Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH3:10].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.O>O1CCCC1.BrC1C=CC=CC=1SC.II>[CH3:10][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[B:11]([OH:16])[OH:12]
Reactant: CSc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccccc1B(O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Magnesium (9.52 g) was suspended in 119 mL of tetrahydrofuran, and to the suspension were added 3.00 g of 2-bromothioanisole and about 20 mg of iodine. After the reaction was started by heating employing a dryer, 72 g of 2-bromothioanisole was dropped to the mixture during 20minutes. After being heated for 1 hour, the reaction mixture was diluted with 1000 mL of tetrahydrofuran, and cooled to 0° C. To the mixture was added 102 mL of triisopropyl borate at the same temperature, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the solvent was removed under reduced pressure. The residue was added 500 mL of 2 mol/L hydrochloric acid, and the mixture was extracted with 300 mL of diethyl ether. The organic layer was extracted with 500 mL of 2 mol/L aqueous sodium hydroxide solution, and the aqueous layer was acidified by addition of concentrated hydrochloric acid under ice-cooling. The residual diethyl ether was removed under reduced pressure, and the precipitate was collected by filtration to give 45.95 g of 2-(methylthio)-phenylboronic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[CH:19][CH:18]=1>>[Cl:33][C:31]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:32]=1
Reactant: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (111 mg, 0.62 mmol) was reacted with the product from Example 127b (190 mg, 0.62 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (45.9 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.86 (t, J=7.54 Hz, 3H) 1.39-1.60 (m, 2H) 2.72 (s, 3H) 3.08-3.26 (m, 2H) 6.72 (d, J=6.99 Hz, 1H) 6.96 (d, J=8.82 Hz, 2H) 7.29 (d, J=8.82 Hz, 1H) 7.61 (dd, J=8.82, 2.57 Hz, 1H) 7.69-7.80 (m, 4H) 8.34 (t, J=5.52 Hz, 1H) 8.53 (d, J=6.99 Hz, 1H) 8.82 (d, J=8.46 Hz, 1H) 10.91 (s, 1H) 14.55 (s, 1H); MS (ESI+) m/z 447 (M+H−TFA)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].Cl.[CH2:11]([O:13][C:14](=[O:17])[CH2:15][NH2:16])[CH3:12].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:8][C:7]1[C:6]([NH:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:17])=[CH:5][N:4]=[N:3][C:2]=1[Cl:1]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1cnnc(Cl)c1Cl
Yield: 30.8 %

Procedure:
A solution of 3,4,5-trichloropyridazine (300 mg), glycine ethyl ester hydrochloride (228 mg) and diisopropylethyl amine (844 μL) in ethanol was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9 to 1:1) to give 126 mg (31% yield) of the title compound as a pale pink amorphous.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:11]=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[CH:13]=1
Reactant: COc1ccccc1CCc1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CCc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {4-[2-(2-methoxy-phenyl)-ethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (143 mg, 0.435 mmol) in dry CH2Cl2 (3 mL) is treated with trifluoroacetic acid (1.0 mL, 13 mmol), and stirred at room temperature. After 18 hours, the reaction mixture is concentrated and the residue is dissolved in CH2Cl2 (10 mL), extracted with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated to give the crude product which is used in the next reaction without purification.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl>C(Cl)Cl>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:10]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Salicylic acid (4.3 g, 0.0312 mol) was taken up in 60 mL of CH2Cl2 along with tert-butyl 2-aminoethylcarbamate (5.0 g, 0.0312 mol) and EDC (6.6 g, 0.0343 mol). The resulting reaction mixture was stirred at room temperature for 8 h and then quenched with saturated aqueous NaHCO3. The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (1:1 pentane/EtOAc) afforded 5.7 g of tert-butyl 2-(2-hydroxybenzamido)ethylcarbamate (65%). tert-Butyl 2-(2-hydroxybenzamido)ethylcarbamate (650 mg, 2.31 mmol) was taken up in 4 mL of 4 N HCl in dioxane and allowed to stir at room temperature for 2 h. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure to afford the HCl salt of N-(2-aminoethyl)-2-hydroxybenzamide. This material was taken up in DMF (15 mL) along with (R)-α-lipoic acid (TCI, 478 mg, 2.31 mmol) along with EDC (443 mg, 2.54 mmol) and DIEA (1.2 mL, 6.93 mmol). The resulting reaction mixture was stirred at room temperature for 4 h and then diluted with EtOAc (60 mL). The organic layer was washed with water (4×5 mL), brine, dried (Na2SO4) and concentrated under reduced pressure to afford (S)—N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)-2-hydroxybenzamide (420 mg, 49%). Mass calculated for C17H24N2O3S2: 368.12. found: [M+H]+=369.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)=[O:6])[CH3:2].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.Cl>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:9][CH:8]=1)=[O:6])[CH3:2]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)C(=O)c1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of (4-amino-phenyl)-oxo-acetic acid ethyl ester (347 mg, 1.8 mmol), 2-chloro-3-nitropyridine (294 mg, 1.8 mmol) and 4M HCl in dioxane (0.45 mL, 1.8 mmol) in ethanol (4 mL) is refluxed for 14 h. An additional 0.45 mL of 4M HCl in dioxane is added and the mixture refluxed for 5 h. The reaction mixture is cooled down to room temperature and the resulting precipitate is filtered off. [4-(3-Nitro-pyridin-2-ylamino)-phenyl]oxo-acetic acid ethyl ester is obtained as an orange solid. Title compound: ES-MS: 315.99 [M+H]+; tR=1.7 min (System 2).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH2:9].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1CCN
Product: CC(=O)NCCc1ccccc1C
Yield: 88 %

