Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:22]Br>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:22][CH:18]([C:15]1[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=1)[C:19]([OH:21])=[O:20]
Reactant: CCCCCCCCCCCCn1nnc(CC(=O)O)n1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCn1nnc(C(Br)C(=O)O)n1
Temperature: 45 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
The 2-dodecyltetrazoleacetic acid (4.7 g, 15.8 mmol) was suspended in carbon tetrachloride (5 mL) and warmed to 45° C. The solution was diluted by dropwise addition of bromine (2.6 g, 16.3 mmol), and the mixture was further heated to reflux with stirring for 5 hours. The solution was cooled to room temperature, diluted with 50 mL of ethyl acetate, washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo to give α-bromo-2-dodecyltetrazoleacetic acid (5.3 g, 86%) as an orange colored liquid;
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21](O)=O)=[C:17]([CH3:26])[C:16]=1[CH3:27]>>[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18](/[CH:19]=[CH:20]/[C:21]2[NH:1][C:2]3[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=3[N:8]=2)=[C:17]([CH3:26])[C:16]=1[CH3:27]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(C)c1C
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(C)c1C
Yield: 21.6 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.74 g (10.2 mmol) of 5,6-diamino-1,3-dimethyluracil and 2.42 g (11.8 mmol) of 4-methoxy-2,3-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from acetonitrile to give 750 mg (yield 22%) of Compound 84 as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[CH3:15].CC(O)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[CH3:15]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)COc1ccc(N)cc1C

Procedure:
A solution of 36.3 g (161 mmol) of the above prepared (2-methyl-4-nitro-phenoxy)-acetic acid methyl ester in 400 ml MeOH and 11.2 ml (177 mmol) AcOH was hydrogenated in the presence of 3.63 g 10% Pd/C for 7 h at atmospheric pressure. After removal of the catalyst the reaction was evaporated, dissolved in toluene and evaporated (5×) to give 32.5g of (4-amino-2-methyl-phenoxy)-acetic acid methyl ester as a brown crystalline residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10](O)[C:9]2=[O:21])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O>CN(C=O)C>[Cl:25][C:10]1[C:9](=[O:21])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12](=[O:13])[C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
After dissolving compound 6d (1.00 g, 3.33 mmol) in MC (10 ml) and anhydrous DMF (10 ml), oxalyl chloride (0.850 g, 6.66 mmoL) was added thereto and the agitation for 30 minutes was carried out. After the identification of the reaction progress with TLC, the reaction was terminated. Then, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the column chromatography was carried out with EA/HX ( 1/15). The suspension was carried out with HX to obtain compound 7d.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[NH4+].[Cl-].O>CN(C=O)C>[N:2]1[NH:15][N:16]=[N:17][C:1]=1[C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)COc1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(-c2nn[nH]n2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution methyl 2-(4-cyanophenoxy)acetate in DMF was treated with NaN3 and NH4Cl and stirred in an oil bath at 80° C. for 18 hours. Then, the mixture was poured into H2O and extracted with Et2O. The aqueous layer was acidified to pH 2-3 with HCl and the precipitate was collected to give methyl 2-(4-(2H-tetrazol-5-yl)phenoxy)acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[N:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:7][NH:8][C:9](=O)[C:10](F)(F)F)[CH3:2].[Br:22][C:23]1[N:27]2[N:28]=C(F)C=[CH:31][C:26]2=[N:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4](=[O:21])[N:5]([CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[CH:31][C:26]2[N:27]([C:23]([Br:22])=[CH:24][N:25]=2)[N:28]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CCOC(=O)N(CCNC(=O)C(F)(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)N(CCNc1ccc2ncc(Br)n2n1)c1ccccc1
Temperature: 85 °C
