Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2
Reactant: O=C(O)CCCc1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Product: O=C1CCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 35.72 of the product from Step B and 50 ml of thionyl chloride was heated at reflux for 2 hours and then stirred at room temperature for 18 hrs. After this time thionyl chloride was removed at reduced pressure and the product was dissolved in carbon tetrachloride and concentrated at reduced pressure. The residue was dissolved in 150 ml of dichloroethane cooled to 0° C. and 28 g of aluminum chloride was added portionwise over about 1 hr in approximately 3 g portions. After stirring for 3 hrs the reaction was poured over a mixture of ice/1N HCl and extracted three times with methylene chloride. The organic extracts were dried over magnesium sulfate and concentrated to approximately 30 g of a brown oil. Chromatography on silica gel with 10% ethyl acetate/hexane afforded 17.83 g of 6-chloro-3,4-dihydro-1(2H)-naphthalenone as a brown oil. 1H NMR was consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:14][S:15]([NH2:18])(=[O:17])=[O:16].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:18][S:15]([CH3:14])(=[O:17])=[O:16])=[O:5]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)NS(C)(=O)=O
Yield: 79.5 %

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 1, using 2-methyl-5-nitrobenzoic acid (5 g, 27.6 mmol), methyl sulphonamide (2.63 g, 27.6 mmol), 4-dimethylaminopyridine (3.37 g, 27.6 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (5.29 g, 27.6 mmol) and anhydrous dichloromethane (200 ml). The title compound (5.67 g, 79%) was afforded as a colourless solid. mp 180° C. (dec.). 1H NMR (360 MHz, D6-DMSO) δ 2.50 (3H, s), 3.42 (3H, s), 7.61 (1H, d, J=8.5 Hz), 8.28 (1H, dd, J=8.4 and 2.5 Hz), 8.36 (1H, d, J=2.5 Hz), 12.46 (1H, brs).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:19][C:20]3[N:25]=[CH:24][N:23]=[C:22]([CH2:26][N:27]4[C:28](=[O:37])[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:35]4=[O:36])[CH:21]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Nc1cc(CN2C(=O)c3ccccc3C2=O)ncn1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Nc2nccc3nc(-c4c(Cl)cccc4Cl)sc23)ncn1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (100 mg, 0.280 mmol), 2-((6-aminopyrimidin-4-yl)methyl)isoindoline-1,3-dione (100 mg, 0.390 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), XantPhos (30 mg, 0.052 mmol), Cs2CO3 (250 mg, 0.770 mmol) in dioxane (5.0 mL). The mixture was degassed with N2 for 10 min. The resulting mixture was irradiated in a microwave reactor at 160° C. for 2 hours and then cooled to room temperature. Insoluble solid was removed via filtration, and the residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (100 mg, 70% yield). LCMS: m/z: 533.1 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:3]=1>C(O)(C)C>[CH:9]([O:12][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:3]=1)([CH3:10])[CH3:8]
Reactant: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OCCOC
Solvent: CC(C)O
Product: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1OCCOC

Procedure:
Similar procedure as described in example 400 was used, starting from isopropyl alcohol and [1-Chloro-6,7-bis-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (Example 9E) to give [1-Isopropoxy-6,7-bis-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 431(MH+).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl>[OH:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1
Reactant: COc1cncc(C#Cc2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.4 %

Procedure:
Add boron tribromide (1 mL, 1 mmol) dropwise to solution of 3-methoxy-5-phenylethynylpyridine, (prepared as described in EXAMPLE 30), (0.073 g, 0.35 mmol) in dichloromethane (0.7 mL) at −78° C. and stir for 15 min. Warm the reaction mixture to room temperature and stir overnight. Add a saturated aqueous solution of sodium bicarbonate to the reaction mixture and stir for 10 min to provide a biphasic solution. Separate the organic layer and wash it sequentially with a saturated solution of aqueous sodium bicarbonate and a saturated aqueous solution of sodium chloride. Dry (sodium sulfate), concentrate and purify by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, to obtain the title compound (0.003 g, 4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20](I)=[CH:21][C:13]1=2)=[O:11].[N:23]1([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([C:36]3[CH:41]=[CH:40][C:39](B4OC(C)(C)C(C)(C)O4)=[CH:38][CH:37]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20]([C:39]3[CH:40]=[CH:41][C:36]([C:34]([N:31]4[CH2:30][CH2:29][CH:28]([N:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[CH2:33][CH2:32]4)=[O:35])=[CH:37][CH:38]=3)=[CH:21][C:13]1=2)=[O:11]
Reactant: O=C(Cc1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Product: O=C(c1ccc(-c2cnc3c(c2)N(C(=O)Cc2cc(F)ccc2F)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 20 %

