Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([NH:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30]O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.CO>[NH2:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][O:20][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:13]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:12][N:11]=1
Reactant: Cc1cccc(-c2cc(=O)[nH]cc2-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(-c2cc(OC[C@@H](N)Cc3ccccc3)ncc2-c2ccncc2)c1

Procedure:
To a stirred mixture of 4-(3-methylphenyl)-5-(4-pyridyl)-1H-pyrid-2-one (12 mg, 0.05 mmole), (S)-2-tert-butoxycarbonylamino-3-phenylpropanol (15 mg, 0.06 mmole), triphenylphosphine (18 mg, 0.07 mmole), in methylene chloride (1 mL) at room temperature was added diethyl azodicarboxylate (12 mg, 0.07 mmol). When the reaction was complete (monitored by TLC), methanol was added (1 mL) and the reaction was concentrated and treated with 1 mL of 1:1 TFA/methanol for 30 minutes. The mixture was concentrated, neutralized with 1 drop conc NH4OH, and purified (SiO2, 10% methanol/methylene chloride) to give the title compound: MS (m/z): Calcd. C26H25N3O (M+): 395, found (M+H)+: 396.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[O:22][CH3:23])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C@@H:10]2[CH2:9][NH:8][CH2:12][C@H:11]2[OH:13])=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(Br)ccc1OC1CN(C(=O)OC(C)(C)C)CC1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Br)ccc1O[C@@H]1CNC[C@H]1O
Temperature: 0 °C
Yield: 94 %

Procedure:
Dissolve 3-(4-bromo-2-methoxy-phenoxy)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (603 mg, 1.55 mmol) in dichloromethane (10 mL) and cool the mixture to 0° C. Add trifluoroacetic acid (2.0 mL, 26.45 mmol) and warm the mixture to room temperature for one hour. Remove the volatiles via reduced pressure and then apply to two 10 g SCX cartridges. Wash the material with methanol then elute the material with 2N ammonia in methanol to give 420 mg (93%) of the title compound as a clear oil. LC-MS/ES m/z (81Br) 290.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:13]C(=O)C)[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1nc(-c2cccc(Br)c2)c[nH]1
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1nc(-c2cccc(Br)c2)c[nH]1
Temperature: 86 °C
Yield: 99.6 %

Procedure:
To a solution of acetylguaniidne (6.07 g, 60 mmol) in DMF (40 ml) was added a solution of 2-bromo-1-(3-bromo-phenyl)-ethanone in DMF (20 ml) dropwise at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction was taken into ethyl acetate and water. After separation, the organic layer was washed with brine, dried (MgSO4) and concentrated to give the crude product. The crude product was purified via flash column (silica gel, 3% methanol in chloroform with 0.3% NH4OH) to give N-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-acetamide as a white solid (2.03 g, 36% yield). The acetamide (1.5 g, 5.38 mmol) was dissolved in a solution of 40 ml methanol and 20 ml water. The concentrated hydrochloric acid was added slowly. The reaction was heated at 86° C. for 4 hours. The reaction was concentrated to provide the HCI salt of 4-(3-bromo-phenyl)-1H-imidazol-2-ylamine (1.276 g, 86% yield). LC/MS (m/z 2378.05, 240.06 (M+H)+); HPLC Rt: 1.86 min.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)[CH3:2].I[CH3:29].[H-].[Na+].Cl>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH3:29])[C:8]=2[N:9]=1)[CH3:2]
Reactant: CI
Reactant: CCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1nc2c(ccc(=O)n2C)c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.75 h

