Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CN(C)C(=O)C>[C:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:13][CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
6-Chloronicotinic acid was dissolved in N,N-dimethylacetamide (10 ml), and tert-butyl piperazine-1-carboxylate (1.2 g) and DIPEA (1.6 g) were added thereto, followed by stirring at 130° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added a 1 M aqueous NaOH solution, followed by washing with CHCl3. The pH of the aqueous layer was adjusted to around 6 to 7 by the addition of 1 M hydrochloric acid, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 6-[4-(tert-butoxycarbonyl)piperazin-1-yl]nicotinic acid (934 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.N#N.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19])=[O:15].Cl>O.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:17]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2F)ccc1OC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N2 inlet was charged with 3-methyloxycarbonyl-4-methoxyaniline (0.88 g, 4.86 mmol), MeOH (3 mL), H2O (7 mL) and 2,4-dichloro-5-fluoropyrimidine (0.81 g, 4.86 mmol). The reaction mixture was stirred at 60° C. for 30 min., diluted with H2O (50 mL), acidified with 2 N HCl (6 mL) and sonicated. The solid obtained was filtered, washed with H2O and dried to produce 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine R940302. 1H NMR (DMSO-d6): δ 10.10 (1H, s), 8.39 (1H, d, J=3.6 Hz), 8.04 (1H, d, J=2.7 Hz), 7.98–7.93 (1H, m), 7.30 (1H, d, J=9 Hz), 3.92 (3H, s), 3.89 (3H, m); purity 96% ; MS (m/e): 312 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11]Br.[CH3:13][C:14]([O-:16])=[O:15].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][O:16][C:14](=[O:15])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1cccc(Br)c1CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(Br)cccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 98.1 %

Procedure:
To a solution of 1-bromo-2-bromomethyl-3-nitro-benzene (3.39 g, 11.53 mmol) in DMF (50 ml) was added KOAc (7.6 g, 77.4 mmol). The reaction was heated at 70° C. for an hour. After cooling to room temperature, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. Acetic acid 2-bromo-6-nitro-benzyl ester (3.1 g) was obtained as a brown oil after concentration under vacuum (˜100%). 1H NMR (CDCl3, 300 MHz) δ: 2.06(s, 3H), 5.46 (s, 2H), 7.377(t, J=8.1 Hz), 7.778(dd, J=1.23 Hz, 8.14 Hz), 7.856(dd, J=1.23 Hz, 8.07 Hz).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]1([CH3:36])[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:21]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1>O.ClCCl.O.[Ru](Cl)(Cl)Cl>[O:2]=[C:24]1[N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:21][CH:20]1[O:19][CH2:18][CH2:17][O:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:36])=[CH:8][CH:9]=1)(=[O:14])=[O:15]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)C1CC(OCCOS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CC(OCCOS(=O)(=O)c2ccc(C)cc2)C(=O)N1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 24 %

Procedure:
A solution of 1.07 g (5.0 mmol) of sodium periodate and 0.338 g (0.15 mmol) of ruthenium(III) chloride hydrate in 12.5 ml of water was added to 0.44 g (1 mmol) of 1-tert-butyl 2-methyl 4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate in 20 ml of dichloromethane. The mixture was left at room temperature for three days with vigorous stirring. Subsequently, the phases were separated, the aqueous phase was extracted twice with ethyl acetate (20 ml) and the combined organic phases were stirred with 5 ml of isopropanol for 30 min. The mixture was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate). 0.11 g (24%) of 1-tert-butyl 2-methyl 5-oxo-4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate (23) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:28])[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)Br)[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[CH2:12]([O:14][C:15](=[O:28])[CH:16]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=1)[CH3:13]
Reactant: CCOC(=O)C(Br)c1cccc(C(F)(F)F)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
4-Trifluoromethylphenol (43.8 g, 0.27 mol), bromo-(3-trifluoromethyl-phenyl)-acetic acid ethyl ester 79 (70 g, 0.225 mol) and potassium carbonate (56 g, 0.405 mol) were stirred in dimethylformamide (200 mL) for 16 hours. Ethyl acetate and brine were added and the organic phase was dried and concentrated. The residue was chromatographed to afford (4-trifluoromethyl-phenoxy)-(3-trifluoromethyl-phenyl)-acetic acid ethyl ester, 80, as an oil. This material was dissolved in tetrahydrofuran/methanol (400 mL/300 mL) and 1N lithium hydroxide (300 mL) was added. After 1 hour, 1N hydrochloric acid (300 mL) was added. The mixture was extracted with ethyl acetate. The extract was dried and concentrated to afford the title compound 39 as a white solid. 1H NMR (d6-DMSO) δ 7.88-7.85 (m, 2H), 7.62-7.55 (m, 4H), 7.09 (d, 2H), 5.52 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]3[C@H:19]([CH:20]4[CH2:22][CH2:21]4)[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[C:32](O)=[O:33])[CH:25]=[CH:24]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[C:32]([N:17]2[CH2:18][C@@H:19]([CH:20]3[CH2:21][CH2:22]3)[C@H:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:33])[CH:25]=[CH:24]1
Reactant: Fc1ccc(C2CCN(C[C@@H]3CNC[C@H]3C3CC3)CC2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Reaction time: 1 h