Procedure:
2-(2,5-Difluorophenyl)-1-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)ethanone (30 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a white foam (20% yield). M.p. (foam), LCMS: m/z=546.09 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.42-1.72 (m, 6H), 2.22-2.42 (m, 2H), 2.54-2.64 (m, 5H), 2.85-3.11 (m, 3H), 3.56-3.62 (m, 2H), 3.88-3.92 (m, 4H), 4.55-4.66 (m, 1H), 5.23 (s, 1H), 6.91-7.07 (m, 3H), 7.41-7.49 (m, 4H), 8.16 (s, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[CH2:18].[Li]CCCC>>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([CH3:13])[CH:15]=3)[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C=Cc1cccc(C)c1
Agent: [Li]CCCC
Product: Cc1cccc(CCN2CCN(c3ccccc3)CC2)c1

Procedure:
According to GP, 2.22 mmol (=0.36 g=0.34 ml) of phenylpiperazine and 2.22 mmol (=0.26 g=0.30 ml) of 3-methylstyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (3:1) gives the product 1-phenyl-4-[2-(3-methylphenyl)-1-ethyl]piperazine as a light-yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[F:18])[CH2:5][CH2:4]1)[CH3:2]>[Ni].CO>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[F:18])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Ni]
Solvent: CO
Product: CCN1CCN(c2ccc(N)cc2F)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of 1-ethyl-4-(2-fluoro-4-nitro-phenyl)-piperazine (1.24 g, 15.1 mmol) and Raney Nickel (13 mg) in MeOH (6 mL) is stirred for 17 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a purple oil: ESI-MS: 224.1 [MH]+; tR=0.90 min (system 1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.Cl.[CH3:13][N:14]([CH2:16][C:17](Cl)=[O:18])[CH3:15]>CN1CCCC1=O.[OH-].[Na+]>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:17](=[O:18])[CH2:16][N:14]([CH3:15])[CH3:13])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN(C)CC(=O)Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
To a solution of 6-iodoimidazo[1,2-b]pyridazin-2-amine (1040 mg, 4.0 mmol) in N-methylpyrrolidone (5.0 mL) was added dimethylaminoacetyl chloride hydrochloride (948 mg, 6.0 mmol), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30), and precipitated from diisopropyl ether to give the title compound (1019 mg, 74%) as a pale-yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:18])[CH2:11]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[C:41]3[C:37]([CH:38]=[N:39][NH:40]3)=[CH:36][CH:35]=2)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH:20]1([NH:19][C:17]([C@H:12]2[CH2:13][CH2:14][C@@H:15]([CH3:16])[N:10]([C:4]3[CH:3]=[C:2]([C:34]4[CH:42]=[C:41]5[C:37]([CH:38]=[N:39][NH:40]5)=[CH:36][CH:35]=4)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:11]2)=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2ccc3cn[nH]c3c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 58 %

