Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.Br[C:13]1[CH:14]=[CH:15][C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[C:17]([CH:20]=1)[C:18]#[N:19].CC(C)([O-])C.[Na+].N[C@@H]1CCCC[C@H]1N>CN(C=O)C.CCOC(C)=O.CCCCCC>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:16]1[CH:15]=[CH:14][C:13]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:2]2)=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1cc(Br)ccc1-c1ccccn1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Agent: CC(C)(C)[O-]
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1cc(-n2ccc(-c3ccccn3)c2)ccc1-c1ccccn1
Temperature: 140 °C
Yield: 24.8 %

Procedure:
2-(1H-Pyrrol-3-yl)pyridine (300 mg, 2.0 mmol), 5-bromo-2-pyridin-2-ylbenzonitrile (538.7 g, 2.0 mmol), sodium tert-butoxide (384 mg, 4.0 mmol) and trans-1,2 diaminocyclohexane (23 mg, 0.2 mmol) were combined in DMF (10 mL) under argon. The reaction mixture was heated at 140° C. overnight. The reaction mixture was allowed to cool to ambient temperature. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (100 mL), and washed with H2O (3×100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil. The crude product was purified by column chromatography eluting with 5.5:4.5 EtOAc:Hexane to afford 2-pyridin-2-yl-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile (160 mg, 27% yield) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.73-8.74 (d, 1H), 8.48-8.49 (d, 1H), 8.14-8.15 (d, 1H), 7.98-8.01 (m, 3H), 7.92-7.94 (d, 1H), 7.86-7.88 (d, 1H), 7.79-7.81 (t, 1H), 7.47-7.53 (m, 2H), 7.22-7.24 (m, 1H), 6.94-6.95 (m, 1H). MS 323.4 (M++H).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][N:10](C2CCCCO2)[CH:11]=1)=[O:5])[CH3:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:37]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][NH:10][CH:11]=1)=[O:5])[CH3:38]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCN3CCCCC3)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(OCCN3CCCCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 38 mg of 1,1-diethyl-3-{3-[5-fluoro-6-(2-piperidin-1-ylethoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl}urea is solubilized in 2 mL of dichloromethane and then 500 μl of trifluoroacetic acid are added. The reaction medium is stirred at ambient temperature overnight. The solvent is evaporated off under vacuum in a rotary evaporator and the crude is reacted again in 500 μL of dichloromethane and 500 μL of trifluoroacetic acid at ambient temperature for one hour. After concentration of the solvent in a rotary evaporator, the reaction crude is purified by flash chromatography on a 4 g silica cartridge, eluent: 100/0 to 90/10 dichloromethane/-methanol. 20 mg of 1,1-diethyl-3-{3-[5-fluoro-6-(2-piperidin-1-ylethoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea trifluoroacetate are isolated in the form of a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm), for this batch, we observe a 60%-40% resolution of tautomers with: 1.24 (m, 6H); from 1.32 to 1.93 (m, 6H); 3.06 (broad m, 2H); from 3.23 to 3.68 (broad m, 4H); 3.41 (m, 4H); 4.44 (broad m, 2H); 7.21 (d, J=8.0 Hz, 0.6H); 7.32 (d, J=11.0 Hz, 0.4H); 7.38 (d, J=8.0 Hz, 0.4H); 7.49 (d, J=11.0 Hz, 0.6H); 8.01 (s, 1H); 9.32 (broad m, 1H); 9.74 (s, 0.4H); 9.77 (s, 0.6H); 13.0 (s, 1.6H); 13.05 (s, 0.4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:6]([N+:9]([O-])=O)=[CH:7][CH:8]=1)[NH2:5]>Cl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:5])[C:6]([NH2:9])=[CH:7][CH:8]=1
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1N
Agent: Cl
Product: Cc1c(Cl)ccc(N)c1N

Procedure:
The reaction sequence set out in FIG. 4 is as follows: 3-chloro-2-methylacetanilide was prepared from 3-chloro-2-methylaniline via acetylation of the aniline with acetic anhydride in an aqueous methanol solution. A mixture of chloro-methylnitro-acetanilide isomers was thereafter formed by nitration of the acetanilide with sulfuric and nitric acid. The 3-chloro-2-methyl4-nitro isomer was removed by precipitation after addition of potassium hydroxide to the mixture of isomer in ethanol. The 3-chloro-2-methyl-6-nitroacetanilide was heated to reflux in an aqueous sodium hydroxide solution. The solid that formed was 3-chloro-2-methyl-6-nitroaniline. Reaction with a solution of stannous chloride in hydrochloric acid yielded a precipitate of 4-chloro-3-methyl-1,2-benzenediamine. Reaction with sodium nitrite in acetic acid yielded a solid 5-chloro4-methylbenzotriazole.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]([O:17]C)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.O.[OH-].[Li+]>CO.O>[Br:1][C:2]1[S:3][C:4]([C:15]([OH:17])=[O:16])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:6]=1
Reactant: COC(=O)c1sc(Br)nc1-c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc(Br)sc2C(=O)O)cc1
Yield: 35.5 %

Procedure:
