Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=O>>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1cc2ccccc2[nH]1

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 1H-indole-2-carbaldehyde (32 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[CH3:20][C:21](CBr)=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:20][CH2:21][CH3:22])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: C=C(C)CBr
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.2 %

Procedure:
A mixture of the product from Example 232b (56 mg, 0.17 mmol), 2-methyl-3-bromo propene (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmole) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (55 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POCl3 (60 mL, 644 mmol) and N,N-dimethylaniline (8 mL, 63.1 mmol) was heated under reflux for 2 h. The excess POCl3 was removed in vacuo, the residue poured into ice, and the resulting precipitate collected by filtration. The crude solid product 2,4-dichloro-quinazoline (6.5 g, 53% yield) was washed with water and dried under vacuum for next step use without further purification. To a solution of the 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) was added 5-methyl-1H-pyrazol-3-yl amine (3.2 g, 32.9 mmol) and the resulting mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 4.0 g (93% yield) of (2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of the (2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19 mmol) in DMF (1.0 mL) was added m-tolyl boronic acid (0.38 mmol), 2M Na2CO3 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). The flask was flushed with nitrogen and the catalyst PdCl2 (dppf) (0.011 mmol) added in one portion. The reaction mixture was then heated at 80° C. for 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate was collected by filtration, washed with water, and purified by HPLC to afford III-50 as a pale yellow solid (61 mg, 75%): 1H NMR (500 MHz, DMSO-d6) δ12.3 (br s, 1H), 10.4 (br s, 1H), 8.75 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.78 (s, 2H), 7.55 (m, 1H), 7.45 (m, 1H), 7.35 (m, 1H), 6.80 (s, 1H), 2.47 (s, 3H), 2.30 (s, 3H); MS 316.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([F:20])[C:14]([O:18][CH3:19])=[C:15]([F:17])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:15]1[CH:16]=[C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:12]=[C:13]([F:20])[C:14]=1[O:18][CH3:19]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)cc(-c2ccncc2)cc1F

Procedure:
In a microwave vial, a mixture of pyridin-4-ylboronic acid (160 mg, 1.3 mmol), 5-bromo-1,3-difluoro-2-methoxybenzene A5a (223 mg, 1 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) is dissolved/suspended in dimethylformamide (3 mL). To the mixture are added cesium carbonate (978 mg, 3 mmol) and water (3 mL). The vial is sealed and subjected to microwave irradiation (150° C., 15 min). The mixture is filtered through a syringe filter and washed with ethyl acetate. Water is added and the mixture extracted with ethyl acetate (4×). The organic phase is dried over sodium sulfate and concentrated. The crude material is purified by flash chromatography (ethyl acetate/hexanes gradient) to afford 4-(3,5-difluoro-4-methoxyphenyl)pyridine A5b as a white solid: 1H-NMR (400 MHz, CDCl3) δ 8.69 (d, J=6 Hz, 2H), 7.44 (d, J=6 Hz, 2H), 7.22 (d, J=9.6 Hz, 2H), 4.09 (s, 3H); MS calcd. for C12H10F2NO ([M+H]+): 222.1, found: 222.1.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH:13]([C:22]2[C:23]([CH3:34])=[N:24][O:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[N:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([O:37][C:38](=[O:58])[CH2:39][C:40]1([C:43]2[CH:48]=[CH:47][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][CH:44]=2)[CH2:42][CH2:41]1)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:58])[CH2:39][C:40]1([C:43]2[CH:48]=[CH:47][C:46]([C:30]3[CH:31]=[CH:32][C:27]([C:26]4[O:25][N:24]=[C:23]([CH3:34])[C:22]=4[CH:13]([C:10]4[O:9][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:12][N:11]=4)[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:28][CH:29]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41]1)[CH3:36]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O[Si](C)(C)C(C)(C)C)c1nnc(Cc2ccccc2)o1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O[Si](C)(C)C(C)(C)C)c4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2-benzyl-5-[[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(tert-butyl-dimethyl-silanyloxy)-methyl]-[1,3,4]oxadiazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:29])/[C:4](=[N:25]\[N:26]([CH3:28])[CH3:27])/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH3:27][N:26]([CH3:28])/[N:25]=[C:4](/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1)\[C:3]([OH:29])=[O:2]
Reactant: COC(=O)/C(=N\N(C)C)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)/N=C(\C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 69.1 %

