Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=4[O:35][CH3:36])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[C@H:13]2[CH3:41])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:42][CH:43]1[CH2:46][NH:45][CH2:44]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=4[O:35][CH3:36])=[CH:23][N:22]=[C:21]([N:45]4[CH2:46][CH:43]([F:42])[CH2:44]4)[N:20]=3)[C@H:13]2[CH3:41])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC1CNC1
Reactant: COc1cc(F)c(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(Br)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(Br)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 100 °C
Yield: 92.1 %

Procedure:
To (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-3-({5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-2-(methylsulfonyl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (175 mg, 0.265 mmol) in THF (1 mL) was added TEA (0.369 mL, 2.65 mmol) and 3-fluoroazetidine (236 mg, 2.120 mmol). The reaction was capped and heated at 100° C. for 10 min by microwave irradiation. The reaction was diluted with EtOAc, washed with sat. aqueous NaHCO3, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated before purification by column chromatography to afford (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-3-({2-(3-fluoroazetidin-1-yl)-5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (160 mg, 0.244 mmol). LCMS calc.=655.2/657.2. found=655.4/657.4.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: Brc1nccs1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1nccs1)OCC2c1ccc(C(C)C)cc1
Yield: 64 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromo-1,3-thiazole, the title compound was obtained in the same manner as in Example 107. Yield: 64%. Melting point: 164-166° C. (ethyl acetate-hexane).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH2:5]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[C:19]=2[F:20])=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH3:2]
Reactant: BrCCCCOc1ccccc1
Reactant: OB(O)c1cccc(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2cccc(F)c2F)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
4-Bromobutoxybenzene (16) (50.0 g), 2,3-difluorophenylboronic acid (17) (37.9 g), potassium carbonate (90.5 g), Pd(Ph3P)2Cl2 (4.6 g), toluene (200 ml), Solmix A-11 (200 ml) and water (200 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25° C., and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from Solmix A-11 and dried, giving 44.7 g of 4′-butoxy-2,3-difluoro-1,1′-biphenyl (18). The yield based on the compound (16) was 78.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c23)cc1

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 4-methoxybenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 434/436 (M+H). 1H-NMR (DMSO-d6) δ 3.20-3.27 (m, 1H), 3.36-3.48 (m, 3H), 3.60-3.71 (m, 2H), 3.71 (s, 3H), 4.20 (s, 2H), 4.53 (t, J=5.6 Hz, 1H), 5.10 (d, J=5.1 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.6 Hz, 1H), 5.40 (d, J=9.0 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=7.6 Hz, 1H), 7.09 (t, J=7.9 Hz, 1H), 7.15 (d, J=8.7 Hz, 2H), 7.20 (s, 1H), 7.54 (d, J=8.2 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[C:12](#N)[CH3:13]>>[CH:7]1([CH2:6][CH:2]([N:1]2[CH2:13][C:12]3[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:3]2=[O:4])[C:3]([OH:5])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC#N
Reactant: NC(CC1CCCC1)C(=O)O
Product: O=C(O)C(CC1CCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 2-Amino-3-cyclopentyl-propionic acid (0.800 g; 5.09 mmol) and phthalic dicarboxaldehyde (0.684 g; 5.10 mmol) in acetonitrile (30 mL) was refluxed for 3 h under nitrogen. The mixture was allowed to cool to room temperature and the solid was filtered off and washed once with cold acetonitrile (5 mL) to give 1.16 g (83%) of 3-Cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a white solid: EI-HRMS m/e calcd for C16H19NO3 (M+) 273.1365, found 273.1374.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([CH3:29])[CH:28]=1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([C:23]3[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([CH3:29])[CH:28]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Product: Cc1cc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)ccc1[N+](=O)[O-]

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (382 mg, 1 mmol) was treated as described in general procedure B using 5-fluoro-2-nitrotoluene (310 mg, 2 mmol) to give 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(3-methyl-4-nitro-phenyl)-1H -imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1I.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Li+].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:15][CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2c1ccc(Br)c2I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1c(Br)ccc2c1COC2=O
Temperature: 95 °C

Procedure:
A mixture of 5-bromo-4-iodo-2-benzofuran-1(3H]-one (2.42 g, 7.13 mmol), allyltributyltin (2.36 g, 7.13 mmol), LiCl (1.50 g, 35.7 mmol) and Pd(PPh3)4 (200 g, 0.173 mmol) in toluene (50 mL) was heated at 90-100° C. under N2 overnight; LC indicated that reaction had gone to completion, to the solution was poured EtOAc (100 mL) and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated to dryness, absorbed into silica gel and was then separated over silica gel column to give 5-bromo-4-prop-2-en-1-yl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.795 (d, J=8 Hz, 1H), 7.680 (d, J=8 Hz, 8.5 Hz, 1H), 5.938-5.925 (m, 1H), 5.302 (s, 2H), 5.192-5.172 (m, 1H), 5.075-5.041 (m, 1H), 3.611-3.599 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([Cl:13])[C:5]([Cl:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([OH:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[C:15]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:3]1[C:2]([Cl:1])=[C:7]([C:8]#[N:9])[C:6](=[C:5]([Cl:12])[C:4]=1[Cl:13])[C:10]#[N:11]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1c(Cl)c(Cl)c(Oc2ccccc2-c2ccccc2)c(Cl)c1C#N