Procedure:
2-(Ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (120 mg) and iodomethane (37.8 μl) were dissolved in N,N-dimethylformamide (2 ml), sodium hydride (60% in oil, 86 mg) was added thereto under ice-cooling, and the mixture was stirred for 45 min. 0.5M Hydrochloric acid (6 ml) was added thereto under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white solid residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (123 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14](O)=[O:15])([O-:3])=[O:2].O.C(OCC)(=O)C>C1COCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
22.6 g (100 mmol) of 2,4-dinitrophenylacetic acid are dissolved in 150 mL of THF and added dropwise in 2 hours to 300 mL of a borane-THF complex 1.0 M solution in THF. After 3 hours at 25° C., 200 ml of water are added. The reaction mixture is then poured to ethyl acetate and water. The organic phase is washed repeatedly with water and dried over sodium sulphate, filtered and concentrated under pressure. Chromatography of the residue using toluene: ethylacetate 1:1 as eluant and crystallization in ethylacetate/hexane yielded to 20.7 g (98%) of 2-(2,4-dinitrophenyl)ethanol as yellowish crystal
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30])=O)C1C=CC=CC=1.[CH:33]([C:35]1[N:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][C:39]([C:45]#[N:46])=[C:38]2[O:47][CH:48]([CH3:50])[CH3:49])=O.N1CCCCC1>CC(O)C>[F:32][C:29]([F:30])([F:31])[C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:11][C:15](=[CH:33][C:35]2[N:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][C:39]([C:45]#[N:46])=[C:38]3[O:47][CH:48]([CH3:50])[CH3:49])[C:14](=[O:16])[N:13]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)=N1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3NC(NCc4ccc(C(F)(F)F)cc4C(F)(F)F)=NC3=O)nc12
Temperature: 25 °C

Procedure:
To a mixture of 2-(2,4-bis-trifluoromethyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (82.7 mg, 0.18 mmol) (prepared as described in C-H Kwon et al. J. Med. Chem. 1991, 34, 1845-1849), 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (45.6 mg, 0.19 mmol) (see Example 1) and iPrOH (5 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 5 h to give a brown solution. The reaction mixture was cooled to r.t. and concentrated to give a light yellow solid, 66.3 mg, which was purified by flash column purification to give 6-[2-(2,4-bis-trifluoromethyl-benzylamino)-5-oxo-3,5-dihydro-imidazol-4-ylidenemethyl]-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile, as a light yellow solid, 20.6 mg (20.9%). HR-ES (+) m/e calcd for C25H18F6N6O2 (M+H)+ 549.1468. found 549.1472.
Reaction SMILES: P(Cl)(C(C)(C)C)C(C)(C)C.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[NH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+]>O1CCOCC1.C(OCC)C.O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: Brc1cccnc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(N(c2ccccc2)c2cccnc2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 50 mg (0.093 mmol) of (t-Bu)2PCl)2PdCl2, 0.50 g (4.4 mmol) of 3-bromopyridine, 0.50 g (3.16 mmol) of Ph2NH and 0.25 g (4.46 mmol) of KOH in 2 mL of 1,4-dioxane. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 3-pyridyldiphenylamine. LC-MS Found: 247.3 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([OH:11])=[O:10].CS(C)=O>O>[C:9]([C:12]1[CH:19]=[CH:18][C:15]([C:16]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1)([OH:11])=[O:10]
Reactant: Nc1ccccc1S
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2nc3ccccc3s2)cc1
Temperature: 145 °C
Reaction time: 3.5 h
Yield: 82 %

Procedure:
A mixture of 2-aminothiophenol (9.00 ml, 0.08 mol), 4-carboxybenzaldehyde (10.1 g, 0.07 mol) and DMSO (40 mL) was heated to 145° C., and held at this temperature for 3.5 hours. The reaction mixture was diluted with water, and separated solids were collected, dried and recrystallized from acetic acid; 14.15 g, (82% yield), white solid, m.p. 294.1-295.5° C. Mass Spectrum: m/z, 255 (M+), 238 (M—OH), 210 (M—COOH), 108. FT-IR (KBr; cm−1): 3051 (br; OH), 1684 (CO), 1609, 1424, 1407, 1291, 970, 756. Anal. Calcd for C14H9NO2S: C, 65.87; H, 3.55; N, 5.49; S, 12.56%. Found: C, 65.71; H, 3.96; N, 5.30; S, 12.66%. NMR: not available due to poor solubility.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([C:17](=O)[C:18]([OH:20])=[O:19])[CH:8]=[CH:9][C:10]=1[S:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[K+].O>C(OCC)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:17][C:18]([OH:20])=[O:19])[CH:8]=[CH:9][C:10]=1[S:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)C(=O)c1ccc(SC2CCCC2)c(Cl)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)Cc1ccc(SC2CCCC2)c(Cl)c1
Temperature: -78 °C