Procedure:
A mix of (Z)-alpha-(dimethylhydrazono)-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid methyl ester (0.45 g) in warm methanol (3 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL), heated on the steam bath for 2 hours, and the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.3 g of pure (Z)-alpha-(dimethylhydrazono)-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid as a colorless solid, mp 136° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[NH:12])[NH:10]O)=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].CCCC(C)C>CO.C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:12][C:14]([C:13]([O:17][CH2:18][CH3:19])=[O:16])=[CH:15][N:10]=2)=[CH:4][CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: N=C(Cc1ccc(Cl)cc1)NO
Solvent: CCCC(C)C
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc(Cc2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Yield: 7 %

Procedure:
4-Chloro-N-hydroxy-benzeneethanimidamide (1.0 g) and ethyl propiolate (0.53 g) were dissolved in methanol (20 ml), heated under reflux for 20 hours and cooled to room temperature. The residue was dissolved in diphenylether, heated under reflux for 1 hour, cooled to room temperature and iso-hexane (300 ml) added. A solid was produced which was collected by filtration, triturated under ether and dried to give the product as a solid (0.1 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][C:8]([N:10](C)C)=O.[CH2:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[S:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[O:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][NH:10][C:33](=[S:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3]1
Reactant: CCCCCCCCCCCCCCCCCCCCC(=S)Cl
Reactant: C1COCCN1
Reactant: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCC(=S)NCCN1CCOCC1

Procedure:
In a 200 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 2.6 g of morpholine and 50 ml of DMAc and the mixture was stirred under ice-cooling. To the solution was gradually added dropwise 7.5 g of 11-decylthioundecanoic acid chloride prepared in Synthetic example 13. After completion of dropwise addition, the mixture was returned to room temperature and further stirred for 2 hours. The reaction solution was diluted with 300 ml of toluene, and washed successively with a 5% aqueous sodium hydrogen carbonate solution, distilled water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to obtain crystals. The crystals were recrystallized from n-hexane to obtain 6.9 g of the title compound. Melting point: 61° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](OC)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C=CC([F:24])=CC=1C(O)=O>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([F:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: COC(=O)c1cc(OC)ccc1N
Product: COC(=O)c1cc(F)ccc1N

Procedure:
In a manner similar to that described above for methyl 2-amino-5-methoxybenzoate, 7.82 g of 2-amino-5-fluorobenzoic acid was converted to i-f (40%): MS m/z═170 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:16]([NH2:18])=O)[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2].COC(OC)[N:30]([CH3:32])C.CC(O)=O.O.[NH2:40]N>>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:4]1[C:3]([C:1]#[N:2])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]2)[S:6][C:5]=1[C:16]1[NH:30][CH:32]=[N:40][N:18]=1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: N#Cc1c(N2CCOC(CF)C2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(N2CCOC(CF)C2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Yield: 58.3 %

Procedure:
A solution of 4-cyano-3-(2,4-dichlorophenyl)-5-[2-(fluoromethyl)morpholin-4-yl]thiophene-2-carboxamide (38 mg, 0.000092 mol) in 1,1-dimethoxy-N,N-dimethylmethanamine (2.0 mL, 0.015 mol) was irradiated in microwave at 160° C. for 40 min. The solvent was removed and the residue was dissolved in AcOH (1.6 mL, 0.028 mol). Hydrazine monohydrate (0.3 mL, 0.006 mol) was added and the mixture was irradiated in microwave at 120° C. for 10 min. The reaction mixture was concentrated and the residue was treated with water, the solid was collected, dried to afford 4-(2,4-dichlorophenyl)-2-(2-(fluoromethyl)morpholino)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (23.5 mg, 60%). LCMS: (FA) ES+ 438, ES− 436; 1H NMR (400 MHz, d6-DMSO) δ: 8.01 (s, 1H), 7.57 (d, 1H), 7.39 (dd, 1H), 7.32 d, 1H), 4.59 (t, 1H), 4.47 (t, 1H), 4.08-4.01 (m, 1H), 4.00-3.81 (m, 5H), 3.32-3.20 (m, 1H), 3.18-3.09 (m, 1H).
Reaction SMILES: C1(N=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])C=CC=CC=1.[CH3:16][C:17]([CH3:21])([CH3:20])[CH:18]=[CH2:19].Cl.C1C[O:26]CC1>C1(C)C=CC=CC=1>[CH3:16][C:17]([CH3:21])([CH3:20])[CH2:18][CH2:19][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:8](=[O:26])[CH3:9]
Reactant: C1CCOC1
Reactant: CC(=Nc1ccccc1)c1ccccc1
Reactant: C=CC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1CCC(C)(C)C
Temperature: 150 °C
Yield: 85 %

