Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[O:14]>C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([O:12][CH3:11])=[O:14])(=[O:23])=[O:22])=[O:26])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(C)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Reaction time: 16 h
Yield: 21.1 %

Procedure:
To a stirred suspension of 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 30 ml of anhydrous methylene chloride was added at ambient temperature 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. After stirring for 16 hours, the foregoing mixture was filtered to remove unreacted amine, and the filtrate evaporated at temperatures up to 40° and reduced pressure. The resultant residue was stirred in 25 ml of water, the pH adjusted to 10 by the addition of 50% sodium hydroxide and the solution filtered. Acidification of the filtrate to pH 3 with hydrochloric acid caused precipitation of the desired product which was removed by filtration and dried to yield 0.8 g of product melting at 173°-179°. It showed infrared absorption peaks at 1720, 1680, 1630 and 1550 cm-1, consistent for N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][C:16]2=[O:24])[CH2:13][O:12]1.C([O-])(=O)C.[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]([CH2:13][C:11]([OH:12])([CH3:10])[CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][C:16]2=[O:24])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(Cn2c(=O)oc3ccccc32)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1c(=O)oc2ccccc21
Yield: 51.2 %

Procedure:
To a suspension of 2-chloro-4-nitro-1H-imidazole (503 mg, 3.41 mmol), 3-(2-methyloxiran-2-yl-methyl)-3H-benzoxazol-2-one (700 mg, 3.41 mmol) in ethanol (7 ml), sodium acetate (336 mg, 4.1 mmol) was added followed by stirring under reflux for 8 hours. The reaction mixture was allowed to return to room temperature. To a mixture, water was added, and the resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-3H-benzoxazol-2-one (616 mg, yield 51%) as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]#[CH:15].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=1I>N1C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=2[CH:15]=1
Reactant: C#CCc1nc(-c2ccccc2)oc1C
Reactant: O=Cc1ccc(O)c(I)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(C=O)ccc2o1

Procedure:
To a slurry of cuprous oxide (12 g, 84 mmol) in pyridine (150 ml) were added a solution of 5-methyl-2-phenyl-4-(2-propynyl) oxazole in pyridine (150 ml) followed by a solution of 4-hydroxy-3-iodobenzaldehyde (35 g, 0.14 mol) in pyridine (100 ml). Bis(triphenyl-phosphine) palladium (II) chloride (0.50 g, 0.7 mmol) was then added as a solid and the mixture was heated to reflux overnight. The mixture was cooled and concentrated. The residue was taken up in ethyl acetate (250 ml+3×50 ml). The ethyl acetate solution was concentrated and the residue was extracted with hot cyclohexane. The hot solution was filtered and cooled and the solid was collected (29 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[N:26]=[CH:25][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:23]=4)[CH:20]=3)[N:15](C3CCCCO3)[N:14]=2)[CH:8]=1)=[O:5]>O1CCOCC1.Cl>[NH:24]1[CH:25]=[N:26][C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)=[N:23]1
Reactant: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: COCC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reaction time: 18 h
Yield: 46 %