Procedure:
(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (700 mg, 1.91 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (607 mg, 2.50 mmol, 1.3 equiv), Pd2(dba)3 (131 mg, 0.14 mmol, 0.075 equiv), tricyclohexylphosphine (80 mg, 0.287 mmol, 0.15 equiv), and K3PO4 (690 mg, 3.25 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (12 mL) and water (4 mL). The mixture was bubbled with argon for 10 minutes, and heated at 100° C. for 20 hours. After cooling to room temperature, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and brine (15 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. Purification was performed by silica gel column chromatography using a gradient elution of 1% A in CHCl3 to 75% A in CHCl3 (A was a mixture of 200/80/800 CH3OH/NH4OH/CHCl3). Trituration of the residue obtained from the chromatography in a mixture of MTBE (3 mL) and hexane (3 mL), followed by drying under vacuum at 65° C. for 24 hours afforded the title compound (496 mg) as solids. LC-MS (ES) m/z=448 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.20-1.30 (m, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.35-1.48 (m, 2H), 1.64-1.74 (m, 1H), 1.75-1.84 (m, 5H), 1.86-1.94 (m, 2H), 1.96-2.08 (m, 1H), 2.34-2.45 (m, 1H), 2.98 (s, 3H), 3.08-3.18 (m, 1H), 3.64-3.71 (m, 1H), 4.50-4.70 (bs, 1H), 4.75-4.95 (bs, 1H), 6.50 (s, 1H), 7.69 (dd, J=8.5, 1.1 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 8.11 (s, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C@H:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:19])[CH:11]=1)[CH2:8][OH:9].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C@H:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:19])[CH:11]=1)[CH2:8][O:9][S:28]([CH3:27])(=[O:30])=[O:29]
Reactant: Cn1cc([C@H](CO)CC2OCCO2)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1cc([C@H](COS(C)(=O)=O)CC2OCCO2)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(R)-Benzoic acid 2-(1-methyl-1H-indol-3-yl)-4-oxo-butyl ester (1.65 g, 5.10 mmol) was dissolved in CH2Cl2 (50 mL). This solution was treated with p-TSA (20 mg) and ethylene glycol (1.4 mL, 26 mmol). The reaction was stirred at room temperature overnight, at which time the organics were removed in vacuo. The solution was diluted with H2O (10 mL) and extracted with Et2O (3×20 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-benzoic acid 3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propyl ester. The unpurified product was dissolved in MeOH/THF (18 mL/18 mL) and allowed to stir at room temperature for 10 min. To this was added a 4% NaOH/MeOH (18 mL) solution. The reaction was allowed to stir at room temperature for 1 h. The solution was diluted with H2O (10 mL) and extracted with Et2O (3×20 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propan-1-ol (600 mg, 2.30 mmol) after silica gel chromatography (50:50 Et2O/hexanes). 50% Et2O/hexanes). (R)-3-[1,3]Dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propan-1-ol (69.5 mg, 0.267 mmol) was dissolved in CH2Cl2 (8 mL) and Et3N (56 μl, 0.40 mmol). The reaction was cooled to 0° C. and treated with methanesulfonyl chloride (31 μl, 0.40 mmol). The reaction stirred for 1.5 h at this temperature then was allowed to warm to room temperature and stirred for an additional 10 min. The solution was diluted with H2O (5 mL) and extracted with Et2O (3×10 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-methanesulfonic acid 3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propyl ester. Deoxygenation was performed following the method of Holder and Matturro (1977) J. Org. Chem. 42:2166.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14]I)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].II.I[C:19]1[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=1.O>CN(C=O)C.[Zn].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].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:19]1[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: O=C1C=C(I)CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC1=CC(=O)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (32.9 g, 0.100 mol) in DMF (20 mL) was added to a mixture of Zn (19.5 g, 0.300 mol) and iodine (6.6 g, 26 mmol) in DMF (30 mL) under nitrogen protection. The mixture was stirred for 1 h at ambient temperature. Then a solution of 3-iodocyclopent-2-enone (20.8 g, 0.100 mol) in DMF (50 mL), Pd2(dba)3 (2.3 g, 2.5 mmol) and S—Phos (2.1 g, 5.0 mmol) were added successively. The reaction mixture was stirred overnight at 50° C. The mixture was cooled to ambient temperature and water (100 mL) was added. The resulting mixture was extracted with EtOAc (150 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=5:1 to 2:1) to afford (S)-methyl 2-(tert-butoxycarbonylamino)-3-(3-oxocyclopent-1-enyl)propanoate (17 g, 60% yield) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:16])=O)=[C:9]2[CH3:17])=[CH:4][CH:3]=1.N=C=N.Cl.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[NH:29])=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CS(C)=O>[C:28]([C:27]1[CH:31]=[CH:32][C:24]([CH2:23][NH:22][C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]=2[CH3:17])=[O:16])=[CH:25][CH:26]=1)(=[NH:29])[NH2:30]
Reactant: Cc1cc(C(=O)O)c(C)n1-c1ccc(F)cc1
Reactant: N=C(N)c1ccc(CN)cc1
Agent: Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
808 mg (4 mmol) of 1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxylic acid (Enamine, Kiev, Ukraine) was dissolved in 100 ml methylene chloride and 30 ml dimethyl sulfoxide, and added with stirring to 4 g of PS-carbodiimide (Biotage, Charlotte, N.C., USA), substituted at 1.33 mmol/g, wetted with 40 ml methylene chloride. 892 mg (4 mmol) of 4-(aminomethyl)benzamidine hydrochloride (Astatech, Bristol, Pa., USA), and 540 mg of HOBt were dissolved in 50 ml dimethyl sulfoxide, added to the stirred mixture, followed by 1.4 ml of diisopropylethylamine (Sigma-Aldrich). The mixture was stirred for seven days at room temperature, followed by filtration to remove the consumed resin. 50 ml of water was added to 150 ml of the filtrate, stirred vigorously for 10 minutes, then allowed to settle for 20 minutes to separate aqueous phase from the methylene chloride. The aqueous phase was carefully removed, neutralized by adding Tris base to 20 mM final concentration, then applied to a 20 ml bed volume CM-Sepharose (Sigma-Aldrich) cation-exchange column equilibriated with 20 mM Tris-HCl, pH 8. The column was washed with 40 ml of methanol and then eluted with 40 ml of 5% formic acid in methanol. The target compound was recovered as a yellowish oily solid following removal of the solvent by evaporation. The mass of the compound was verified by LC-MS/MS.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16](Br)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CN(C=O)C.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([S:3][C:1](=[O:4])[CH3:2])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
2.2 g (19.3 mmol) Potassium thioacetate and 2.65 g (10 mmol) 4-Bromo-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 50 ml of DMF and stirred at 100° C. for 4 h. The mixture was taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (10% to 20% ethyl acetate in heptane) gave 2.15 g of the expected compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[O:14]([C:21]([N:23]1[CH2:28][CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[CH2:25][CH:24]1[CH2:37][CH3:38])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([C:21]([N:23]1[CH2:28][CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:25][CH:24]1[CH2:37][CH3:38])=[O:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCC1CC(OS(=O)(=O)C(F)(F)F)=CCN1C(=O)Oc1ccccc1
Reactant: OB(O)c1ccc2ccccc2c1
Product: CCC1CC(c2ccc3ccccc3c2)=CCN1C(=O)Oc1ccccc1
Yield: 75.3 %