Procedure:
In a 500 ml pressure reactor, N-phenyl-(1-phenylethylidene)-amine 63 mg (0.32 mmol), tristriphenylphosphine rhodium (I) chloride 6 mg (0.0065 mmol) and 3,3-dimethyl-1-butene 27 mg (0.32 mmol) were placed and dissolved in toluene 100 mg. While the reactor was stopped with a stopper, the reactants were heated at 150° C. for 2 hours with stirring. After completion of the reaction, the reactant mixture was dissolved in THF 3 ml and then combined with 1 N HCl soln. 10 ml, followed by hydrolysis with stirring for 12 hours at room temperature. After the mixture was three times extracted with Et2O and CH2Cl2, the organic layer was dried over MgSO4 and then filtered, and the solvent was evaporated under reduced pressure. The reactant mixture of the organic layer was purified by column chromatography on silica gel (5:2 hexane:ethyl acetate) to obtain 2-(3,3-dimethylbutyl)phenyl-1-ethanone 56 mg (0.27 mmol). Yield: 85%. Under the same conditions, various ketamines were employed. The results are given in Table 2, below.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCN3CCOCC3)cccc21
Solvent: CO
Product: NCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 4-morpholinylbutylphthalimide (231 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH3:16])[C:13](Cl)=O>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][N:10]=[C:11]2[CH:12]([CH3:16])[CH3:13])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C1=NCCc2ccc(Br)cc21