Procedure:
Hydrazine hydrate (10 equiv.) is placed in a three neck flask fitted with an overhead mechanical stirrer and a reflux condenser and cooled in a dry ice acetone bath at −78° C. After the solution reached −50° C. the bath is removed and (3-chloro-4-cyclopentylsulfanyl-phenyl)-oxo-acetic acid (15.00 mmol) is added in one portion. It is then heated in an oil bath to 80° C. After the reaction is at 80° C. it is treated with potassium hydroxide (0.60 equiv.) and stirred vigorously. When the reaction returns to 80° C. a second portion of potassium hydroxide (0.60 equiv.) is added and allowed to cool back to 80° C. This cycle is repeated two more times adding potassium hydroxide (0.60 equiv.) each time. The reaction is then heated at 100° C. for 16 h. It is then cooled to 25° C. and water (3 mL) added to the reaction. It was then transferred to a separatory funnel and another portion of water (3 mL) is added and diethyl ether (10 mL). The layers are separated and the aqueous layer separated into a flask. The organic layer is then extracted with water (5 mL) and this aqueous layer combined with the first. To the aqueous layer is then added heptane (5 mL) and stirred vigorously. This solution is cooled to 0° C. in an ice bath and is treated dropwise with concentrated hydrochloric acid (˜7 mL) over 30 min until the aqueous layer is at pH=2 keeping the temperature of the solution below 50° C. during the addition process. It is then allowed to cool to 25° C. and stirred for 3 h. It is then filtered to remove the solids and the solids are washed with 1N aqueous hydrochloric acid (1.5 mL), water (2×1.5 mL), heptane (5 mL) and 1:1 heptane:diethyl ether (5 mL) and the solid is then dried in a vacuum oven to afford (3-chloro-4-cyclopentylsulfanyl-phenyl)-acetic acid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13]O>>[CH3:13][O:1][CH:2]1[O:10][CH:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[CH:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: COC1OC(CO)[C@@H](O)C(O)[C@H]1O
Temperature: 160 °C
Reaction time: 0.03 h

Procedure:
A mixture of methanol and glucose was initially charged in a stirred vessel A. The fraction of glucose was 30% of the methanol fraction. The mixture was conveyed by a suitable pump B at a pressure of 120 bar continuously through the reactor C. The tubular reactor C was heated to a temperature of 160° C. by the heater D. A carrier stream comprising pure methanol from the reservoir F was heated to approx. 300° using the preheater G. At the mixing point H, the carrier stream was mixed with the reactant stream and fed to the reactor. The preheating temperature was sufficiently high that reaction temperature was already present at the mixing point, so that the temperature gradient in the reactor was sufficiently low to prevent carbonization at the wall. The residence time in the tubular reactor was approx. 2 min. With the aid of the control valve E, the pressure was kept at the target value mentioned. At the outlet of the system, the reacted product mixture was collected. According to HPLC, the product mixture contained 3% product.
Reaction SMILES: [OH:1][C@@H:2]([C:19]1[C:20]([CH3:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[O:23][CH2:22]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12]C(C)(C)C)=[O:11])[CH2:6][C@H:5]1[CH2:17][OH:18].FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(O[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=O>C(Cl)Cl>[OH:1][C@@H:2]([C:19]1[C:20]([CH3:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[O:23][CH2:22]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:11])[CH2:6][C@H:5]1[CH2:17][OH:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1c([C@H](O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc2c1COC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1c([C@H](O)CN2CCN(C(=O)OCc3ccccc3)C[C@H]2CO)ccc2c1COC2=O

