Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](Br)=[CH:20][C:19]=1[C:33]1[O:37][N:36]=[C:35]([CH3:38])[C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[CH:48]=[CH2:49]>C(O)CCC.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:52]([O:51][C:47](=[O:50])[CH:48]=[CH:49][C:21]1[CH:20]=[C:19]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[C:34]=2[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:23][C:22]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(-c2c(C)noc2-c2cc(C=CC(=O)OC(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Temperature: 140 °C
Yield: 52.2 %

Procedure:
Diisopropylethyl amine (1 ml, 5.7 mmol) was added to a suspension of 5-(2,4-Bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (0.56 g, 1.0 mmol) in tert-butyl acrylate (1 ml, 6.8 mmol) and 1-butanol (8 ml) under a nitrogen atmosphere. Dichlorobis(tri-o-tolylphosphine)palladium (II) (cat.) was added and the suspension heated, 140° C. for ˜18 hrs., to give a yellow/green solution. The solution was allowed to cool and concentrated to a yellow/green gum. The crude product was purified by column chromatography, silica, eluting with ethyl acetate/hexane (1:9), to give 3-{2,4-Bis-benzyloxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-phenyl}-acrylic acid tert-butyl ester as a yellow/green gum (315 mg). Starting material (170 mg) was recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:18]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:30][CH:29]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1cc2c(Cl)c(C#N)cnn2c1
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Product: CCOC(=O)c1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnn2c1
Yield: 53 %

Procedure:
Compound 403 was prepared from 403C and 4-phenoxy-phenylamine by a route analogous to that used for the preparation of 388D. Yield: 53%. MS Found: (M+H)+=399.2; 1H NMR (CDCl3) δ 8.1 and 7.9 (s, 1H each), 7.3 (m, 2H), 7.26 (m, 2H), 7.2 (m, 2H), 7.15 (m, 4H), 6.2 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:46][O:47][CH2:48][CH2:49][CH2:50][NH2:51]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:51][CH2:50][CH2:49][CH2:48][O:47][CH3:46])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: COCCCN
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCCNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, 3-methyoxypropylamine (12 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-{1-[2-(3-methoxy-propylcarbamoyl)-ethyl]-1H-pyrazol-3-yl}-propionamide (16 mg, 27%) as a white solid: ESI-LRMS m/e calcd for C25H35ClN4O5S [M+] 538.2, found 539.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.21 (m, 2H, CH2), 1.43-1.97 (m, 10H, 5×CH2), 2.17-2.28 (m, 1H, CH), 2.61 (t, J=6.3 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.27-3.34 (m, 2H, CONCH2), 3.31 (s, 3H, OCH3), 3.41-3.46 (m, 2H, OCH2), 3.55 (t, J=7.5 Hz, 1H, CH), 4.30 (t, J=6.3 Hz, 2H, NCH2), 6.19 (brm, 1H, NH), 6.60 (d, J=2.3 Hz, 1 H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 8.08 (d, Jo=8.2 Hz, 1H, Ar), 8.13 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[O:13]1[CH:17]=[CH:16][C:15]([Li])=[CH:14]1>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([C:15]1[CH:16]=[CH:17][O:13][CH:14]=1)([C:15]1[CH:16]=[CH:17][O:13][CH:14]=1)[OH:6]
Reactant: [Li]c1ccoc1
Reactant: COC(=O)c1cc(Br)ccc1N
Product: Nc1ccc(Br)cc1C(O)(c1ccoc1)c1ccoc1

Procedure:
Prepared from methyl 2-amino-5-bromobenzoate and 3-furyllithium following the procedure described in example 24. 1H NMR (DMSO-d6): δ 7.6 (t, J=1.73 Hz, 2H), 7.25 (q, J=1.51, 0.81 Hz, 2H), 7.10 (q, J=8.46, 2.43 Hz, 1H), 6.79 (d, J=2.43 Hz, 1H), 6.56 (d, J=8.46 Hz, 1H), 6.46 (d, J=8.46 Hz, 1H), 6.39 (q, J=1.73, 0.81 Hz, 2H), 5.35 (s, 2H); MS (ESI) m/z 332/334 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH:15]1([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:19]2=[O:34])[CH2:17][CH2:16]1.[H-].[Na+]>CN(C=O)C.CO>[CH:15]1([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:29][CH:28]=3)[C:19]2=[O:34])[CH2:17][CH2:16]1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(Oc2ccc(-n3c(=O)n(C4CC4)c4cccnc43)cc2)nc2cccnc21
Temperature: 180 °C
Yield: 53.7 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (79 mg) was added to a solution of 1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and NaH (17.96 mg) in DMF (2 ml) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)N1C=CC=CC1.[NH2:43][C:44](=[N:48]O)[C:45]([NH2:47])=[O:46]>CN(C)C=O>[NH2:48]/[C:44](=[N:43]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[C:45]([NH2:47])=[O:46]
Reactant: NC(=O)C(N)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: CN(C)N1C=CC=CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (3.47 g, 11.6 mmol) in dimethylformamide (21 ml) was treated with 1,1′-carbonyldiimidazole (1.97 g, 12.2 mmol) and the mixture was stirred at ambient temperature for 1 hour. N-Dimethylaminopyridine (1.43 g, 11.7 mmol) was then added in one portion, followed by the addition of 2-amino-2-(hydroxyimino)acetamide (1.25 g, 12.1 mmol, Helv.Chim.Acta; 47; 1964; 33-46). The resulting mixture was stirred at room temperature for 24 hours. The mixture was partitioned between ethyl acetate and a 10% solution of citric acid in demineralised water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with demineralised water (×4) and brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was crystallised from n-hexane, the precipitate was collected by filtration and dried in vacuo to afford the title compound as a colourless solid (3.30 g, 74% yield).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].C[N:17](C)C1C=CC=CC=1>>[NH2:17][C:9]1[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: c1ccc(Sc2cccnc2)cc1
Reactant: CN(C)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Product: Nc1ncccc1Sc1ccccc1