Procedure:
Beginning with 3.62 gm (21.1 mMol) naphthalene-2-boronic acid and 5.70 gm (15.0 mMol) 1-phenoxycarbonyl-2-ethyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine, 4.04 gm (75%) of the desired compound were prepared substantially as described in EXAMPLE 11.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]=[CH:13][N+:14]([O-:16])=[O:15])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:7]2[OH:8]
Reactant: Cc1ccc(NC=C[N+](=O)[O-])c(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2ncc([N+](=O)[O-])c(O)c2c1

Procedure:
5-Methyl-2-(2-nitrovinylamino)benzoic acid (Compound of step 1, 1.5 g, 6.756 mmol) and potassium acetate (1.3 g, 13.51 mmol) were stirred in acetic anhydride (8 ml, 148 7 mmol) for 3 hours at 120° C. The precipitate was filtered and washed with acetic acid until the filtrate is colorless and then washed with water and dried in vacuo to obtain the title compound. Yield: 610 mg (64%); 1H NMR (DMSO-d6, 300 MHz): δ 9.126 (s, 1H), 8.035 (s, 1H), 7.606 (s, 2H), 2.432 (s, 3H); MS: m/z 203 (M−1).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]3[C:20]4[C:25]([CH:26]=[CH:27][C:12]2=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:8]=[CH:9][CH:10]=1)=[NH:4].N1C=CC=CC=1.[C:34](Cl)(=O)[O:35]C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl.O>[O:35]=[C:34]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([N:11]3[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]4[C:20]5[C:25]([CH:26]=[CH:27][C:12]3=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:8]=[CH:9][CH:10]=2)[NH:4]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N=C(NO)c1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2cccc(-c3noc(=O)[nH]3)c2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
To a suspension of 5-[3-(N-hydroxyamidino)phenyl]-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione (36 mg, 0.1 mmol) in dichloromethane (18 mL) was added pyridine (0.012 mL, 0.15 mmol) and phenyl chlorocarbonate (0.016 mL, 0.13 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, and cold water was added. After the mixture was stirred for 20 min, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. A suspension of the obtained pale yellow crystal in acetonitrile (10 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (0.03 mL, 0.2 mmol), stirred at room temperature for 15 minuets. After the solvent was removed, the residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give a pale yellow crystal. The crystal was washed with chloroform to give the titled compound as white crystal (20 mg, yield 52%).