Procedure:
In close analogy to the procedure described above, 2-o-tolyl-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:19]=2[OH:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:35]1[CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:19]=2[O:26][CH:35]2[CH2:38][CH2:37][CH2:36]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: BrC1CCC1
Reactant: CCOC(=O)C1(NC(=O)c2cc(Cl)cc(Cl)c2O)Cc2ccc(F)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cc(Cl)cc(Cl)c2OC2CCC2)Cc2ccc(F)cc2C1
Yield: 51.8 %

Procedure:
To a suspension 2-(3,5-dichloro-2-hydroxy-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester (19) (624 mg, 1.51 mmol), anhydrous Cs2CO3 (984 mg, 3.02 mmol), and KI (50 mg, 0.30 mmol) in DMF (20 mL) is added bromocyclobutane (711 μL, 7.55 mmol). The resulting reaction suspension is covered with argon and ran in a microwave reaction: 110° C., 2 h. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10%-50% EtOAc in heptane) to give a pure product (20) as white solid (365 mg, 52%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:4][C:5]2[CH:6]=[C:7]3[C:14](=[O:15])[NH:13][CH2:12][C@@H:11]([CH3:16])[N:8]3[C:9]=2[CH:10]=1.[H-].[Na+].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[Br:1][C:2]1[C:3]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:4][C:5]2[CH:6]=[C:7]3[C:14](=[O:15])[N:13]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH2:12][C@@H:11]([CH3:16])[N:8]3[C:9]=2[CH:10]=1
Reactant: CC(C)N1CCC(Oc2cc3cc4n(c3cc2Br)[C@H](C)CNC4=O)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cc3cc4n(c3cc2Br)[C@H](C)CN(CC2CC2)C4=O)CC1

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-7-bromo-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 93), sodium hydride and 1-(bromomethyl)cyclopropane, to give the product as a white solid (55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH:19](O)=O>>[CH3:19][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Product: CNc1ccc(-c2cc3[nH]c(=O)[nH]c3nc2C)cc1

Procedure:
It is contemplated that 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one can be alkylated by reacting it with formic acid followed by reduction of the intermediate formylamino derivative to obtain 6-[4-(methylamino)phenyl]-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one [I; Ar=4-CH3NHC6H4, R1 and R3 =H, R5 =CH3 ]; or by reacting it with formaldehyde under reducing conditions to obtain 6-[4-(dimethylamino)phenyl]-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one [I; Ar=4-(CH3)2NC6H4, R1 and R3 =H, R5 =CH3 ].
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][C:5](OC)=[O:6].[NH2:10][NH2:11]>C(O)C>[NH2:10][NH:11][C:5](=[O:6])[CH2:4][CH2:3][N:2]([CH3:9])[CH3:1]
Reactant: COC(=O)CCN(C)C
Reactant: NN
Solvent: CCO
Product: CN(C)CCC(=O)NN