Procedure:
Hydrolysis was performed by stirring 2-methoxy-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)acetamide (0.141 g, 0.207mmol) in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.ON aqueous HCl, at room temperature for 18 hours. The title compound was purified by preparative HPLC (15-80% acetonitrile in water) (0.033 g, 46% yield) 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 10.0 (s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.7 (d, 2H), 7.5 (dd, 1H), 4.06 (s, 2H), 3.4 (s, 3H); ES-MS (mlz) 349 [M+1]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]3[C:18]4[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:19]=4[NH:20][C:16]=3[C:15]([C:26]#[N:27])=[N:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[OH-:28].[K+]>C1COCC1.OO>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]3[C:18]4[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:19]=4[NH:20][C:16]=3[C:15]([C:26]([NH2:27])=[O:28])=[N:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(C#N)c3[nH]c4ncc(C)cc4c23)c1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cccc(-c2cnc(C(N)=O)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Compound 48 (10 mg, 0.027 mmol) stirred in THF (1 mL). A solution of KOH (25 mg, 0.44 mmol) in 30% H2O2 (0.5 mL) was added, and the reaction stirred for 3 h at r.t. Purification by prep-HPLC gave 8.2 mg (77%) of the title compound as an off-white solid. 1H NMR (400 MHz, MeOD-d4): δ 8.49 (br s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.15 (d, 1H, J=7.6 Hz), 8.06 (d, 1H, J=7.6 Hz), 7.92 (t, 1H, J=7.6 Hz), 7.85 (s, 1H), 3.32 (q, 2H, J=7.2 Hz), 2.39 (s, 3H), 1.31 (t, 3H, J=7.6 Hz). MS (ES) [m+H] calc'd for C20H18N4O3S, 395; found 395.
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3](=O)[CH3:4].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:14][C:2]([CH3:6])=[C:3]([CH3:4])[N:15]=2)=[CH:11][CH:10]=1
Reactant: CC(=O)C(C)Cl
Reactant: COc1ccc(C(N)=O)cc1
Product: COc1ccc(-c2nc(C)c(C)o2)cc1
Temperature: 115 °C
Yield: 83.6 %

Procedure:
A mixture of 3-Chloro-2-butanone (2.1 g, 10.0 mmol) and 4-methoxybenzamide (0.30 g, 1.0 mmol) was heated at 115° C. for 15 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 20% EtOAc-Hexane) to get the desired product (0.17 g, 42%) as a white solid. The corresponding chloro derivative was also prepared by the same general method.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[Cl:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[Cl:19][CH2:20][CH2:21][CH2:22][NH:23][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: NCCCCl
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCCCCl)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(3-chloropropyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 1 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 1.3 mmol of 3-chloropropylamine. LC/MS [9.24 min; 434 (M+1)]
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CC(O)C.[CH2:32]([CH:34]1[O:36][CH2:35]1)[Cl:33]>O>[Cl:33][CH2:32][CH:34]([OH:36])[CH2:35][NH:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: ClCC1CO1
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCC(O)CCl)no2)cc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a flask containing (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (84 mg, 0.23 mmol) was added 2 mL of IPA. The cloudy, white mixture was cooled to 0° C. and epichlorohydrin (20.7 μL, 0.26 mmol) was added and the reaction mixture stirred at room temperature overnight. The IPA was removed by concentration in vacuo and water (500 μl) and aliquots of epichlorohydrin (20.7 μL, 0.26 mmol) were added every hour (4 total) at room temperature until conversion was complete. The reaction mixture was concentrated, dissolved in DCM and purified by chromatography (MeOH/DCM) to provide 19.3 mg (18%) of 5-(3-((1R)-1-(3-chloro-2-hydroxypropylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile INT-15 as a white solid. LCMS-ESI (m/z) calculated for C24H25ClN4O3: 452.9. found 453.1 [M+H]+, tR=2.62 min.
Reaction SMILES: [Br:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:25].[C:26](OC(=O)C)(=[O:28])[CH3:27].O>N1C=CC=CC=1>[C:26]([O:25][C@@H:3]1[C@@H:2]([Br:1])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1)(=[O:28])[CH3:27]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]3[C@@]2(C)C[C@@H]1Br
Reaction time: 8 h

Procedure:
2β-Bromo-3α-hydroxy-5α-pregnane-11,20-dione (750 mg.) in pyridine (2 ml.) was treated with acetic anhydride (1 ml.) and the mixture was allowed to stand at room temperature overnight. It was then poured into water to give a white solid (720 mg.) which was recrystallised from methanol to give the title compound (471 mg.) as white crystals, m.p. 154°-156°, [α]D + 128.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=1>>[C:17]1([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: COc1cccc(O)c1
Product: COc1cccc(Oc2cccc(-c3ccccc3)c2)c1

