reactant: CNC
Solvent: CN1CCCC1=O
Product: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2cccc(N(C)C)n2)cc1
Temperature: 190 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
A mixture of N-{2-[5-(6-Bromo-pyridin-2-yl)-3-thiophen-2-yl-1H-pyrazol-4-yl]-ethyl}-4-pentyl-benzenesulfonamide (5 mg, 8.9 μmol) and dimethylamine (2.0M in MeOH, 8.0 ml) in 1-methyl-2-pyrrolidinone (500 μL) was stirred at 190° C. in a seal tube for 3 h. The reaction mixture was concentrated to 2 ml. The crude product was purified by Prep-HPLC. Removal of the solvent in vacuo provided the title compound (1.2 mg, 26% yield). MS m/e 524; HPLC retention time 3.34 min (Method A).
Reaction SMILES: CS(O[CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1)(=O)=O.[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][N:21]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)[CH2:8][N:9]=1)=[CH:20]2)[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23]
Reactant: c1nc[nH]n1
Reactant: CN(c1cccc2cc(C3=NCC(COS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(Cn4cncn4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 60 °C
Reaction time: 15 h
Yield: 59.3 %

Procedure:
A mixture of (2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)methyl methanesulfonate (1.0 g), 1H-1,2,4-triazole (290 mg), potassium carbonate (580 mg) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate-methanol (50:50:0-0:100:0-0:95:5, volume ratio) to give N-methyl-N-{2-[5-(1H-1,2,4-triazol-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}pyridine-2-sulfonamide (560 mg, yield 59%) as a pale-yellow amorphous solid.
Reaction SMILES: [CH:1]1([N:6]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.C([O-])(O)=[O:27].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[C@H:2]12[O:27][C@H:3]1[CH2:4][CH2:5][C@@H:1]2[N:6]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N(C1C=CCC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N([C@H]1CC[C@@H]2O[C@@H]21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl cyclopent-2-en-1-yl((2-nitrophenyl)sulfonyl)carbamate (2.75 g, 7.46 mmol) and NaHCO3 (1.254 g, 14.93 mmol) in CH2Cl2 (60 mL) was added in one portion meta-chloroperoxybenzoic acid (2.58 g, 14.93 mmol). The resulting reaction mixture was stirred overnight at RT. The reaction mixture was diluted with CH2Cl2 and washed with 20% aqueous Na2SO3 solution, saturated NaHCO3 solution and water. The organic phase was dried over MgSO4 and concenrated. The title compound was obtained after crystallization from EtOAc as white crystals (2.01 g, 68%): TLC (heptane-EtOAc 1:1) Rf=0.48; tR=1.20 min (UPLC 1), tR=1.12 min (LC-MS 3); ESI-MS: 329 [M-isobutylene]+ (LC-MS 3).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]([CH3:16])([C:13](=O)[CH3:14])[C:9]([O:11][CH3:12])=[O:10]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:13](=[CH2:14])[C:8]([CH3:16])([CH3:7])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(C)(C)C(C)=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(Cl)C(C)(C)C(=O)OC
Temperature: 25 °C
Yield: 38.6 %