To a solution of 2-bromo-4-[(4-methoxy)phenyl]-5-(methoxycarbonyl)thiazole (6.24 g, 19.74 mmol) in 20 mL of methanol and 20 mL of water was added lithium hydroxide monohydrate (0.91 g, 21.7 mmol). The mixture was stirred at ambient temperature for 1 h, whereupon aditional lithium hydroxide monohydrate (0.91 g, 21.7 mmol) was added. After stirring an additional hour, the volatiles were removed in vacuo and the residue was quenched with 10% aq HCl. The mixture was extracted with ethyl acetate and the organics were washed with brine, dried (MgSO4) and concentrated. The residue was recrystallized from chloroform/hexane to afford 2.2 g (37%) of the title compound as a white solid. LRMS (ES−): 303 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[O:15][CH2:16][CH3:17])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])/[C:5](/[O:15][CH2:16][CH3:17])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)/C(=C/c1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], (Z)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-acrylic acid ethyl ester (example 1a c]) was reacted with 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (example 6 a]) in the presence of cesium carbonate and potassium iodide to yield (Z)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid ethyl ester as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.N1CCCC1.Cl>CO>[O:10]=[C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[O:1][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1ncccc1O
Agent: Cl
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ncccc1O2
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A solution of 1-(3-hydroxy-2-pyridyl)ethanone (2.4 g, 18 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.5 g, 18 mmol) and pyrrolidine (1.5 mL, 18 mmol) in MeOH (12 mL) was stirred at 80° C. for 2 hours. After cooling to room temperature 1M aqueous HCl was added until pH 4 was reached and the reaction mixture was stirred for further 30 minutes. Methanol was evaporated, the remaining mixture was poured into water, and the pH adjusted to pH 7 with saturated aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate (3×), washed with brine (3×), dried over sodium sulfate and evaporated to dryness. Purification by silica gel chromatography (50-100% ethyl acetate in hexane) afforded tert-butyl 4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (2.2 g, 40%) as an orange oil that solidified upon standing. ESI-MS m/z talc. 318.2, found 319.3 (M+1)+; Retention time: 1.16 minutes (3 min run).
Reaction SMILES: [SH:1][C:2]1[C:11]([C:12]([NH:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C=O)C>[CH2:28]([S:1][C:2]1[C:11]([C:12]([NH:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1S
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCSc1nc2ccccc2cc1C(=O)NCc1cccs1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 300 mg (1.0 mmol) 2-mercapto-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV02) in DMF (2.3 ml) was mixed with 151 mg (1.1 mmol) K2CO3 at room temperature and stirred for 30 min. Then 131 μl (1.0 mmol) 1-iodopentane were added and the mixture was stirred for a further 3 days at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with EE and washed with water. The aqueous phase was extracted with EE and the combined organic phases were dried over MgSO4, filtered and concentrated to small volume under vacuum. Crystallisation of the residue from EE yielded 146 mg (0.4 mmol, 39%) 2-(pentylthio)-N-(2-thienylmethyl)-3-quinoline carboxamide. MS: m/z 371.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36]([O:40][C:41](=[O:44])[CH:42]=[CH2:43])([CH3:39])([CH3:38])[CH3:37]>CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])[CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccc3oc(-c4ccc5c(c4)CCNC5)cc3c2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(Cc5ccccc5)ccc4o3)ccc2C1
Reaction time: 0.5 h

Procedure:
6-(5-benzylbenzofuran-2-yl)-1,2,3,4-tetrahydroisoquinoline (67 mg, 0.2 mmol) was dissolved in methanol (2 ml). DIEA (0.35 ml) and acrylic acid tert-butyl ester (51 mg, 0.4 mmol) were added. The mixture was headed to 90° C. for 30 minutes using microwave irradiation. All the solvents was evaporated and the crude product of tert-butyl 3-(6-(5-benzylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate was used in the next step without further purification. MS (ESI) m/z: Calculated: 467.25; Observed: 468.30 (M++1).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=1)[C:13]([N:16]1[CH2:20][C:19]([CH3:21])=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]1=[O:28])([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl.O>[Cl:35][C:33]1[CH:34]=[C:29]([C:12](=[O:11])[C:13]([N:16]2[CH2:20][C:19]([CH3:21])=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]2=[O:28])([CH3:15])[CH3:14])[CH:30]=[C:31]([Cl:36])[CH:32]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)c2cc(Cl)cc(Cl)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)c2cc(Cl)cc(Cl)c2)C1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of 2.2 g (27.6 mmol) of dimethyl sulfoxide in 10 ml of dichloromethane was dropwise added over a period of 15 minutes at -60° C. to a solution of 2.65 g (20.8 mmol) of oxalyl dichloride in 40 ml of dichloromethane. A few minutes later, a solution of 5.4 g (13.8 mmol) of 1-[2-hydroxy-1,1-dimethyl-2-(3,5-dichlorophenyl)ethyl]-4-methyl-3-phenyl -3-pyrrolin-2-one in 20 ml of dichloromethane was dropwise added thereto at -60° C. The mixture was stirred at the same temperature for further 30 minutes. Then, 7 g (69 mmol) of triethylamine was dropwise added thereto, and the mixture was stirred at -60° C. for further 15 minutes. The reaction solution was restored to room temperature, and 20 ml of water was added thereto. The mixture was thoroughly stirred. The organic layer was treated by a conventional method, and crystals thereby obtained were washed with isopropyl ether to obtain 4.6 g (yield: 87%) of the desired product having a melting point of from 157° to 160° C.