Procedure:
Under the Ullmann conditions used in Example 8, steps A and B, above, 13.3 g of 3-methoxyphenol (107 mmole) was condensed with 1-bromo-3-phenylbenzene, giving, after purifying over silica gel, (0-30% EtOAc in hexane gradient) 17.8 g (60%) of 3-(3-phenylphenoxy)anisole as a crystalline solid, melting at 41-42° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.[SH:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:31][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[S:25][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1SCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (193 mg, 0.61 mmol) and 2-mercapto-1-methylimidazole (80 mg, 0.7 mmol) in dry DMF (2 mL) was treated with K2CO3 (97 mg, 0.7 mmol). The mixture was stirred at rt for 2 h, and then it was poured into ice-water. The mixture were extracted with EtOAc and the extract was washed with water and brine, dried over anhydrous MgSO4, and evaporated to yield the crude product, which was crystallized from EtOAc-hexane to give the title compound as colorless rods (142 mg); mp 155-160° C.; 1H NMR (CDCl3) 7.36 (s, 1H), 7.27 (s, 1H), 7.17 (d, J=7.7, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 6.95 (d, J=7.7, 1H), 6.91 (s, 13H), 6.14 (s, 2H), 6.07 (s, 2H), 4.53 (s, 2H), 3.51 (s, 3H). Anal. calcd. for C21H16N4O4S: C, 59.99; H, 3.84; N 13.33. Found: C, 59.78; H, 3.82; N, 13.20.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH3:19])[O:9][C:8]=1[CH2:20][O:21][CH3:22])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:9][C:8]([CH2:20][O:21][CH3:22])=[C:7]([CH:2]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:11]=2)=[C:13]([CH3:19])[CH:14]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COCc1oc(-c2ccc(F)cc2C)cc1C(Cl)CC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCc1oc(-c2ccc(F)cc2C)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-5-(4-fluoro-2-methylphenyl)-2-(methoxymethyl)furan (487 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 60% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.4 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (45 mg, 6%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[CH3:41][NH:42][C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1>ClCCl>[CH3:41][N:42]([C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)=[O:3]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-(1,1-dimethylethyl) 4-[4-carboxy-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 1, Step B) (3.84 g, 12.29 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.36 g, 12.29 mmol) and triethylamine (2.3 mL, 16.76 mmol) in 50 mL dichloromethane was stirred for 15 minutes at room temperature. (1R)-1,2,3,4-Tetrahydro-N-methyl-1-naphthalenamine (i.e. the product of Example 6, Step A) (2.18 g, 13.5 mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with 20 mL of dichloromethane, washed with 1 N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 20% to 100% of ethyl acetate in hexanes to give 2.4 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][CH2:13][C:14](Cl)=[O:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:12][CH2:13][C:14]([N:9]1[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)CCl)CC1
Temperature: 27 °C
Yield: 93 %

Procedure:
piperazine-1-carboxylic acid ethyl ester (200 mg, 1.26 mmol) was treated with chloroacetyl chloride (186 mg, 1.65 mmol) in anhydrous CH2Cl2 (10 mL) containing DIEA (490 mg, 3.80 mmol) at 0° C. The mixture was stirred and warmed to 27° C. for 4 h. The mixture was washed with 1 M HCl(aq). The organic phase was dried over MgSO4, and concentrated under reduced pressure to give ethyl 4-(2-chloroacetyl)piperazine-1-carboxylate (275 mg, 93% yield). C9H15ClN2O3; transparent oil; 1H NMR (400 MHz, CDCl3) δ 4.15 (2H, q, J=7.2 Hz) 4.06 (2H, s), 3.60 (2H, m), 3.54 (2H, m), 3.49 (4H, m), 1.27 (3H, t, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 164.3, 154.3, 61.4, 45.8, 43.5, 43.1, 41.8, 40.8, 14.7; ESI-HRMS calcd for C9H16ClN2O3: 235.0849. found: m/z 235.0852 [M+H]+.
Reaction SMILES: [Br:1]Br.[C:3]([N:7]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9](=[O:19])[CH2:8]1)([CH3:6])([CH3:5])[CH3:4].C([O-])(=O)C.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Br:1][C:16]1[CH:17]=[CH:18][C:11]2[NH:10][C:9](=[O:19])[CH2:8][N:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: BrBr
Reactant: CC(C)(C)N1CC(=O)Nc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)N1CC(=O)Nc2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 29 h
Yield: 64.3 %