Procedure:
To a suspension of PCl5(270 g, 1.3 mol) in CH2Cl2(1000 mL) was added dropwise methyl 2,2-dimethyl-3-oxobutanoate (85 g) at 0° C., following by addition of approximately 30 drops of dry DMF. The mixture was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and slowly poured into ice water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2(500 mL×3). The combined organic layers were washed with saturated aqueous NaHCO3 and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was distilled under reduced pressure to give methyl 3-chloro-2,2-dimethylbut-3-enoate (37 g, 23%). 1 H NMR (400 MHz, CDCl3) δ 5.33(s, 1 H), 3.73(s, 3 H), 1.44(s, 6 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][Br:36])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To 3.4 g of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (15.79 mmol) in 80 ml of THF, cooled in an ice/water bath, was added 4.76 g triphenylphosphine (18.16 mmol) and then 6.05 g total of carbon tetrabromide (18.16 mmol) in two portions. The reaction was stirred to room temperature over 16 hours. 1.2 g carbon tetrabromide (3.6 mmol) was added twice more over 24 hours before the reaction mixture was filtered. Approximately 240 ml of diethyl ether was added and the resulting mixture was filtered and evaporated. The residue was purified by chromatography on silica gel in 5-10% ethyl acetate/hexanes to give 3.3 g 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (MS: M+H=263/265).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
4-Methylbenzenesulfonyl chloride (52.1 g) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (50.0 g) in pyridine (248 mL) at room temperature. The mixture was stirred at room temperature overnight. After evaporation of the solvent, water and ethyl acetate were added to the residue. The organic layer was separated, washed with 1M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated in diisopropyl ether at 0 C (“C” represents “degrees Celsius”) to give the title compound (76.1 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[N+:8]([C:7]1[C:2]([NH:14][C:13]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[CH3:11])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: Cc1cc(C)c(Nc2ncccc2[N+](=O)[O-])c(C)c1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (24.05 g, 152 mmol), 2,4,6-trimethylaniline (60 ml, 427 mmol), and Cs2CO3 (59.4 g, 182.4 mmol) was heated at 100° C. for 24 h. Flash chromatography using 1) methylene chloride/Hexanes (1:4) and 2) methylene chloride, followed by recrystallization from 95% ethanol. The title compound was obtained as an orange-yellow crystals (17.0 g, 44% yield). 1H NMR (CDCl3, 5 MHz) δ 9.38 (s, 1H), 8.51 (d, J=5.8 Hz, 1H), 8.38 (s, 1H), 7.00 (s, 2H), 6.73 (s, 1H), 2.34 (s, 3H), 2.18(s, 6H); 13C NMR (CDCl3, 100 MHz) δ 156.2, 152.1, 137.2, 135.7, 135.4, 132.3, 129.1, 128.3, 112.8, 21.1, 18.5.
Reaction SMILES: Cl.[NH2:2]O.[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:24])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:11]([CH3:15])[O:12]2)=[CH:7][C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>N1C=CC=CC=1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:11]([CH3:15])=[N:2][O:24][C:9]=2[C:8]2[CH:7]=[C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]([OH:4])=[CH:14][C:13]=2[OH:12])=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2c(C)oc3cc(O)c(-c4ccccc4)cc3c2=O)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2c(C)noc2-c2cc(-c3ccccc3)c(O)cc2O)cc1
Yield: 73.9 %

Procedure:
Hydroxylamine hydrochloride (75 mg, 1.08 mmol) was added to a suspension of 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-6-phenyl-chromen-4-one (105 mg, 0.29 mmol) in pyridine (2 ml) and the mixture heated under reflux for ˜6 hrs., to give a pale yellow solution. The solution was allowed to cool and water (20 ml) added. The mixture was extracted with diethyl ether (2×10 ml). The combined extracts were washed with water (2×20 ml) and saturated aqueous sodium chloride solution (10 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate/hexane (1:1), to give the title compound as an off-white powder (80 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:6]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[N:5]2.C(N(CC)CC)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:7]2[C:6]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=4)(=[O:41])=[O:40])[CH:3]=3)[N:8]=2)[CH2:13][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCN(c2nc3ccc(N)cc3nc2N2CCN(C)CC2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccc3nc(N4CCN(C)CC4)c(N4CCN(C)CC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 6.41 g. (.020 mole) portion of 6-amino-2,3-bis-(4-methyl-1-piperazinyl)quinoxaline (prepared as in Example 1) is dissolved in 200 ml. of chloroform. Then 3.0 ml. (0.021 mole) of triethylamine is added plus 3.81 g. (0.020 mole) of p-toluenesulfonyl chloride. The resulting solution is stirred at room temperature for three hours and is left standing in a sealed flask for 18 hours. It is washed with two 50 ml. portions of distilled water and is dried over anhydrous sodium sulfate and anhydrous calcium sulfate. The solution is stripped of solvent by water pump evacuation to give a yellow solid which is dissolved in 100 ml. of hot benzene and filtered. A 200 ml. portion of cyclohexane is added to the filtrate and the resulting suspension is cooled at 4° C. and then is filtered. The collected solid is dried in vacuo at 78° C. over phosphorous pentoxide, dissolved in 475 ml. of hot acetonitrile and is filtered hot. The filtrate is cooled at -10° C. to recrystallize 3.2 g. of the final product which is collected by filtration, m.p. 234°-237° C.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:14][C:15]([O:17]C)=O)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[NH3:19]>O>[C:15]([CH2:14][CH:3]([CH2:2][SH:1])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:17])[NH2:19]
Reactant: COC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: N
Solvent: O
Product: NC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
2.1 g of the product from Example 62, Step (d) is dissolved in a mixture of water (40 ml) and concentrated ammonia (40 ml). After one hour the reaction mixture is concentrated in 1/3 volume, and applied to a column of Dowex 50 resin in the hydrogen cycle. The product is eluted with water. The aqueous is extracted with ethyl acetate and then concentrated to dryness to yield 1.4 g of the named product, Rf =0.50 (silica gel-chloroform:methanol:acetic acid:water).