Procedure:
To a solution of 0.02 g (0.067 mmol) of 3-(S)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine and 0.0012 g of (0.01 mmol) dimethylanrinopyridine (DMAP) in 2 mL of CH2Cl2 at rt was added 0.019 g (0.1 mmol) of 1,3-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 0.016 g (0.1 mmol) of 7-indolecarboxylic acid and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between ethyl acetate and sat'd NaHCO3 solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (HPLC Waters Nova-Pak 8×10 RCM 25-40% MeOH in H2O 0.5% TFA) to give the title compound.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[C:38](=O)[CH2:39]Br>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:38]2[N:1]=[C:2]([N:4]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)[CH2:5][CH2:6][C:7]3[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=3)[S:3][CH:39]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Product: COc1cccc(-c2csc(N(CCc3ccc(OC(C)(C)C(=O)O)cc3)Cc3ccc(C(F)(F)F)cc3)n2)c1

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3-methoxyphenacyl bromide.
Reaction SMILES: P(=O)(O)(O)O.OO.Cl[CH2:9][CH2:10][S:11]([CH2:14][CH:15]([S:23]([CH2:26][CH2:27]Cl)(=[O:25])=[O:24])[CH2:16][S:17]([CH2:20][CH2:21]Cl)(=[O:19])=[O:18])(=[O:13])=[O:12]>>[CH:20]([S:17]([CH2:16][CH:15]([S:23]([CH:26]=[CH2:27])(=[O:25])=[O:24])[CH2:14][S:11]([CH:10]=[CH2:9])(=[O:13])=[O:12])(=[O:19])=[O:18])=[CH2:21]
Reactant: O=S(=O)(CCCl)CC(CS(=O)(=O)CCCl)S(=O)(=O)CCCl
Agent: O=P(O)(O)O
Agent: OO
Product: C=CS(=O)(=O)CC(CS(=O)(=O)C=C)S(=O)(=O)C=C
Temperature: 25 °C