Reaction SMILES: Cl.N[C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[OH-].[Na+].N([O-])=O.[Na+].C(OC([S-])=[S:23])C.[K+]>O>[Cl:12][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([SH:23])[CH:11]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a cooled mixture of concentrated hydrochloric acid (6 mL) and ice (10 g) was added slowly a solution of 2-amino-4-chlorobenzoic acid (4 g, 23.3 mmol), sodium hydroxide (0.94 g, 23.5 mmol) and sodium nitrite (1.6 g, 23.3 mmol) in water (30 mL) in an ice bath. The resulting mixture was stirred at 0° C. for 1 hour. A solution of potassium ethoxymethanedithioate (20.8 g, 65.2 mmol) in water (40 mL) in a beaker was heated to 65° C. The cold diazonium salt solution was added slowly to the above hot solution while evolution of gas was observed. After the addition the mixture was cooled to room temperature and acidified to about pH 3 with an aqueous solution of hydrochloric acid (4 N). The aqueous phase was decanted from the resulting semisolid and the sludge was dissolved in 10% aqueous sodium hydroxide (20 mL). The solution was heated for 2 hours at 100° C. followed by addition of sodium hydrosulfite (2 g). The resulting mixture was heated with stirring at 100° C. for an additional 10 minutes, then cooled to room temperature and filtered through a pad of celite. The filtrate was acidified to about pH 4 with concentrated hydrochloric acid. The formed solid was collected by filtration, washed with water, and dissolved in methanol (10 mL) and diethyl ether (150 mL). The solution was dried over sodium sulfate and concentrated in vacuo to afford 2.8 g of 4-chloro-2-sulfanylbenzoic acid as a yellow solid (yield was 63%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([N+:25]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[C:15]=3[CH3:24])[C:6]=2[CH:5]=[C:4]([NH2:25])[CH:3]=1
Reactant: Cc1c(Cn2c(CF)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Cc1c(Cn2c(CF)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (3.05 g, 6.84 mmol) in Methanol (40 mL) in a 250 ml round bottomed flask was added Tin(II)chloride dihydrate (9.25 g, 41.0 mmol) and HCl (1.869 mL, 61.5 mmol). The reaction mixture was left to stir at 50° C. for 1 h; reaction mostly complete with a very small amt of starting material and a very small amt of des-fluoro product. The solvent was removed and diluted with water (100 mL) and this solution was decanted into a 250 mL Erlenmeyer flask. This solution was neutralized with 6N NaOH to pH 9—a white solid was observed. The brown residue in the rb flask was dissolved in 100 mL of EtOAc and washed with 1N NaOH, brine, dried and evaporated to yield a brown oil. The water layer was extracted with EtOAc to which yielded an additional oil. The oils were combined and purified by reversed phase HPLC; eluted with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (25-70%) over 12 minutes. The fractions were collected and evaporated to yield the expected compound 4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (2.3 g, 5.53 mmol, 81% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.54 (s, 3H) 5.39 (s, 2H) 5.51 (s, 1H) 5.63 (s, 1H) 6.32 (d, J=2.02 Hz, 1H) 6.56 (d, J=7.83 Hz, 1H) 6.96 (d, J=2.02 Hz, 1H) 7.16 (t, J=7.83 Hz, 1H) 7.61 (d, J=7.83 Hz, 1H); LC/MS: MS (ES+) m/e 417 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:36])[CH2:16][CH2:17][C:18](=[O:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.C1(C[C@H](NC(OC(C)(C)C)=O)C(=O)CCC(O)=O)C=CC=CC=1.COC(=O)[C@H](CC1[C:75]2[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=2)[NH:69]C=1)N.O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][O:8][C:9](=[O:37])[C@H:10]([CH2:14][C:13]1[C:75]2[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=2)[NH:69][CH:12]=1)[NH:11][C:15](=[O:36])[CH2:16][CH2:17][C:18](=[O:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 81 %

