Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:28]2[N:37]=[CH:36][C:35]3[C:30](=[C:31]([F:42])[CH:32]=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:34]=3)[C:29]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH2:24][CH3:25])[N:20]=2)[C:15](=[O:26])[N:14]([CH3:27])[CH:13]=1)(=O)C.C1COCC1.O>ClCCl>[C:38]([C:33]1[CH:34]=[C:35]2[C:30](=[C:31]([F:42])[CH:32]=1)[C:29](=[O:43])[N:28]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[CH:22][N:21]([CH2:24][CH3:25])[N:20]=4)[C:15](=[O:26])[N:14]([CH3:27])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:37]=[CH:36]2)([CH3:40])([CH3:39])[CH3:41]
Reactant: CCn1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)n1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCn1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
Into a 1 dram vial was added 142d (1 equiv) in a 4:1 mixture of THF and water (1 mL) Lithium hydroxide (1.5 equiv) was then added to the mixture and the reaction was stirred at room temperature for 16 hours. The reaction was then diluted with dichloromethane (3 mL) and washed with water (2×3 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by reverse-phase chromatography to give 142 (7.6 mg, 19% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.16 (s, 1H), 8.06 (d, J=2.5 Hz, 1H), 7.89 (m, 1H), 7.75 (dd, J=13.1, 1.9 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.51 (d, J=12.6 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 6.07 (s, 1H), 4.46 (br s 1H), 4.00 (q, J=7.2 Hz, 2H), 3.60 (s, 3H), 3.17 (s, 2H), 1.39 (s, 9H), 1.34 (t, J=7.2 Hz, 3H). ES-MS m/z 544.3 [M+1].
Reaction SMILES: [NH2:1][C:2]1([CH:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>C(Cl)Cl>[Cl:17][C:12]1[CH:11]=[C:10]([CH:8]([OH:9])[C:2]2([NH:1][S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:15]=[C:14]([Cl:16])[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(C(O)c2cc(Cl)cc(Cl)c2)CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC2(C(O)c3cc(Cl)cc(Cl)c3)CCCCC2)cc1
Temperature: 35 °C

Procedure:
To a stirred solution of (1-amino-cyclohexyl)-(3,5-dichloro-phenyl)-methanol and pyridine (100 μL, 1.24 mmol) in CH2Cl2 (4 mL) was added p-toluenesulfonyl chloride. The mixture was heated at ca. 35° C. for 8 hours. The mixture was applied to a 10 mL Chem Elut cartridge pre-wetted with 5% aqueous HCl (5 mL) and eluted with CH2Cl2 (25 mL). The eluate was applied to a second Chem Elut cartridge pre-wetted with saturated aqueous NaHCO3. The eluate from the second cartridge was evaporated to leave N-{1-[(3,5-dichloro-phenyl)-hydroxy-methyl]-cyclohexyl}-4-methyl-benzenesulfonamide (139 mg) as an oil. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.7 (d, 2H), 7.2 (s, 2H), 7.15 (d, 2H), 7.1 (s, 1H), 4.82 (s, 1H), 4.16 (s, 1H), 2.33 (s, 3H), 0.9-1.9 (m, 10H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[C:10](Cl)(Cl)[CH:11]([OH:13])O.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:24][OH:25].Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11](=[O:13])[CH:10]=[N:24][OH:25])=[CH:4][CH:3]=1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccc(Br)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a slurry of 4-bromo-phenylamine (10 g, 58.13 mmol) in water (200 mL) was added chloral hydrate (11.65 g, 69.76 mmol), sodium sulphate (50 g), hydroxylamine hydrochloride (12.8 g, 186 mmol) and conc. HCl (15 mL). The reaction mixture was then heated to 85° C. and stirred for another 2 h. After completion of the reaction, a solid separated out. The mixture was cooled to room temperature, filtered and washed with water (2-3 times) and dried to obtain the title compound as off white solid (12 g, 84.9%).
Reaction SMILES: [CH3:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][CH:14]([CH2:21][CH3:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:13][CH:14]([CH:15]([C:2]([OH:12])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:21][CH3:22]
Reactant: CCOC(=O)CC(C)CC
Reactant: CCCCCCCCCC(C)=O
Product: CCCCCCCCCC(C)(O)C(C(=O)OCC)C(C)CC