Procedure:
To a solution of methyl 3-(dimethylamino)propanoate (1.0 g, 7.62 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.370 mL, 7.62 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure. (quantitative yield): 1H NMR (CDCl3) δ 9.49 (br s, 1H), 3.88 (br s, 2H), 2.53-2.52 (m, 2H), 2.44-2.36 (m, 2H), 2.24 (s, 6H); ES-MS (m/z) 132 [M+H]+.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:51]2[N:52]=[C:53]([NH:56]C(OC(C)(C)C)=O)[S:54][CH:55]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[CH2:40][C@@H:39]([CH2:41][NH:42]C(OC(C)(C)C)=O)[O:38][C:37]2=[O:50])=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][CH2:41][C@H:39]1[O:38][C:37](=[O:50])[N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]3)/[C:51]3[N:52]=[C:53]([NH2:56])[S:54][CH:55]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[CH2:40]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Yield: 53.1 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((R)-5-(((tert-butoxycarbonyl)amino)-methyl)-2-oxooxazolidin-3-yl)methyl)-4-oxoazetidine-1-sulfonic acid (725 mg, 0.794 mmol), DCM (8.0 mL) and TFA (3.7 mL, 48.0 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (231 mg, 52%) as a white powder. LCMS: Rt=0.41 min, m/z=548.1 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J=8.8 Hz, 1H), 8.00 (t, J=5.8 Hz, 3H), 6.83 (s, 1H), 5.22 (dd, J=8.8, 5.9 Hz, 1H), 4.68 (tdd, J=9.0, 5.8, 3.4 Hz, 1H), 4.24 (ddd, J=9.3, 5.9, 3.6 Hz, 1H), 3.75 (t, J=8.8 Hz, 1H assumed; obscured by water), 3.61 (dd, J=8.7, 5.8 Hz, 1H assumed; obscured by water), 3.41 (dd, J=14.7, 9.0 Hz, 1H), 3.30 (dd, J=14.7, 3.7 Hz, 1H), 3.25-3.05 (m, 2H), 1.40-1.27 (m, 4H). 1H NMR (400 MHz, D2O) δ 7.18 (d, J=2.4 Hz, 1H), 5.45 (d, J=5.8 Hz, 1H), 5.02-4.93 (m, 1H), 4.70 (ddd, J=9.2, 5.8, 3.7 Hz, 1H), 4.04 (t, J=9.2 Hz, 1H), 3.78 (dd, J=15.0, 9.0 Hz, 1H), 3.60-3.56 (m, 1H), 3.54 (dd, J=11.3, 3.6 Hz, 1H), 3.40 (s, 1H), 3.38 (d, J=2.0 Hz, 1H), 1.57-1.49 (m, 2H), 1.49-1.40 (m, 2H).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:7]2.[C:19]1(C)C=C(C)C=C(C)C=1.Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH:14]([CH3:18])[C:15]([O:17][CH3:19])=[O:16])[CH:5]=[CH:4]2
Reactant: Cc1cc(C)cc(C)c1
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
16.1 Grams of the methyl ester of the 2-(5-bromo-6-methoxy-2-naphthyl)propionic acid are dissolved in 65 ml of methylene chloride and then 10.4 ml of mesitylene and 12 ml of anhydrous titanium tetrachloride are added while keeping the temperature at about 20° C. The reaction mixture is kept under stirring at room temperature for 80 hours and then is poured into a mixture made of 68 g of crushed ice and of 15 ml of a 35% (w/v) aqueous solution of hydrochloric acid. The layers are separated after 15 minutes of stirring, the aqueous layer is extracted with 30 ml of methylene chloride and then is discarded. The organic layers are collected, first washed with 50 ml of a 1N aqueous solution of hydrochloric acid, then with 50 ml of water and lastly with 50 ml of a 8% (w/v) aqueous solution of sodium bicarbonate. The organic solution is dried over anhydrous sodium sulfate and then is evaporated under vacuum. The residue is crystallized first with n-hexane and then with methyl alcohol obtaining 4 g of product with a yield equal to 32.7%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][C@H:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[O:23][CH2:24][CH2:25][N:26]([CH3:32])C(NC)CC)=[CH:18][CH:17]=1>>[CH3:6][N:1]([CH2:2][CH2:3][CH2:4][N:26]([CH2:25][CH2:24][O:23][CH:22]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=1)[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)[CH3:32])[C:12]([C@@H:10]1[CH2:9][S:8][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:11]1)=[O:14]
Reactant: O=C(O)[C@@H]1CSC(c2cccnc2)N1
Reactant: CCC(NC)N(C)CCOC(c1ccc(F)cc1)c1ccc(F)cc1
Product: CN(CCCN(C)C(=O)[C@@H]1CSC(c2cccnc2)N1)CCOC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 52 %

Procedure:
Following a procedure similar to that described in Example 1, but using (4R)-2-(3-pyridyl)thiazolidine-4-carboxylic acid and N-{2-[bis(4-fluorophenyl)methoxy]ethyl}-N-methyl-N'-methylpropanediamine (prepared as described in Preparation 3), the title compound was obtained in a yield of 52%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCOCC1>[F:11][C:9]1[CH:10]=[C:2]2[NH:1][C:14](=[O:17])[O:6][C:4](=[O:5])[C:3]2=[CH:7][C:8]=1[I:12]
Reactant: Nc1cc(F)c(I)cc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Yield: 90.4 %