Procedure:
The experimental procedure employed for the synthesis of (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoyl-L-proline benzyl ester was followed using the free acid compound 9 (98 mg, 0.3054 mmol, 1.0 eq.), L-tryptophan methyl ester (67 mg, 0.3054 mmol, 1.0 eq.), 1-Hydroxybenzotriazole hydrate (HOBt) (42 mg, 0.3054 mmol, 1.0 eq.), N-ethyl-IV-(dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HCl) (59 mg, 0.3054 mmol, 1.0 eq.), iPr2NEt (0.055 mL, 0.3054 mmol, 1.0 eq.) and dry DMF/CH2Cl2 (2:8 ratio)(5 mL). Work-up as usual and column chromatography on silica gel elution with 50% EtOAc-hexane afforded the (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoyl-L-tryptophan methyl ester (NACE 118) as a cream white solid (0.129 g, 81%): mp 54-57° C.; Rf 0.34 (50% EtOAc-hexane); IR (KBr) ν 1680 (CO) and 3000 (broad, NH) cm−1; 1H NMR (400 MHz, CDCl3) δH 1.40 (9H, s, (CH3)3), 2.41 (2H, t, J=6.6 Hz, —CH2CO), 2.74 (2H, m, —CH2CO), 2.88 (1H, m, —CHαPh), 3.10 (1H, m, —CHβPh), 3.30 (2H, m, —CH2Trp), 3.68 (3H, s, OCH3), 4.47 (1H, br s, —NH), 4.89 (1H, dd, J=5.5 and 11.0 Hz, —CH—), 5.03 (1H, m, —CH—), 6.07 (1H, d, J=7.3 Hz, —NH), 7.08-7.58 (10H, m, Ar—H) and 8.15 (1H, br s, —NH-indole); 13C NMR (100 MHz, CDCl3) δC 27.5, 28.3, 30.8, 35.4, 37.5, 52.3, 52.9, 53.0, 60.1, 111.2, 118.5, 119.7, 122.2, 122.9, 123.0, 126.9, 127.7, 128.6, 129.2, 129.3, 136.1, 136.3, 136.4, 155.4, 172.2, 172.3 and 204.6; EI-MS m/z calcd for C29H35N3O6 (M+) 521.2526, found 521 (M+).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.N([O-])=[O:35].[Na+]>CC(O)=O.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([OH:35])[N:7]=4)=[CH:13][CH:12]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: O=N[O-]
Reactant: C[C@@H](c1ccc(-c2ccnc(N)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccnc(O)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of (R)-3-((S)-1-(4-(2-aminopyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (40 mg, 0.089 mmol) in CH3COOH (0.3 mL) and H2O (0.13 mL) was added an aqueous solution of NaNO2 (2 mol/L, 0.5 mL) dropwise at 0° C. The reaction was stirred for 10 min at this temperature before heating at 60° C. for 3 h. After the mixture was evaporated to dryness, the mixture was adjusted pH 9 with aqueous NaHCO3 solution. The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to give the residue, which was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-hydroxypyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one (3.18 mg, 8%). LC-MS Method 2 tR=0.87 min, m/z=452. 1H NMR (CD3OD): 1.19-1.23 (m, 2H), 1.48 (d, 3H), 1.82-1.86 (m, 2H), 2.05-2.41 (m, 3H), 3.01-3.10 (m, 1H), 3.37 (t, 2H), 5.50 (q, 1H), 6.90 (d, 1H), 6.95-7.02 (m, 4H), 7.18-7.22 (m, 2H), 7.00-7.05 (m, 3H), 7.21-7.24 (m, 2H), 7.80 (d, 2H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>ClCCl>[Cl:42][C:38]1[CH:37]=[C:36]([C:26]2([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)[CH:34]3[CH:30]([CH2:31][N:32]([C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CN(C(=O)Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Triethylamine (0.45 cc) and then phenylacetyl chloride (0.49 g) are added to a solution of 7,7-bis-(3-chlorophenyl)-4-perhydroisoindolone hydrochloride (1.06 g) in dichloromethane (20 cc) cooled to +4° C. The reactio mixture is stirred for 2 hours at 25° C. and then washed with water (3×30 cc) and with saturated sodium chloride solution (3×30 cc). The organic phase is dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 2.2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting 15 cc fractions. Fractions 7 to 18 are concentrated to dryness under reduced pressure (2.7 kPa) and the residue is crystallized from acetonitrile. The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-bis-(3-chlorophenyl)-2-(phenylacetyl)-4-perhydroisoindolone (0.21 g) is obtained. m.p.=160° C.