Procedure:
Pyrolysis of a sample of the prepared hydroxy-ester at about 300° C. for 2 minutes yields a 1:1 mixture of 2-undecanone and ethyl 3-methylvalerate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1.C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1
Reactant: COC(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)c(F)cc43)OC2(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(C(=O)O)cc1
Temperature: 60 °C

Procedure:
To a solution of methyl 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate (100 mg, 0.25 mmol) in a 1:1 mixture of THF/MeOH (5 mL/5 mL), was added 1M NaOH (2 mL). The mixture was heated in 60° C. bath for 1.5 hours, poured into 100 mL of water and acidified with 2M HCl (2 mL). The precipitates were filtered, washed with water, and dried in vacuum to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid as yellow solid. Yield: 90 mg, 93%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[N:31][N:30]=[N:29]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:29]3[N:30]=[N:31][CH:32]=[N:28]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3ncnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=444.3 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:40])[C@@H:37]([CH3:39])[NH2:38])=[CH:31][CH:30]=1)[CH3:21]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:40])[C@@H:37]([CH3:39])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1)[CH3:21]
Reactant: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccc(N2C(=O)N[C@H](C)C2=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 168.5 %

Procedure:
In a 50 mL round-bottomed flask N1-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 48, 170.0 mg) was dissolved in dichloromethane (5 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (35.7 mg, 0.292 mmol), triethylamine (0.203 mL, 1.460 mmol) and triphosgene (87 mg, 0.292 mmol) were added. The reaction mixture was stirred at 0° C. After 20 min, the reaction mixture was evaporated in vacuo affording yellow solid that was purified by silica gel chromatography (Biotage system, 10 g SNAP column) eluting with a gradient Cyclohexane/EtOAc from 2:1 to 1:3 in 20 CV; then 1:3 for 5 CV. The collected fractions afforded the title compound as a colourless oil (153.2 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH:8]([F:10])[F:9])=[N:6][CH:7]=1.[CH3:16][N:17](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1(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)C=CC=CC=1>[C:16]([C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH:8]([F:10])[F:9])=[N:6][CH:7]=1)#[N:17]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(Br)cnc1C(F)F
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1cc(C#N)cnc1C(F)F
Temperature: 100 °C

Procedure:
In a flask, dissolve ethyl 5-bromo-2-(difluoromethyl)pyridine-3-carboxylate (150 g, 536 mmol, 1.0 equiv) in DMF (1.5 L). Degas the resulting mixture by evacuating then backfilling the flask with nitrogen three times. Add zinc(II) cyanide (51 g, 434 mmol, 0.81 equiv), followed by tetrakis(triphenylphosphino)palladium (25.2 g, 21.8 mmol, 0.04 equiv). Heat the resulting suspension to an internal temperature of 100° C. for 3 h. Cool the mixture to room temperature; dilute with water (2 L); and extract with diethyl ether (3×2.5 L). Wash the combined organic phases with brine (3×2.5 L). Extract the combined aqueous phases with Et2O (2.5 L). Combine all organic phases, and dry over MgSO4. Remove the solids by filtration, and concentrate the filtrate under reduced pressure. Purify the resulting material by flash chromatography on silica gel (2 kg), eluting with a gradient of 1:1 DCM/isohexane to 100% DCM. Obtain the title compound as colorless oil, which solidifies on standing (114 g, 94.1%). MS (m/z) 227 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](C(O)=O)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C(=O)(O)[O-].[Na+].[Br:23]NC(=O)CCC(N)=O>CN(C=O)C.O.C(OCC)(=O)C>[Br:23][C:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:11][N:10]2[CH2:12][CH2:13][CH2:14][C:9]=12
Reactant: NC(=O)CCC(=O)NBr
Reactant: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c(-c2ccccn2)nn2c1CCC2
Yield: 70.5 %

Procedure:
Stir a mixture of 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (Preparation 3; 2 g, 8.7 mmol), sodium bicarbonate (3.3 g, 38.4 mmol) and N-bromosuccinamide (1.7 g, 9.6 mmol) in DMF (50 mL) at room temperature for 2 h. Dilute the crude mixture with 50 mL of water and 100 mL of ethyl acetate. Separate the ethyl acetate layer, extract with saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate to a solid mass. Purify by MPLC (SiO2, 50% ethyl acetate-hexane) to obtain the title compound (1.62 g, 70%) as a cream solid. MS ES+ m/e 264 (M+1), MS ES+ m/e 266 (M+2).
Reaction SMILES: N1CCC[C@H:2]1[C:3](O)=[O:4].[OH:9][C@H:10]1[CH2:14][NH:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11]1>>[OH:4][CH2:3][CH2:2][N:13]1[CH2:14][C@H:10]([OH:9])[CH2:11][C@H:12]1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1CCO