Procedure:
A mixture of 59.1 g. (0.316 mole) of 3-phenylthiopyridine, 14.7 g. (0.318 mole) of sodium amide and 84 gms. of dimethyl aniline is heated at 150°-160° C. for 6 hours. After dilution with 100 ml. of water, the reaction mixture is extracted with chloroform. The combined extracts are washed with water and dried. Evaporation of the solvent in vacuo yields an oily residue. The residue is triturated with three 100 ml. portions of petroleum ether yielding 17 gm. of crude insoluble product. Proton magnetic resonance spectroscopy indicates the material is a 50/50 mixture of 2- and 6-amino derivatives. The isomers are separated on silica gel eluted with 10% ethylacetate 90% methylene chloride affording pure 2-amino 3-(phenylthio) pyridine, m.p. 108°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([NH2:32])[S:31][C:27]=2[CH:26]=1>>[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([NH:32][C:17](=[O:19])[C:16]3[CH:15]=[CH:14][C:13]([S:10](=[O:12])(=[O:11])[N:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH3:22])=[CH:21][CH:20]=3)[S:31][C:27]=2[CH:26]=1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: COc1ccc2nc(N)sc2c1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc4ccc(OC)cc4s3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 6-methoxybenzo[d]thiazol-2-amine (47 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(6-methoxybenzo[d]thiazol-2-yl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide as a yellow solid. Yield: 26 mg (21%). 1H-NMR: 8.28 (d, J=8.5 Hz, 2H), 7.74-7.61 (m, 4H), 7.08 (dd, J=9.0, 2.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H), 6.91-6.88 (m, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: C([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])(OC(C)(C)C)=O.[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N[C@H](C(O)=O)CO)(=O)CCCCCCC/C=C\CCCCCCCC.N1C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:8][C@H:9]([C:12]([O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:13])[CH2:10][OH:11]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](CO)C(=O)O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC(=O)[C@@H](N)CO
Temperature: 25 °C