Procedure:
To a 250 mL flask, 4.8 g of tetrachlorophthalonitrile, 4.3 g of biphenyl-2-ol, 5 g of potassium carbonate (K2CO3) and 55 mL of acetonitrile are added, followed by heating for 12 hours while refluxing. After completion of the reaction, 30 mL of ethyl acetate is added and filtered to remove the solvent. To the obtained solid, a suitable amount of dichloromethane is added to dissolve the solid, followed by adding hexane for crystallization. The obtained solid is filtered and dried under vacuum to obtain a compound, 4-[(biphenyl-2-yl)oxy]-3,5,6-trichlorophthalonitrile. The second step reaction may be represented by Reaction Scheme 2:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:29]=[N:28][NH:27][C:14]3=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:29]=[N:28][NH:27][C:14]3=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Solvent: CO
Product: COc1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a solution of 5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (90 mg, 0.2 mmol, obtained in example 127) in MeOH (5 mL) in a closed vessel, sodium methoxide (11 mg, 0.2 mmol) was added and heated to 60° C. for 24 h. Then, sodium methoxide (11 mg, 0.2 mmol) was added and it was stirred at 60° C. for 2 h more. It was allowed to cool and was concentrated. EtOAc and buffer (pH=5.3) were added. The phases were separated and the organic phase was washed with water, dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures at 50%, to afford 38 mg of the title compound (yield: 47%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.N([O-])=[O:26].[Na+].OS(O)(=O)=O>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:26])=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(O)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of afford 4-amino-2-(4-tert-butyl-benzoylamino)-benzoic acid methyl ester (0.711 g, 2.18 mmol) in trifluoroacetic acid cooled to 0° C. was added NaNO2 (0.182 g, 2.64 mmol, 1.21 eq) as a solution in water (4 mL) and the reaction was stirred 5 minutes. It was then added dropwise to 30% solution of H2SO4 (50 mL) at 65° C. and stirred for 15 minutes. It was extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 2-(4-tert-butyl-benzoylamino)-4-hydroxy-benzoic acid methyl ester (0.508, 71%) as a white solid. mp=146.0-148.4° C.; mass spectrum (−ES, M−H) m/z 326. 1H NMR (400 MHz, DMSO-d6); δ 11.95 (bs, 1H), 10.60 (bs, 1H), 8.26 (d, 1H), 7.88 (m, 3H), 7.62 (d, 2H), 6.58 (dd, 1H), 3.85 (s, 3H), 1.32 (s, 9H). Elemental analysis: Calcd. for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.20; H, 6.54; N, 4.17.
Reaction SMILES: C(O)C.Cl.[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].[N:20]([O-])=[O:21].[Na+]>O>[N:20]([C:13]1[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]([OH:19])=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=1)=[O:21]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
Ethanol (75 ml) was cooled to 15° C and saturated with hydrogen chloride gas. This solution was diluted by addition of another 400 ml of ethanol. To this alcoholic solution was added 82.4 grams of 2,6-di-tert-butylphenol. After it was dissolved, a solution of 30.4 grams of sodium nitrite in 40 ml of water was added at 15°-20° C over a period of one hour with stirring. Stirring was continued for another two hours with the temperature allowed to rise to room temperature. The solution was diluted with 200 ml of water, and the product formed was collected by filtration and washed well with water. The filter cake was then slurried in 300 ml of petroleum ether, filtered, washed with another 100 ml of petroleum ether and dried in a vacuum oven at 70°-80° C to yield the desired intermediate 4-nitroso-2,6-di-tert-butylphenol, melting at 219° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].S([O-])(O[O-])(=O)=[O:23].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:23])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(SC)cc2F)n1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(S(C)=O)cc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.5 %

Procedure:
To a solution of methyl 6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylate (150 mg, 0.479 mmol) in DCM (3.0 mL) was added potassium peroxymonosulfate (147 mg, 0.958 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solution was partitioned between EtOAc and water. The organic layer was dried, filtered. The filtrate was concentrated and then purified by silica gel column chromatography using CombiFlash® (0 to 100% EtOAc in hexanes) to give the sub-title compound as a white powder (37 mg, 23%). LCMS calc. for C14H11F3NO3S (M+H)+: m/z=330.0. Found: 330.2.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.BrBr.[CH3:11][C:12]1[C:20]([C:21](=[S:23])[NH2:22])=[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1>C(O)(=O)C>[CH3:11][C:12]1[C:20]([C:21]2[S:23][C:3]3[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=3[N:22]=2)=[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1
Reactant: O=C1CCCCC1=O
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
In a 250 mL round bottomed flask were placed 1,2-cyclohexanedione (1.32 g, 11.8 mmol) and acetic acid (30 mL). To the solution was added dropwise a solution of bromine (1.67 g, 10.4 mmol) in acetic acid (20 mL). The mixture was stirred for 30 min at rt. To the mixture was added 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide (1.92 g, 10.0 mmol) and the resulting suspension was stirred for 1 hr at 120° C. After 30 min the suspension turned into a clear brown solution. After 1 hour the mixture was allowed to cool to rt during which time an off-white solid precipitated. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL) and a saturated aqueous solution of NaHCO3 (100 mL). The resulting bi-phasic mixture was vigorously stirred for 30 min at rt. The aqueous phase was separated and the organic phase was washed with a 10% aqueous solution of NaHSO3 (50 mL), then a saturated aqueous solution of NaHCO3 (50 mL). The organic phase was dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from EtOAc and ether to yield the title compound (1.0 g; 35%) as a yellowish off-white crystalline solid. From the mother liquor, a 2nd crop of title compound (1.5 g; 53%) was obtained. LCMS: (FA) ES+ 284; 1H NMR (400 MHz, d6-DMSO) δ ppm 8.75 (dt, 1H), 8.29 (dt, 1H), 7.54 (dd, 1H), 7.07 (td, 1H), 3.16 (t, 2H), 2.65 (s, 3H), 2.60 (dd, 2H), 2.14-2.21 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][CH2:11][CH2:12][O:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: BrCCBr
Reactant: Oc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(F)c1OCCBr
Temperature: 75 °C