Yield: 52.1 %

Procedure:
Crude phenyl-[2-(2,2,2-trifluoro-acetylamino)-ethyl]-carbamic acid ethyl ester (2.2 g, 7.3 mmol) was combine with 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (892.5 mg, 4.1 mmol) and potassium carbonate [584-08-7] (2.9 g, 20.6 mmol) in a 20% (v/v) solution of water in 1,2-dimethoxyethane (25 mL) and heated to 85° C. for 5 d. The reaction mixture was then partitioned between water and ethyl acetate and the extract flash chromatographed (silica gel eluted with 100% ethyl acetate) to yield 863.1 mg of white crystalline powder, mp. 160-161° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (t, J=7.06 Hz, 2H) 2.51 (dt, J=3.58, 1.85 Hz, 1H) 3.35 (s, 1H) 3.46 (q, J=6.39 Hz, 2H) 3.90 (t, J=6.50 Hz, 2H) 4.04 (q, J=7.06 Hz, 2H) 6.65 (d, J=9.70 Hz, 1H) 7.19-7.25 (m, 1H) 7.31-7.39 (m, 4H) 7.48 (s, 1H) 7.69 (d, J=9.70 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 14.16, 38.85, 47.84, 60.82, 98.79, 112.62, 125.31, 125.99, 126.79, 128.63, 130.18, 136.35, 141.81, 153.79, 154.64. LRMS (ESI) m/z 403.9/405.9 [(M+H)]+, calc'd for C17H18BrN6O2: 404.27.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]1([Li])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:7]1([C:5]2[CH2:4][CH:3]=[CH:2][CH:1]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1C=CCC1
Solvent: CCOCC
Product: C1=CCC(c2ccccc2)=C1
Yield: 120.1 %

Procedure:
100 ml (1.2 mol) of 2-cyclopenten-1-one in 400 ml of diethyl ether are added dropwise to 2.3 mol of phenyllithium in 1000 ml of diethyl ether at −5° C. After hydrolysis and extraction of the aqueous phase with the diethyl ether, the combined organic phases are dried over sodium sulfate. After the solvent has been stripped off, 205 g of crude product are obtained. The product is heated to 180° C. for three hours in a vigorous argon stream in a
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:12])=[O:11]>C1(C)C=CC=CC=1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:10]([OH:11])([CH3:12])[CH3:9])=[N:3][CH:4]=1
Reactant: CC(C)=O
Reactant: Clc1cnc(Br)cn1
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cnc(Cl)cn1
Temperature: -78 °C
Yield: 56.1 %

Procedure:
2-Bromo-5-chloropyrazine (900 mg, 4.65 mmol) was dissolved in toluene (20 mL). The reaction vessel was flushed with nitrogen and cooled to −78° C. n-Butyllithium (2.5M solution in hexanes, 2.23 mL) was added slowly under stirring and allowed to stir for a further 10 minutes upon complete addition. Acetone (3.42 mL, 46.53 mmol) was added and the reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature and the solvent was removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed using saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The crude brown oil was purified by chromatography on silica (Biotage, 25 g cartridge), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (450 mg, 56%) as a yellow oil. Method B HPLC-MS: MH+ m/z 173, RT 1.31 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][CH2:21][CH3:22])[CH:3]=1.CN.[C:25]([BH3-])#[N:26].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:26][CH3:25])[C:12]=2[O:19][CH2:20][CH2:21][CH3:22])[CH:3]=1
Reactant: CCCOc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCOc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Yield: 57.7 %

Procedure:
4-Chloro-2-(3-formyl-2-propoxyphenoxy)benzonitrile (0.68 g, 2.2 mmol), methylamine (2M in methanol, 3.2 mL, 6.4 mmol) and sodium cyanoborohydride (0.15 g, 2.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (70 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (250 mg, 2.2 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-(3-methylaminomethyl-2-propoxyphenoxy)benzonitrile fumarate (567 mg, 59%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23](OC(ON=C(C#N)C(OCC)=O)=O)[CH:24]([CH3:26])[CH3:25]>O1CCCC1>[CH2:23]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:24]([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(C#N)=NOC(=O)OCC(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)COC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 142.7 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.7 ml) in dry tetrahydrofuran (15 ml), ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate (2.42 g) is added, and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine isobutyl ester (1.9 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH:10]([N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[C:32]([Cl:33])=[C:31]([CH3:34])[NH:30][C:29]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:35]([C:29]2[NH:30][C:31]([CH3:34])=[C:32]([Cl:33])[C:28]=2[Cl:27])=[O:36])[C@H:10]([N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(N=[N+]=[N-])C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])c(Cl)c1Cl