Procedure:
Bromine (1.72 g, 10.8 mmol) is added to a mixture of 4-tert-butyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 4.3 mmol) and sodium acetate (0.39 g, 4.8 mmol) in acetic acid. The reaction mixture is stirred at room temperature for 29 hours, concentrated in vacuo, diluted with ethyl acetate, washed sequentially with 0.1N sodium hydroxide solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. Chromatography of the residue using silica gel and 20% to 25% ethyl acetate in hexanes solutions gives the title product as a white solid (0.86 g, mp 205°-208° C.).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]([C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][C:26]=1[Sn:27]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].O[N:43]1[C:47](=[O:48])[CH2:46][CH2:45][C:44]1=[O:49].CCN=C=NCCCN(C)C>C(#N)C>[F:41][C:2]([F:1])([F:40])[C:3]([C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][C:26]=1[Sn:27]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:15][NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O:22][N:43]1[C:47](=[O:48])[CH2:46][CH2:45][C:44]1=[O:49])=[O:21])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC(=O)CCC(=O)O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC(=O)CCC(=O)ON2C(=O)CCC2=O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Compound 9 (66 mg, 93 μmol) was dissolved in acetonitrile (2 mL), N-hydroxysuccinimide (21.5 mg, 187 μmol) and EDCI (36 mg, 187 μmol) were added and the mixture stirred at 20° C. overnight. The solvent was removed under vacuum and the residue was purified over silica gel using dichloromethane/AcOEt (4/1) as eluant to give 45 mg (93 μmol, 60% yield) of a colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2C=CN=C(NN)[C:21]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:16][CH:15]=1.O>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:11]=[CH:12][N:8]3[C:1](=[O:2])[NH:3][N:10]=[C:9]3[C:21]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1nccc(-c2ccc(Cl)cc2)c1-c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a stirring solution of 1,1′-carbonyldiimidazole (2.5 g, 15.4 mmol) in THF (15 mL) at room temperature under argon was added 4-(4-chlorophenyl)-2-hydrazinyl-3,4′-bipyridine (0.92 g, 3.1 mmol). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was then concentrated under vacuum to produce a yellow solid. This solid was stirred in an ice bath and water (25 mL) was added. Solid was collected by filtration and further washed with water (15 mL×2). After drying in an oven at 50° C. under reduced pressure overnight, 960 mg of the title compound was obtained as a yellow solid. HPLC/MS: retention time=1.985 min, [M+H]+=323. 1H NMR (DMSO-d6, 500 MHz): δ 12.61 (s, 1H), 8.50 (d, J=6.05 Hz, 2H), 7.94 (d, J=7.15 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.23 (d, J=6.05 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H), 6.68 (d, J=7.15 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20].[ClH:23].O>C(O)C>[ClH:23].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12](=[O:15])[CH2:13][NH:22][CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1cccc(OCc2ccccc2)c1
Reactant: CC(C)N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)NCC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.01 h

Procedure:
In 425 ml of ethanol, 64 g of 3-benzyloxyphenacyl bromide and 212 ml of iso-propylamine are stirred at 5° C. under N2 atmosphere, and the temperature is allowed to rise to 12° C. After 0.75 minutes, the clear solution is poured into 2 liters of crushed ice containing 500 ml of concentrated HCl and 1.5 liters of H2O. The mixture is stirred for 20 minutes, filtered and the solid is washed with water to afford 3'-(benzyloxy)-2-isopropylamino-acetophenone hydrochloride, mp 213°-215° C. dec. A 5 g.-sample of this material is stirred in 50 ml of methanol, and the mixture is cooled in ice and neutralized with 10% NaOH until a clear solution is obtained. To this solution, 2 g of NaBH4 is added and after 0.75 hours of stirring, the mixture is evaporated in vacuo, and the resulting solid is collected and washed with H2O. This gives, after drying, 4.4 g of m-(benzyloxy)-α-[(isopropylamino)methyl]benzyl alcohol, mp 83°-85° C.