Procedure:
To a solution of (S)-tert-butyl 4-((S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2.57 g, 6.32 mmol) in methylene chloride (3 mL) was added trifluoroacetic acid (10 mL, 130 mmol) at rt for 1 h. After removing the volatiles under reduced pressure the residue was dissolved in methylene chloride (100 mL). To the above solution was added triethylamine (4.40 mL, 31.6 mmol) and benzyl chloroformate (0.95 mL, 6.64 mmol) at 0° C. for 0.5 h. The reaction was quenched by water followed by addition of saturated sodium carbonate. The mixture was extracted with methylene chloride, dried over sodium sulfate, concentrated and the residue was purified by MPLC on a Biotage system using 40-100% EtOAc/hexane to give the title compound. LC/MS: (M+1)+: 441.11.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[O:17]=[C:18]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:63][C:64]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][C:65]=1[C:66](O)=[O:67]>CN(C=O)C.O>[Cl:63][C:64]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][C:65]=1[C:66]([N:38]1[CH2:39][CH2:40][N:35]([C:18](=[O:17])[CH2:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[O:22])[CH2:36][CH2:37]1)=[O:67]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 31.8 %

Procedure:
DIPEA (110 mg, 0.85 mmol) was added to a stirred solution of biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (100 mg, 0.22 mmol) in DMF (3 mL). HOBT (28.3 mg, 0.2 mmol) and EDCI.HCl (91.25 mg, 0.47 mmol) were then added. After 2 minutes 2,5-dichlorobenzoic acid (36.4 mg, 0.19 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the product was precipitated and isolated by filtration to afford crude product, which was purified by preparative HPLC (Column: Zorbax-XDB-9.4×250 mm, 5 μm, mobile phase: A-0.1% Trifluoroacetic acid, B-Acetonitrile, Flow: 7 ml/min). The product obtained was extracted with ethyl acetate and the ethyl acetate layer was washed with NaHCO3 solution, saturated brine solution, dried over sodium sulphate and concentrated to afford 30 mg (26.5% yield) of biphenyl-4-carboxylicacid {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 99.5%, 1H NMR: (DMSO) δ 8.6 (t, 1H), 8.0 (d, 2H), 7.7 (q, 4H), 7.5 (m, 5H), 7.4 (t, 1H), 4.25-4.1 (m, 2H), 3.8-3.6 (m, 4H), 3.5-3.4 (m, 2H), 3.25 (m, 2H).
Reaction SMILES: COC(=O)[NH:4][C:5]1[O:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.[C:18]1([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Cu]I>[CH3:16][O:15][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[O:6][C:7]=2[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccccc2)c2oc(N)nc12
Temperature: 80 °C
Yield: 35.3 %