Procedure:
A mixture of 10 g of 2,6-difluorophenol, 40.5 cm3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 300 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with 3 times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 200 cm3 of petroleum ether (40-65° C.), filtered and washed with 3 times 30 cm3 of petroleum ether (40-65° C.). The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm), eluting with petroleum ether (40-65° C.) and collecting 100-cm3 fractions. Fractions 22 to 58 were combined and then concentrated to dryness under the above conditions. 14.5 g of 1-(2-bromoethoxy)-2,6-difluorobenzene were obtained in the form of a thick colorless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]([N:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:20][CH3:21])[CH:17]=2)[N:12]=[CH:11]1)[C:7](O)=[O:8])(=[O:3])[NH2:2]>C(OC(=O)C)(=O)C.C(Cl)(=O)C>[CH3:21][O:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]([CH:6]1[CH2:5][CH2:4][C:1](=[O:3])[NH:2][C:7]1=[O:8])[CH2:19]2
Reactant: COc1ccc2c(c1)CN(C(CCC(N)=O)C(=O)O)C=N2
Solvent: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C=N2
Reaction time: 1 h

Procedure:
A solution of 1.20 g of the crude product from stage 4 in 7 ml of acetic anhydride and 7 ml of acetyl chloride was stirred for 5 hours at 70° C. and then concentrated by evaporation in vacuo. The residue was taken up in 20 ml of methanol and stirred for 1 hour with Amberlyst A-21 ion exchanger. After filtration the filtrate was concentrated by evaporation in vacuo and the residue was purified by flash chromatography with chloroform/methanol (4/1) as eluent. The free base of the title compound thereby obtained was dissolved in 4 ml of methanol and 0.5 ml of a saturated solution of HCl gas in diethyl ether followed by 150 ml of diethyl ether were added to the solution. The salt formed was separated and dried in vacuo, 0.29 g (23% of theory referred to L-glutamine in stage 4) of the title compound being obtained.
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][O:10][C:11](=[O:16])[C@H:12]([CH2:14][OH:15])[NH2:13].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:16])[CH:12]([NH:13][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][OH:15]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A solution of Et3N (13.4 mL, 96.78 mmol) in CH2Cl2 (40 mL) was added to a solution of L-serine methyl ester hydrochloride (5.0 g, 32.26 mmol) and Ph3CCl (13.5 g, 48.39 mmol) in CH2Cl2 (129 mL) at 0° C. under N2 atmosphere. The reaction was then allowed to warm to room temperature and was stirred overnight. The reaction was quenched with saturated NaHCO3, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with brine, dried and concentrated, the residue was purified by silica gel column chromatography which gave the title compound as a colourless solid (11.41 g, 98%).
Reaction SMILES: [CH2:1]1[O:21][C:4]([CH2:19][CH3:20])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[N+:16]([O-])=O)[O:3][CH2:2]1>C(O)C.[Pd]>[CH2:2]1[O:3][C:4]([CH2:19][CH3:20])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH2:16])[O:21][CH2:1]1
Reactant: CCC1(Cc2cccc(C(=O)OC)c2[N+](=O)[O-])OCCO1
Agent: [Pd]
Solvent: CCO
Product: CCC1(Cc2cccc(C(=O)OC)c2N)OCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
To a solution of 1-(3-methoxycarbonyl-2-nitrophenyl)butan-2-one ethylene ketal (36) (1.12 g) (prepared, e.g., as described in Preparation 24), in absolute ethanol (50 ml) was added palladium on carbon (150 mg, 10%), and the mixture stirred under hydrogen at atmospheric pressure and room temperature for 6 hours. The reaction mixture was passed through a Celite pad to remove catalyst, and the pad was washed with methylene chloride. The combined filtrate and washings were concentrated under reduced pressure to give 1-(2-amino-3-methoxycarbonyl-phenyl)butan-2-one ethylene ketal (0.98 g), a compound of Formula (37), as a colorless oil.