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Crude tert-butyl-4-amino-3-azidopiperidine-1-carboxylate (Intermediate 270, 3.3 mmol) was dissolved in anhydrous CH2Cl2 (10 ml) and DIEA (1.27 g; 1.6 ml; 9.9 mmol; 3 eq.). The solution was cooled to 0 C and 3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl chloride (736 mg; 3.5 mmol; 1.05 eq.) was added. The reaction was complete within 30 minutes. Dilute with CH2Cl2 and wash with H2O (×2), brine and dried over Na2SO4. Filter and concentrate. Purify by flash column chromatography (0-60% EtOAc/hexanes). Isolation gave 967 mg in 69% yield over the two-step sequence. LC/MS (ES−)[(M−H)+]: 415, 417 for C16H22Cl2N6O3.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])[O:6][CH3:7])[CH3:2].C(N(CC)CC)C.[CH3:19][N:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=[N:21]1>C1COCC1>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])/[C:5](=[N:8]/[C:25]([C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)=[O:26])/[O:6][CH3:7])[CH3:11]
Reactant: Cn1nccc1C(=O)Cl
Reactant: CCOC(OCC)C(=N)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(OCC)/C(=N/C(=O)c1ccnn1C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
To a stirred solution of diethoxyacetonitrile (60 g, 0.465 mol) in absolute methanol (150 mL) under an atmosphere of argon was added a solution of sodium methylate (2.5 g; 0.047 mol) in absolute methanol (20 mL), and the reaction mixture was stirred at room temperature until the nitrile disappeared completely (70–75 h). The reaction was monitored by 1H NMR. The reaction mixture was treated, while stirring, with CO2 until the precipitate of sodium carbonate ceased to form. The latter was filtered off and washed with methanol (50 mL). The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C. The resulting liquid was dissolved in ether (250 mL), filtered to remove the remaining inorganic salts, and evaporated again to give the crude methyl 2,2-diethoxyethanimidoate (71.0 g, 95%). It was distilled under vacuum through a 15-cm Vigreux column, affording 56.2 g (75%) of methyl 2,2-diethoxyethanimidoate (bp. 77–78° C. at 20–22 mm Hg) with a purity of more than 95% by 1H NMR. To a solution of the methyl 2,2-diethoxyethanimidoate (52.1 g, 0.321 mol) and triethylamine (49 mL, 0.353 mol) in absolute THF (300 mL) was added a solution of 1-methyl-1H-pyrazole-5-carbonyl Chloride (46.5 g, 0.321 mol, from Step 1) in absolute THF (150 mL) dropwise under an atmosphere of argon at 0–5° C. over a period of 2 h. The reaction mixture was stirred overnight at a room temperature. The residue the formed was filtered off, and the filtrate was evaporated on a rotary evaporator to give methyl (1Z)-2,2-Diethoxy-N-[(1-methyl-1H-pyrazol-5-yl)carbonyl]ethanimidoate (90 g) as a yellow viscous mass, which was used at the next stage without additional purification. The 90 g of the crude product N-acylated imidate ester obtained at the previous stage was dissolved in absolute dichloromethane (450 mL), and treated with methylhydrazine (17.1 mL, 0.321 mol) with stirring over a period of 10 min. The reaction mixture was stirred at room temperature for 3 h, washed with water (3×300 mL), and dried with anhydrous sodium sulfate. The solvent was removed under vacuum on a rotary evaporator, and the residue (56.5 g) was purified chromatographically on silica gel using hexane/ethyl acetate (1:2) as the eluent. The solvent was evaporated to give 40.1 g (47% based on 1-methyl-1H-pyrazole-5-carbonyl chloride) of the pure title product.