Procedure:
To a stirred solution of 820 mg (2.36 mmol) (7-iodo-4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester in 20 ml N,N-dimethylformamide were added 1.17 ml (3.58 mmol) phenyltri-n-butylstannane, 162 mg (0.18 mmol) tris(dibenzylideneacetone) dipalladium(0), 65 mg (0.21 mmol) triphenylarsine and 208 mg (1.09 mmol) copper(I) iodide. The mixture was heated at 80° C. for 16 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) followed by trituration in ether afforded 200 mg 4-methoxy-7-phenyl-benzooxazol-2-yl-amine as a white solid. ES-MS m/e (%): 241 (M+H+, 100).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[CH:7]=[CH:6][C:5]=12.[OH-].[Na+].Cl>CO>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)c1ccc2nonc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nonc2c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a room temperature, stirred solution of ethyl benzo[c][1,2,5]oxadiazole-5-carboxylate (0.7 g, 3.626 mmol) in MeOH (30 mL) was added 10% NaOH solution (6 mL) and the reaction mixture was then stirred at 40° C. for 3 h. The reaction mixture was then acidified to pH ˜2 with 2 N HCl and the aqueous layer was extracted with DCM (3×150 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford benzo[c][1,2,5]oxadiazole-5-carboxylic acid (0.49 g, 82%) as a solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:31]=[CH:30][C:29]4[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=4[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.O.CC(=O)OCC>C1COCC1>[CH3:32][C:28]1([CH3:33])[CH2:27][CH2:26][C:25]([CH3:34])([CH3:35])[C:24]2[CH:23]=[C:22]([C:20]3[N:21]=[C:17]([N:14]4[CH2:15][CH2:16][CH:11]([NH:10][CH2:9][CH:7]5[CH2:8][CH:6]5[CH2:4][OH:3])[CH2:12][CH2:13]4)[S:18][CH:19]=3)[CH:31]=[CH:30][C:29]1=2
Reactant: CCOC(=O)C1CC1CNC1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCC5CC5CO)CC4)n3)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
49 mg (0.10 mmol) of 2-({1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamino}methyl)cyclopropanecarboxylic acid ethyl ester from step a were dissolved in 2 ml of THF under nitrogen. 475 μl of a 1M diisobutylaluminium hydride solution in THF were added dropwise. The mixture was stirred at 60° C. overnight, water and EA were added, the mixture was filtered through Cellite, evaporated and purified by means of flash chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[Li+].CC([N-]C(C)C)C.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>C1COCC1>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([S:9][CH3:10])=[N:5][C:6]=1[Cl:8])[OH:23]
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: O=Cc1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C(O)c2ccccc2Cl)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (Aldrich) (5.0 g, 25.64 mmol) in dry THF (130 mL) at −78° C. under nitrogen was slowly added a solution of 2.0 M LDA (23.0 mL, 1.8 eq) in THF via a syringe. The resulting mixture was stirred at −78° C. for an additional 20 minutes, after which 2-chlorobenzaldehyde (Aldrich) (7.2 mL, 2 eq) was added dropwise via a syringe. The reaction mixture was stirred for an additional 30 minutes at −78° C. and then quenched with saturated ammonium chloride solution. Ethyl acetate was added, and the mixture was allowed to warm to room temperature. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude product (14.2 g) as an oil. Purification using Flash Column Chromatography on Silica Gel, eluting with 5% ethyl acetate in hexanes gave the title compound (8.60 g, (M+H)+=336, M.P.=109.5-112.5° C.) which crystallized upon standing to give a white solid.
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[I:12][C:13]1[CH:22]=CC2[C:15](=[CH:16][NH:17][C:18](=O)[N:19]=2)[CH:14]=1>ClCCCl>[I:12][C:13]1[CH:22]=[C:7]2[C:16](=[CH:15][CH:14]=1)[N:17]=[CH:18][N:19]=[C:6]2[Cl:11]
Reactant: O=c1nc2ccc(I)cc2c[nH]1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C

Procedure:
To a stirred solution of DMF (6.3 mL) in DCE (20 mL) cooled to 0° C. was added dropwise a solution of oxalyl chloride (60 mL of a 2M solution in DCE). After addition was complete, the cooling bath was removed and 6-iodo-3H-quinazolinone (10 g, 36.8 mmol) was added as a solid. The resulting mixture was heated to reflux under nitrogen for 3 hours. Upon cooling to room temperature, the reaction was quenched cautiously with H2O. CH2Cl2 was added and the bilayer transferred to a separatory funnel. The aqueous layer was extracted with CH2Cl2 (2×50 mL) and the combined organic layers dried (Na2SO4). The solvent was removed in vacuo to provide a yellow solid which was triturated with diethyl ether to remove any remaining impurities. The resulting yellow solid obtained by filtration was shown to be pure by NMR. 1HNMR (CDCl3, 400 MHz): δ: 9.05 (s, 1H), 8.65 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 1H).