Procedure:
0.03 moles of N-Boc-serine was constantly stirred under nitrogen in 100 mL of chloroform. 0.03 mole of oleoyl chloride was dissolved with 100 mL of chloroform and added to this heterogeneous mixture of N-Oleoylserine and followed by adding 10 mL of anhydrous pyridine. The reaction for 30 minutes under constantly stirring at room temperature, the mixture turned to homogeneous and the reaction was completed when no detectable oleoyl chloride was in the mixture. The bulk solvent was removed under vacuum and the crude product was used to next step without further purification. The resulting product (% of yields 75-80) is showed in Chemical Structure 4.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH:24]2[CH2:25][CH2:26][CH:20]1[CH2:21][C:22](=[O:27])[CH2:23]2)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH:24]2[CH2:25][CH2:26][CH:20]1[CH2:21][C:22]([OH:27])([C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=1)[CH2:23]2)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Brc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccc3ccccc3c1)C2
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a −78° C. solution of 6.20 g (29.9 mmol) 2-bromonaphthalene and 125 mL THF is added 12 mL of 2.5 M n-BuLi/hexanes. After stirring at −78° C. for 30 mins a solution of 6.40 g (28.4 mmol) 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 14 mL THF is added dropwise. The reaction is allowed to proceed at −78° C. for 30 mins and then warmed to 23° C. over 6 h. After quenching with 100 mL 1N NaOH and extraction with 3×100 mL of EtOAc, the combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles removed. Flash chromatography in SiO2 gel, eluting with hexanes/EtOAc (4/1 to 1/1) gives 7.00 g (19.8 mmol, a 66% yield) of the title compound as a white solid. MS (ES) m/z 354 (M++H, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][N:9]2[C:13]([CH:14]=[CH:15][C:16](OCC)=[O:17])=[C:12]([Cl:21])[N:11]=[C:10]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].C([Al+]C(C)C)(C)C>C1COCC1.CCOCC>[N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([Cl:21])[N:11]=[C:10]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(C=CC(=O)OCC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.5 g of 3-[1-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propenoic acid, ethyl ester, E isomer in 20 mL of THF was cooled with an ice bath, 1.7 mL of 1.5M diisopropylaluminum hydride (in toluene) was added slowly. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched with 3 mL of conc. NH4Cl solution and the mixture was stirred for an additional 30 minutes. During this period an extensive gel-like material formed. The reaction mixture was further diluted with ether and filtered through celite. The filtrate was concentrated and the crude product was purified by flash column chromatography on silica gel (Hexane:EtOAc=1:1 elution). The desired compound was obtained as a thick liquid; NMR (200 MHz, CDCl3): δ6.5-6.15 (m, 2H); 5.21 (s, 2H); 4.25 (d, 2H, J=4.5 Hz); 2.35 (t, 3H, J=7.4 Hz); 1.68 (m, 2H); 1.34 (m, 2H); 0.86 (t, 3H, J=7.4 Hz).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]=2)[C:5]1=O.Cl>O1CCCC1.CO>[CH3:3][C:4]1[CH2:12][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]=2
Reactant: CC(C)Cc1ccc2c(c1)CC(C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2ccc(CC(C)C)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
2.4 g (62 mmol) of sodium borohydride were added to a solution of 8.3 g (41 mmol) of 1 in 50 ml of tetrahydrofuran/methanol (2:1), and the mixture was stirred at room temperature for 16 hours. 50 ml of conc. aqueous HCl were subsequently added, and the mixture was extracted 3 times with 50 ml of diethyl ether in each case. The combined organic phases were dried (MgSO4) and freed from solvent on a rotary evaporator. The residue was taken up in 100 ml of toluene, 0.4 g of p-toluenesulfonic acid was added, and the mixture was refluxed for 2 hours. The reaction mixture was washed twice with 50 ml of saturated aqueous NaHCO3 solution in each case and freed from solvent on a rotary evaporator. The residue was purified by chromatography on 400 g of silica gel (hexane), giving 7.17 g (95%) of 2 as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:7]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:7]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])=[C:6]([CH:28]([CH3:29])[CH3:30])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a 1:1 mixture of olefins): δ 0.75-0.87 (m, 3 H), 1.13-1.37 (m, 14 H), 1.65-2.0 (m, 2 H), 3.20-3.51 (m, 2 H), 4.30 (m, 1 H), 4.42 (m, 1 H), 5.31-5.50 (m, 1 H), 6.0 (m, 1 H), 7.05 (m, 1 H), 7.28 (m, 1 H), 7.47 (m, 1 H). Rf0.38 (10% ethyl acetate/n-hexane).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=[N:12][CH:11]=2)=O)=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.[CH3:24][NH:25][NH2:26].N1C=CC=CC=1>C(#N)C>[Cl:23][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[N:25]([CH3:24])[N:26]=[C:8]([C:10]3[N:14]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=4)[CH:13]=[N:12][CH:11]=3)[C:7]=12
Reactant: CNN
Reactant: CCc1ccc(-n2cncc2C(=O)c2c(Cl)ncnc2Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCc1ccc(-n2cncc2-c2nn(C)c3ncnc(Cl)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4,6-dichloropyrimidin-5-yl)[1-(4-ethylphenyl)-1H-imidazol-5-yl]methanone (C21) (136 mg, 0.392 mmol) in acetonitrile (3 mL) was added to a solution of methylhydrazine (18.1 mg, 0.393 mmol) in acetonitrile (3 mL). After addition of pyridine (41 mg, 0.52 mmol), the reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptane) afforded the product, along with recovered starting material (35 mg, 0.10 mmol). Yield: 81 mg, 0.24 mmol, 61% (82% based on recovered starting material). LCMS m/z 339.0 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.21 (t, J=7.6 Hz, 3H), 2.62 (q, J=7.6 Hz, 2H), 4.11 (s, 3H), 7.11-7.15 (m, 4H), 7.52 (d, J=0.8 Hz, 1H), 7.85 (d, J=1.0 Hz, 1H), 8.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:24]([O:23][C:21]([CH2:20][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21

Procedure:
A mixture of 4.00 g (14.9 mmol) of tert-butyl 5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIa), 3.19 g (16.4 mmol) of tert-butyl bromoacetate and 7.28 g (22.3 mmol) of cesium carbonate in acetonitrile (80 ml) was heated under reflux for 3 h. The solvent was removed in vacuo, the residue was mixed with water, and the aqueous mixture was extracted four times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% ethyl acetate in dichloromethane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[Br:12]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 22 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). NMR (500 MHz, DMSO) δ 8.19 (1H, d, J=8.1 Hz), 7.06 (br. s, 2H), 6.64 (d, 1H, J=14.3 Hz).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].[NH2:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:13]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(Br)c1
Reaction time: 1 h

Procedure:
0.056 mL of triethylamine and 0.029 mL of 3-bromobenzoyl chloride were added to 3.0 mL of methylene chloride solution containing 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(3-bromobenzamido)-4-phenoxybenzoate.