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[CH2:7]([C@@H:14]1[C@@H:22]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C@H:21]([CH3:28])[O:20][C:19](=[O:29])[C@@H:18]([NH:30][C:31](=[O:41])[C:32]2[C:37]([OH:38])=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][N:33]=2)[CH2:17][O:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:1]([O:4][CH2:5][O:38][C:37]1[C:32]([C:31](=[O:41])[NH:30][C@H:18]2[CH2:17][O:16][CH2:15][C@H:14]([CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C@@H:22]([O:23][CH2:24][CH:25]([CH3:26])[CH3:27])[C@H:21]([CH3:28])[O:20][C:19]2=[O:29])=[N:33][CH:34]=[CH:35][C:36]=1[O:39][CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OCBr
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccccc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccccc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1OCOC(C)=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
Bromomethyl acetate (48 uL, 0.49 mmol) was added to a suspension of N-((3S,7S,8R,9S)-7-benzyl-8-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (160 mg, 0.33 mmol), sodium iodide (NaI, 2.5 mg, 0.02 mmol) and sodium carbonate (Na2CO3; 56 mg, 0.53 mmol) in acetone (3 mL). The mixture was heated to 50° C. and stirred overnight. The suspension was diluted with acetone and filtered. The yellow solution was concentrated and purified by flash chromatography (50% EtOAc in hexanes) to furnish the product as a white foam (97 mg, 53%): IR (film) 3370, 3025, 2957, 2874, 1752, 1677 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=8.2 Hz, 1H), 8.27 (d, J=5.4 Hz, 1H), 7.34-7.23 (m, 2H), 7.20 (dd, J=7.2, 4.8 Hz, 3H), 6.95 (d, J=5.4 Hz, 1H), 5.80-5.64 (m, 2H), 5.13-4.92 (m, 2H), 4.02 (dd, J=11.7, 7.4 Hz, 1H), 3.90 (s, 3H), 3.54-3.28 (m, 5H), 3.14 (dd, J=11.7, 6.4 Hz, 2H), 2.40-2.23 (m, 1H), 2.06 (s, 3H), 2.01-1.82 (m, 2H), 1.50 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.81, 170.31, 163.18, 160.20, 145.79, 143.93, 142.15, 140.02, 129.21 (2), 128.44 (2), 126.10, 109.69, 89.41, 84.58, 79.26, 75.74, 72.34, 72.16, 56.19, 51.81, 47.45, 35.09, 29.19, 20.88, 19.50 (2), 18.83; ESIMS m/z 560.36 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>O>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:13][C:14](=[O:15])[NH:1]2)=[CH:7][C:8]=1[F:12]
Reactant: Nc1cc(Br)c(F)cc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(F)c(Br)cc2[nH]1
Temperature: 200 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a 100 mL round bottom flask, 2-amino-4-bromo-5-fluoro-benzoic acid (0.7 g, 0.003 mol) and urea (1.07 g, 0.0018 mol) were added. The reaction mixture was stirred at 200° C. for 2 h. The reaction mixture was allowed to reach 100° C. and water was added. The aqueous reaction mixture was refluxed for 5-10 min, cooled to room temperature, to get the precipitate. The solid was filtered and dried to afford the title compound (400 mg, 51%). This material was taken for next step without any further purification.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([OH:31])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:31]
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 49 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 49% yield: mp 107-108° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.44 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.23-7.19 (m, 1H), 5.59 (s, 1H), 4.55 (d, J=5.7 Hz, 2H), 4.47 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H), 2.55 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.2, 155.4, 153.5, 149.1, 148.6, 139.6, 135.8, 134.1, 130.5, 128.4, 125.8, 123.6, 122.1, 117.1, 47.5, 42.0, 41.8, 41.3, 17.2; MS (ES+) m/z 476.3 (M+1).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([OH:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1.[Cu-]=O>[O:10]([C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccccc1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=[Cu-]