Procedure:
The desired product was prepared from 2-(4-bromophenyl)ethylamine and 2-methylpropanoyl chloride according to the procedure described in J. Org. Chem. 1991, 56, 6034.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[Li])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC1C=C(OC)C=CC=1Br)C1C=CC=CC=1.[Li]CCCC>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:10]([C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: [Li]c1ccc(OC)cc1OCc1ccccc1
Agent: COc1ccc(Br)c(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ncccc2C(=O)O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a THF (20 ml) solution of pyridine-2,3-dicarboxylic acid anhydride (1.92 g, 12.9 mmol) was added a THF solution of 2-benzyloxy-4-methoxyphenyllithium (10 ml), which was prepared from 2-benzyloxy-4-methoxyphenyl bromide (3.77 g, 12.9 mmol) and BuLi (1.6M hexane solution, 8.85 ml, 14.2 mmol) at -78° C., at -78° C. over a period of 5 min. The temperature of the mixture was raised to room temperature and the mixture was additionally stirred at the same temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 1N HCl and AcOEt. The organic layer was washed with 1N HCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 1N NaOH and the solution was washed with AcOEt and chloroform. The aqueous layer was acidified with conc. HCl and extracted with AcOEt. The AcOEt layer was washed with 1N HCl and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from chloroform and chloroform-ether to give 2-(2-benzyloxy-4-methoxyphenylcarbonyl)-3-pyridine carboxylic acid (2,03 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([CH:12]=1)[O:7][CH2:8][C@@H:9]1[CH2:11][O:10]1.[H][H].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(C(C)C)C(C)C)C>C(OCC)(=O)C.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:18](=[O:20])[CH3:19])=[C:6]([O:7][CH2:8][C@@H:9]2[CH2:11][O:10]2)[CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)cc1OC[C@@H]1CO1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(F)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
(2S)-2-[(5-fluoro-2-nitrophenoxy)methyl]oxirane (0.32 g, 1.5 mmol) was dissolved in ethyl acetate (40 ml). Platinum on charcoal (0.15 g) was added, and the mixture was stirred in the atmosphere of hydrogen for 3 h at room temperature and atmospheric pressure. The catalyst was filtered and washed on the filter with ethyl acetate (10 ml). Acetic anhydride (0.31 g, 0.28 ml, 3 mmol) and ethyldi(i-propyl)amine (0.39 g, 0.52 ml, 3 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 3 h, then washed with 1M sodium hydroxide (NaOH) (30 ml) and brine (30 ml), and dried with sodium sulphate (Na2SO4). Evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (from 25 to 75%) afforded the subtitle compound (0.21 g, 0.92 mmol, 61%) as a colourless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+].[Br:15]Br.CO>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:15][C:5]1[S:1][C:2]([C:6]([OH:9])([CH3:8])[CH3:7])=[N:3][CH:4]=1
Reactant: BrBr
Reactant: CC(C)(O)c1nccs1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(O)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
The product of Step 1 (8.97 g, 62.6 mmol) was dissolved in CHCl3 (125 mL), and NaHCO3 (5.79 g, 68.9 mmol) was added. Bromine (15.01 g, 94 mmol) was then added dropwise. After stirring for 2 h at room temperature, LC/MS showed a mixture of starting material and product (50% conversion). Additional NaHCO3 (2.89 g, 34.5 mmol), bromine (7.51 g, 47.0 mmol), and methanol (15 mL) were added, and the reaction was stirred for another 2 h at room temperature. The reaction was diluted with 10% Na2S2O3, neutralized with saturated NaHCO3, and extracted with dichloromethane (2×). The combined organic layers were dried (MgSO4), filtered and evaporated. Flash chromatography (0-15% ethyl acetate in toluene) afforded 9.38 g (67%) of 2-(5-bromo-1,3-thiazol-2-yl)propan-2-ol as a white solid. ESI: [M+H]+ m/z 221.9/223.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])[C:26](O)=[O:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[C@H:25]([C:22]1[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=1)[C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33]
Reactant: CCCC(CC(=O)OC)c1ccc(Cl)c(N)c1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OC)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
1.45 g (5.67 mmol) of (+/−)-methyl 3-(3-amino-4-chlorophenyl)hexanoate and 1.81 g (6.80 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 5.0 ml of pyridine and 10.0 ml of DMF, and 2.80 g (7.37 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then diluted with ethyl acetate. The mixture was washed with 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase initially cyclohexane, then cyclohexane/ethyl acetate 50:1). In two fractions, in total 2.02 g of the target product were obtained (70.6% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[O:33]1[C:37](=[O:38])[CH2:36][CH2:35][C:34]1=[O:39].CN(C=O)C.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][O:20][C:37](=[O:38])[CH2:36][CH2:35][C:34]([OH:39])=[O:33])[O:16][N:15]=2)=[N:10][CH:9]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 150 mg, 0.342 mmol), dihydrofuran-2,5-dione (83 mg, 0.83 mmol), and 4-dimethylaminopyridine (10.5 mg, 0.09 mmol) were added to DMF (2.5 ml) and pyridine (0.5 ml). The reaction was allowed to stir overnight at room temperature followed by addition to Et2O (100 ml). The precipitate was collected by filtration and washed with additional Et2O (2×20 ml). The precipitate was then suspended in CH2Cl2 (20 ml) and the precipitate was collected by filtration and then washed with additional CH2Cl2 (2×20 ml) to yield the product as a white solid (131 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:34]=1[NH2:35]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][C:5]([C:6]([NH:35][C:34]2[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:33]=2[CH3:32])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: Cc1cccc(C)c1N
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.9 %

Procedure:
To 4-chloro-2-methoxy-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl chloride (70 mg, 0.19 mmol) in DCM (0.5 mL) were added triethylamine (39 μL, 0.28 mmol) and 2,6-dimethylaniline (28 μL, 0.22 mmol). The mixture was stirred at rt for 12 hrs and was purified via a prep TLC plate eluting with ethyl acetate in hexane (30%) to give 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-benzamide (55.0 mg). MS [M+H]+460.2; tR=2.85 min (method 1)