Procedure:
The procedure was as in Example 5 but in place of (2S)-proline there were employed 39.3 grams of (2S, 4R)-4-hydroxy-proline (0.3 mole). There were obtained 35.4 grams (67.4% of theory) of colorless crystals of (2S, 4R)-N-(2-hydroxyethyl)-4-hydroxy-proline.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5].[N-:16]=[N+:17]=[N-:18].[Na+].[I-].[Na+]>O>[N:16]([CH2:2][CH2:3][C:4]([C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCBr)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 5 L round bottom three-necked flask, equipped with a heating mantle, an overhead stirrer, and a thermometer, is charged with 150 gm bromoethylmannose (525 mmol). The oil is dissolved in 2 L water and treated with 68.3 gm sodium azide (1.05 mol, 2 equiv.; 65 gm/mol; Alfa-Aesar) followed by 7.9 gm sodium iodide (52.5 mmol, 0.08 equiv.; 149.89 gm/mol; Alfa-Aesar) and the solution warmed to 50 C and stirred overnight. The solution is cooled to room temperature and concentrated to dryness on the rotovap. The solid residue is digested with 3×500 mL of 5:1 vol. CHCl3:MeOH at 40 C. The combined organic portions are filtered and evaporated to dryness to afford azidoethylmannose as an off-white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24]OS(C)(=O)=O)=[CH:20][CH:19]=3)=[C:14]([F:30])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:8]3[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]3=[O:11])=[CH:13][C:14]=2[F:30])=[CH:23][CH:22]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(COS(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CN=[N+]=[N-])cc3)c(F)c2)C(=O)O1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
A solution of 52 (9.27 g, 21.26 mmol) in anhydrous N,N-dimethylformamide (DMF, 50 mL) was treated with sodium azide (NaN3, 5.53 g, 85.04 mmol, 4.0 equiv) at 25° C., and the resulting reaction mixture was warmed to 70-80° C. for 4 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being treated with H2O (150 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The solid precipitates were collected by filtration, washed with H2O (2×100 mL) and 20% EtOAc/hexane (2 X 50 mL), and dried in vacuo. The crude desired N-[3-(4′-azidomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 53 (7.16 g, 88% yield) was obtained as off-white solids. The material was found to be essentially pure by TLC and HPLC and was directly used in the subsequent reaction without further purification. LCMS (ESI) m/e 384 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][C:23]([F:25])([F:26])[F:24])[C:17]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCOC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CCOC(F)(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
330 mg (766 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoic acid (racemate), 148 mg (766 μmol) of tert-butyl 4-aminobenzoate, 109 mg (766 μmol) of Oxima and 120 μl (766 μmol) of DIC in 7.7 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (40 g cartridge, 40 ml/min, cyclohexane/ethyl acetate gradient). Yield: 329 mg (64% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1F.[CH3:14][O-:15].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:15][CH3:14]
Reactant: C[O-]
Reactant: CCS(=O)(=O)c1ccc(Br)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Br)c(OC)c1
Temperature: 100 °C
Yield: 75 %

Procedure:
In a sealed vessel 1-bromo-4-(ethylsulfonyl)-2-fluorobenzene (Preparation 19, 34.89 g, 0.131 mol) was dissolved in MeOH (400 mL) and sodium methoxide (35.3 g, 0.653 mol) was added. The reaction was heated at 100° C. for 12 hours and then allowed to cool to room temperature. The reaction mixture was diluted with water (750 mL) and the aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and reduced to dryness to give a solid. The crude was purified by silica gel column chromatography eluting with cyclo-hexane/EtOAc gradient from 95/5 to 8/2 to afford the title compound as colourless solid in 75% yield, 27.32 g.
Reaction SMILES: [CH2:1]([C:6]1([CH:13]=[O:14])[CH2:11][CH:10]2[CH2:12][CH:7]1[CH:8]=[CH:9]2)[CH2:2][CH2:3][CH2:4]C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([CH:6]1[CH2:11][CH:10]2[CH2:9][CH:8]([CH:7]=[CH:12]2)[C:13]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC1(C=O)CC2C=CC1C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC1CC2C=CC(C2)C1=O
Temperature: -50 °C
Yield: 39.3 %