Agent: Cl
Solvent: c1ccncc1
Product: c1ccc(Oc2cnc3[nH]ccc3c2)cc1
Temperature: 115 °C

Procedure:
To 1H-Pyrrolo[2,3-b]pyridin-5-ol (6, 645 mg, 4.81 mol) and copper(I) oxide (860 mg, 6.0 mmol) in pyridine (10 mL), bromobenzene (31, 422 uL, 4.01 mmol) was added. The mixture was heated to 115° C. for 24 hours. The reaction mixture was treated with 1N HCl and extracted with ethyl acetate. The organic layer was washed with NH4OH/NH4Cl (1:4), saturated aqueous NH4Cl twice, water, and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography (50-70% ethyl acetate/hexane) to provide the compound (P-0035, 88 mg, 10%). MS (ESI) [M+H+]+=211.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[Br:11].N1C=CC=CC=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=O>O>[Br:11][C:3]1[C:2]2[N:1]=[C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)[O:9][C:8](=[O:10])[C:7]=2[CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1c(Br)cncc1C(=O)O
Solvent: c1ccncc1
Solvent: O
Product: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2c(Br)cncc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
A mixture of 5-bromo-4-aminonicotinic acid 46 (10.5 g, 48.4 mmol) and pyridine (60 mL) was heated at 60° C. until homogeneous. 3-(trifluoromethyl)benzoyl chloride 2 (8.0 mL, 53.0 mmol) was added and stirring continued for 2 h. H2O (200 mL) was added and the mixture cooled to 0° C. The resulting yellow precipitate was collected by filtration, rinsed with H2O (100 mL) then pentane (100 mL), and dried under vacuum to give the 47 (8.50 g, 47% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:15]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([OH:12])=O.[CH3:22][O:23][CH:24]([O:33][CH3:34])[CH2:25][NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:26]([CH2:25][CH:24]([O:33][CH3:34])[O:23][CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][O:7][CH2:6][CH2:5][C:4]2[CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:15]=[C:2]([F:1])[CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: Cn1cc(-c2cc(F)cc(CCOCCC(=O)O)c2)cn1
Product: COC(CN(C(=O)CCOCCc1cc(F)cc(-c2cnn(C)c2)c1)C1CCCCC1)OC

Procedure:
The subtitled compound (3.3 g) was prepared from 3-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 17, Step v)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii). MS [M+H-MeOH]+=430 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.81 and 7.80 (2×s, 1H), 7.19 (m, 1H), 7.09 (dt, J=10.0, 1.9 Hz, 1H), 6.80 (m, 1H), 4.52 and 4.36 (2×t, J=5.0 Hz, 1H), 4.00 and 3.64 (2×tt, J=3.6 and 11.7 Hz, 1H), 3.902 and 3.898 (2×s, 3H), 3.76-3.64 (m, 4H), 3.34 (s, 3H), 3.33 and 3.25 (2×d, J=5.1 Hz, 2H), 3.32 (s, 3H), 2.85 and 2.84 (2×t, J=6.2 Hz, 2H), 2.65 and 2.63 (2×t, J=6.1 Hz, 2H), 1.79-1.69 (m, 2H), 1.68-1.49 (m, 3H), 1.49-1.19 (m, 4H), 1.16-1.01 (m, 1H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.[N:33](=[CH:41][CH2:42]Cl)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Cl>>[N:33]1([CH2:41][CH2:42][S:16][C:13]2[S:12][C:11]([NH:10][C:8](=[O:9])[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: ClCC=NCCCCCCCl
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCCCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino)ethylchloride