Procedure:
Anhydrous dioxane (0.5 liters), 2-amino-4-fluoro-5-iodo-benzoic acid (46 grams, 164 mmoles), and trichloromethylchloroformate (97.4 grams, 492 mmoles) were added to a one liter one neck flask equipped with a magnetic stir bar and reflux condenser. The solution was placed under anhydrous nitrogen, stirred and heated to reflux for 16 hours. The reaction mixture was allowed to cool and was poured into one liter of hexanes. The solid was collected by suction filtration, washed with an additional 0.5 liters of hexanes, and dried under vacuum at room temperature to yield 45.5 grams (90%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.86 (s, 1H), 8.24 (d, 1H), 6.84 (d, 1H). ESI-MS m/z 308 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23]OS(C)(=O)=O)[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Li+].[Li+].[Br-:35].[Li+].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][Br:35])[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Reactant: [Br-]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C(=O)CC(CCBr)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Yield: 91.9 %

Procedure:
3,4-Dichloro-beta-(2-methanesulfonyloxyethyl)-N-methyl-N-(4-chlorophenyl)benzene propanamide (6.3 g) in THF (50 mL) was treated with lithium carbonate (2.0 g) and lithium bromide (2.34 g). The mixture was heated at reflux temperature for 2 hours. The cooled reaction mixture was diluted the CH2Cl2 (100 mL) and washed with H2O (2×100 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil, (5.6 g).
Reaction SMILES: Cl.[C:2]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)(=[O:4])[CH3:3].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>CN(C)C1C=CN=CC=1.C1COCC1>[C:2]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:39](=[O:41])[CH3:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)(=[O:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 3-acetyl-2-(4-aminomethylbenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one hydrochloride (100 mg) and triethylamine (0.09 ml) and 4-dimethylaminopyridine (24 mg) in THF (5 ml) was added acetic anhydride (0.08 ml) and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1→1/9) to give the title compound (93 mg, 92%).
Reaction SMILES: [C:1]([CH:3]1[CH2:13][C:12]2[C:14]3[C:9]([N:10]([CH2:15][C:16]4[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=4)[N:11]=2)=[N:8][C:7]([N:26](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6][C:5]=3[S:4]1)#[N:2].C[O:42]C1C(C)=CN=C(CN2C3C4C(CC(C)SC=4N=C(N)N=3)=N2)C=1C.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:26][C:7]1[N:8]=[C:9]2[C:14]3[C:12]([CH2:13][CH:3]([C:1]([NH2:2])=[O:42])[S:4][C:5]=3[N:6]=1)=[N:11][N:10]2[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C)C3)c1C
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SC(C#N)C3)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(N)=O)C3)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A mixture composed of di-tert-butyl {7-cyano-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylen-4-yl}imidodicarbonate of Step 4) of Example 3 (30 mg) and concentrated hydrochloric acid (1 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and neutralized with a saturated sodium bicarbonate solution. The precipitate was collected by filtration and sequentially washed with a saturated sodium bicarbonate solution and water. Then, the resulting solid was dried to obtain the title compound (18.5 mg, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[NH2:19][C:20]1[C:29](Br)=[N:28][C:27]([Br:31])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[NH2:19][C:20]1[C:29]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:28][C:27]([Br:31])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc([N+](=O)[O-])cc2)c1N
Temperature: 110 °C
Yield: 700 %

Procedure:
A flask containing a mixture of 4-nitrophenylboronic acid (5.5 g, 32 9 mmol), sodium carbonate (10.3 g, 97 mmol), tetrakistriphenyphosphine palladium(0) (1.86 g, 1.61 mmol), and methyl 3-amino-2,6-dibromoisonicotinate (10 g, 32 3 mmol) was flushed with nitrogen, 1,4-dioxane (60.0 mL) followed by methanol (20 mL) were added, and the reaction heated at 110° C. for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with sat. aq. Sodium bicarbonate solution and brine, dried with sodium sulfate, and the solvents removed. The residue was suspended and a mixture of EtOAc:hexane=1:4 and then filtered to give methyl 3-amino-6-bromo-2-(4-nitrophenyl)isonicotinate (9.3 g, 21 mmol, 66% yield). MS (ESI) m/z 354.04 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.37 (2 H, d, J=8.85 Hz), 7.91 (1H, s), 7.88 (2H, d, J=8.85 Hz), 5.98 (2H, br. s.), 3.98 (3H, s).