Procedure:
To 300 parts of ethanol were successively added 6.9 parts of metallic sodium, 23.4 parts of 2-mercaptoethanol and 14.7 parts of 1,2,3-trichloropropane in this order, and the resulting mixture was heated under reflux. Thereafter, the deposited sodium chloride was removed, and the solution was concentrated to obtain 1,2,3-tris(2-hydroxyethylthio)propane. This compound was added to 80 parts of chloroform, and 45 parts of thionyl chloride was dropped into the resulting mixture. Subsequently, the mixture was heated under reflux, and then the solvent chloroform and unreacted thionyl chloride were removed by distillation under reduced pressure. The residual oily substance was poured into ice water and extracted with ether, and the ether extract was dehydrated over anhydrous sodium sulfate and then freed from the solvent by distillation to obtain 1,2,3-tris(2-chloroethylthio)propane. To this compound were successively added 0.3 part of phosphoric acid and 60 parts of 30% aqueous hydrogen peroxide, and the resulting mixture was heated under reflux and then cooled to deposit 1,2,3-tris(2-chloroethylsulfonyl)propane. The deposited compound was recovered by filtration and dissolved in 100 parts of dimethyl sulfoxide, and the resulting solution was incorporated with 30 parts of triethylamine and then stirred at room temperature to deposit triethylamine hydrochloride. This hydrochloride was removed, and then the dimethyl sulfoxide was removed by distillation to deposit solids. The deposited solids were recrystallized from ethanol to obtain 1,2,3-tris(vinylsulfonyl)propane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](OC)=[O:15])[C:9]=2[O:18][CH3:19])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[C:9]=2[O:18][CH3:19])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(-c2ccc(Cl)cc2)c1OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(CO)cccc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Methyl 4′-chloro-2-methoxybiphenyl-3-carboxylate (1.7 g, 6.14 mmol, 1.0 eq) was dissolved in dry THF under nitrogen and cooled to 0° C. Then 1M LAH solution (0.349 g, 9.22 mmol, 1.5 eq) was slowly added. The reaction mixture was stirred for 1 h at 0° C. Saturated aqueous NH4Cl solution was added dropwise at 0° C. and the resulting mixture was stirred for 30 minutes. The mixture was further diluted with water and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum to give the desired product (1.4 g, 92%). 1H NMR (400 MHz, CD3OD) δ 3.42 (s, 3H), 3.88-3.90 (d, 1H), 4.77-4.78 (m, 2H), 7.18-7.21 (t, 1H), 7.26-7.29 (t, 1H), 7.34-7.43 (m, 3H), 7.51-7.54 (t, 2H). MS (ESI): 248.2 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([F:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:21](OC)([N:23]([CH3:25])[CH3:24])[CH3:22]>>[CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([F:18])=[C:13]([C:15](=[O:17])/[CH:16]=[C:21](/[N:23]([CH3:25])[CH3:24])\[CH3:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1cc(SCc2ccccc2)ccc1F
Product: C/C(=C\C(=O)c1cc(SCc2ccccc2)ccc1F)N(C)C
Yield: 63.6 %

Procedure:
A solution of 1-(5-(benzylthio)-2-fluorophenyl)ethanone (3.6 g, 13.83 mmol) in N,N-dimethylacetamide dimethyl acetal (12.13 mL, 83 mmol) was irradiated at 130° C. for 10 minutes in a microwave reactor (Biotage Initiator). The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was concentrated. The crude product was purified by column chromatography, eluting with 20-100% ethyl acetate in heptane, to provide (E)-1-(5-(benzylthio)-2-fluorophenyl)-3-(dimethylamino)but-2-en-1-one (2.9 g, 8.80 mmol, 63.7% yield) as a tan solid. m/z (ESI) 330.0 (M+H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-:11]>>[CH2:16]([O:15][C:13]([C:12]1[NH:10][N:11]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]=1[NH2:9])=[O:14])[CH3:17]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)c1[nH]nc(-c2ccccc2)c1N