Procedure:
Compound VII (570 g, 3.2 mol) was loaded into a 3-liter round bottom flask fitted with a condenser and an overheard stirrer. This was followed by one liter of methylene chloride. The resulting solution was cooled to −50° C. using a dry ice bath. After this temperature was reached, anhydrous aluminum chloride (215 g, 1.6 mol) was added in one portion. The light yellow solution changed color to orange, then dark red with a simultaneous increase in reaction temperature, up to roughly −30° C. A GC sample taken after the addition was complete showed little reaction. The reaction temperature was allowed to gradually increase to 15° C., and GC monitoring showed the complete consumption of start material after one hour at this temperature. The reaction mixture was then poured onto ice and 10% sulfuric acid, and the organic layers were separated and washed once with 10% sodium hydroxide solution. The methylene chloride solvent was then removed under reduced pressure, and the resulting oil was purified by simple distillation to yield 224 g (49% yield) of VIII.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(#N)C>[C:24]([O:23][C:21](=[O:22])[CH2:20][O:12][C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(O)c(C(C)(C)C)c1
Yield: 27.3 %

Procedure:
tert-Butyl-hydroquinone (500 mg, 3.0 mmol) and K2CO3 (1.11 g, 8.0 mmol) were mixed in acetonitrile (4 mL). t-Butyl bromoacetate (0.53 mL, 3.6 mmol) was added and the mixture was heated to reflux. After the reaction was over, it was concentrated and purified by silica gel chromatography (10% –25% EtOAc/Hexane) to give the title phenol (230 mg, 40%). MS (DCI) m/z 297 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[N:24][C:25]([CH3:29])=[C:26]([CH3:28])[N:27]=2)=[CH:18][C:17]=1[NH2:30]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:30][C:17]1[CH:18]=[C:19]([C:22]2[N:23]=[N:24][C:25]([CH3:29])=[C:26]([CH3:28])[N:27]=2)[CH:20]=[CH:21][C:16]=1[Cl:15])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Cc1nnc(-c2ccc(Cl)c(N)c2)nc1C
Solvent: CC#N
Product: Cc1nnc(-c2ccc(Cl)c(NC(=O)NC(=O)c3cc(F)c(F)cc3Cl)c2)nc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 75 mg of 2-chloro-5-(5,6-dimethyl-[1,2,4]triazin-3-yl)phenylamine in 8 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O-:11].[Na+]>CN(C=O)C>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)cc(C)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
2-chloro-4,6-dimethylpyridine (CAS number: 30838-93-8) (400 mg) was added to DMF (3.3 mL). Sodium methoxide (28% solution in methanol, 2.6 mL) was added to the solution, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (380 mg) as a 50% solution in DMF.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=3)[C:11]([CH2:13][CH3:14])=[N:12][C:7]2=[C:6]([CH3:40])[CH:5]=1.[CH3:41]I.O>CN(C)C=O>[CH3:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:41])=[CH:20][CH:21]=3)[C:11]([CH2:13][CH3:14])=[N:12][C:7]2=[C:6]([CH3:40])[CH:5]=1
Reactant: CI
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1ccc(Cn2c(CC)nc3c(C)cc(C)nc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)C(c1ccccc1)c1ccc(Cn2c(CC)nc3c(C)cc(C)nc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a suspension of 55% sodium hydride in 103 mL of dimethylformamide, cooled with an ice bath, was added dropwise 13 g (25.3 mmol) of the compound obtained in example 59 dissolved in 51 mL of dimethylformamide, followed by 4.6 mL (75.9 mmol) of methyl iodide. After the addition was complete, the reaction mixture was stirred at room temperature overnight. Then, water was added and the solvent was removed. The residue was taken up in ethyl acetate and washed with brine. The organic phase was dried and the solvent was removed to yield 13 g of a crude product. This was chromatographed on silica gel (ethyl acetate-hexane mixtures of increasing polarity) to afford 10.2 g of the title compound of the example (yield: 76%).