Procedure:
4-Amino-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester is prepared from benzyl cyanide and ethyl diazoacetate, using the condition described in Rochais, C.; Lisowski, V.; Dellemagne, P.; Rault, S. Tetrahedron Lett. 2004, 45, 6353. HPLC-MS calculated for C12H13N3O2 (M+H+) 232.1. Found: 232.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72])=[O:9]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1OC)C1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1OC)C1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of 5-chloro-3-[ethyl(oxan-4-yl)amino]-2-methoxybenzoic acid (111 mg, 0.35 mmol) in DMF (3 ml) at room temperature under nitrogen was added PyBOP (220 mg, 0.42 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (92 μl, 0.53 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 66 mg, 0.39 mmol). After stirring for 1.5 hours at room temperature no starting material was observed by LCMS. Deionized water (20 ml) was added to the reaction mixture and the resultant precipitate was collected by filtration. The solid was washed with deionized water (3×5 ml) before being air dried. The solid was further purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 97:3 DCM:MeOH). The sample was dried in a vacuum oven for 18 hours to give 105 mg (64%) the title compound as an off-white solid. LC-MS 98%, m/z=449.5/452.1, 1H NMR (500 MHz, Chloroform-d) δ ppm 11.47 (s, 1H), 8.79 (t, J=5.8 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.05 (d, J=2.6 Hz, 1H), 5.92 (s, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.98 (dd, J=11.3, 3.8 Hz, 2H), 3.78 (s, 3H), 3.35 (t, J=11.6 Hz, 3H), 3.12 (q, J=7.0 Hz, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.92-1.61 (m, 4H), 0.94 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1.[C:12]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[C:12]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:9]2[CH2:10][CH2:11][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7][CH2:8]2)=[O:25])=[CH:27][CH:28]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: c1cc2c(o1)CCNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.128 g of the above crude 5,6,7,8-tetrahydro-4H-furo[2,3-d]azepine hydrochloride, 0.22 g (0.97 mmol) of 4-benzoylbenzoic acid and 0.45 ml (3.2 mmol) of triethylamine in 30 ml of dichloromethane, 0.15 ml (0.97 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:22][CH2:23][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)([OH:9])[CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: CC[Mg+]
Reactant: O=C(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
To a solution of (4-fluorophenyl)(2-(piperazin-1-yl)pyrimidin-5-yl)methanone (4.0 g, 21.84 mmol) in dry THF (150 mL) was added EtMgBr (1 M in THF, 150 mL) at 0° C. under nitrogen. The mixture was stirred at RT for 3 h, then quenched with NH4Cl solution and extracted with ethyl acetate (200*3 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by combi-flash with dichloromethane:methanol=10:1 to give the title compound (440 mg, 10%) as a yellow solid. MS (ES+) C17H21FN4O requires: 316. found: 317 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[N:26]1[S:27][N:28]=[C:29]2[CH:34]=[C:33]([N:35]=[C:36]=[S:37])[CH:32]=[CH:31][C:30]=12>C(#N)C>[N:26]1[S:27][N:28]=[C:29]2[CH:34]=[C:33]([NH:35][C:36]([NH:1][C:2]3[C:15]4[C:6](=[CH:7][C:8]5[C:9]6[C:14]=4[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:11](=[O:22])[C:10]=6[CH:23]=[CH:24][CH:25]=5)[CH:5]=[CH:4][CH:3]=3)=[S:37])[CH:32]=[CH:31][C:30]=12
Reactant: S=C=Nc1ccc2nsnc2c1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc6nsnc6c5)c4c(c23)C1=O
Temperature: 25 °C
Yield: 89.2 %

Procedure:
215 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.645 mmole) were dissolved in 10 ml of acetonitrile. 250 mg (2 molar equivalents) of 2,1,3-benzothiadiazol-5-yl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 303 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=89%) which was characterized as follows:
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].[Cl-].[NH4+].C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:38])[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 52 %

Procedure:
To a solution of (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-methyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 19, 4.16 g, 8.36 mmol) in DMF (35 mL) at room temperature was added ammonium chloride (0.895 g, 16.72 mmol), HATU (4.77 g, 12.54 mmol) and DIEA (5.84 mL, 33.45 mmol). After 15 minutes the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-80% ethyl acetate/hexanes) was run twice to afforded the desired product (2.16 g, 52%) as a yellow foam.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[I:23])[C:16]([O:18][CH3:19])=[O:17]>C(C(C)=O)C.CCCCCCC>[CH2:2]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[I:23])[C:16]([O:18][CH3:19])=[O:17])[CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCC(C)=O
Product: CCCCOc1cc(C(=O)OC)ccc1I
Yield: 97.3 %

Procedure:
6.15 mL (54 mmol) of iodobutane and then 14.9 g (108 mmol) of potassium carbonate are added to 10 g (36 mmol) of methyl 3-hydroxy-4-iodobenzoate in 100 mL of methyl ethyl ketone. The reaction mixture is heated at reflux for 1 hour 30 minutes. The reaction medium is filtered off and the filtrate is evaporated to dryness. The solid obtained is taken up in heptane, filtered and dried. 11.7 g (97%) of methyl 3-butoxy-4-iodobenzoate are obtained in the form of off-white crystals.