Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[CH3:30][O-:31].[Na+]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:6]2[CH:5]=[CH:4][C:3](=[O:29])[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:7]=2[N:8]=[C:9]([O:31][CH3:30])[N:10]=1
Reactant: C[O-]
Reactant: COC(=O)/C=C/c1c(Nc2ccccc2Cl)nc(SC)nc1-c1ccccc1Cl
Agent: [Na+]
Product: COc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(2-chloro-phenylamino)-6-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.71 (s, 3H), 6.55 (d, 1H, J=9.6 Hz), 7.24-7.60 (m, 9H). LC MS (m/e)=398 (MH+). Rt=2.27 min
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([CH3:18])=[CH:16][C:15](=[O:19])[NH:14]1)=[O:12].Cl[Si](C)(C)C.[Cl:40][CH2:41][CH2:42]OS(C(F)(F)F)(=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17](=[CH2:18])[CH:16]([CH2:42][CH2:41][Cl:40])[C:15](=[O:19])[NH:14]1)=[O:12]
Reactant: COC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC(=O)C=C1C
Reactant: O=S(=O)(OCCCl)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C1C(CCCl)C(=O)NC1(C(=O)OC)C(O[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Lithium diisopropylamide solution (0.67 M solution in tetrahydrofuran, 0.09 ml, 0.06 mmol, 1.0 equiv) was added dropwise via syringe to a stirred solution of 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (23 mg, 0.06 mmol, 1.0 equiv) in tetrahydrofuran (1.5 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Chlorotrimethylsilane (8 μl, 6.8 mg, 0.06 mmol, 1.0 equiv) was added and the resultant solution was stirred at −78° C. for 2.5 h. Another equiv of lithium diisopropylamide solution (0.67 M solution in tetrahydrofuran, 0.09 ml, 0.06 mmol, 1.0 equiv) was added dropwise at −78° C. The reaction mixture was stirred −78° C. for 30 min. A stock solution of trifluoro-methanesulfonic acid 2-chloro-ethyl ester in toluene (2.45 M, 0.1 ml, 0.24 mmol, 4.0 equiv) was added dropwise via syringe at −78° C. The reaction mixture was stirred at −78° C. for 50 min. A buffer solution (pH=7, 5 ml) was added at −78° C. The organic layer was separated, washed with brine solution (5 ml), dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) to furnish 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-4-(2-chloro-ethyl)-3-methylene-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (16 mg, 59%) along with recovered starting material (5 mg, 22%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[NH2:8].[CH3:22][C:23]([OH:27])([C:25]#[CH:26])[CH3:24]>>[NH2:8][C:7]1[C:6]([NH2:9])=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[CH:3][C:2]=1[CH2:26][CH2:25][C:23]([CH3:24])([OH:27])[CH3:22]
Reactant: C#CC(C)(C)O
Reactant: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Product: CC(C)(O)CCc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N

Procedure:
The title compound was prepared from 3-iodo-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (as prepared in Example 9, step A) and 2-methyl-but-3-yn-2-ol according to the procedures described in Example 10, steps A and B.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([O:17]C)=[O:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:8]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([OH:17])=[O:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: COC(=O)c1nn(-c2ccncc2)cc(OC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cn(-c2ccncc2)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of methyl 5-methoxy-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxylate (0.50 g, 1.9 mmol) in MeOH (10 mL) and THF (10 mL) was added 1 M NaOH aqueous solution (3.0 mL, 3.0 mmol), and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. To the residue was added 1 M HCl aqueous solution (3.1 mL). The formed precipitate was collected by filtration, washed with water and dried to give the title compound (0.47 g, 99% yield) as an off-white solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.98 (3H, s), 7.97 (2H, dd, J=4.7, 1.7 Hz), 8.83 (2H, dd, J=4.7, 1.7 Hz), 8.92 (1H, s), 14.63 (1H, brs).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[CH2:10]([S:12](Cl)(=[O:14])=[O:13])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1ccc(Br)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a solution of (5-bromopyridin-2-yl)methanamine (250 mg, 1.34 mmol) in CH2Cl2 (3 mL) is added ethyl sulfonyl chloride (95 mg, 0.74 mmol) followed by triethylamine (0.3 mL, 2.0 mmol). The reaction is stirred at room temperature for 1.5 hours. The reaction is directly injected onto a 12 g silica gel column and chromatographed eluting from 100% hexanes to 50:50 ethylacetate:hexanes to afford the title compound (158 mg): m/z (Cl) M+H 279+281.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)([CH2:11][CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[I-:29].[Na+].O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][I:29])([CH2:11][CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)C(CCCCCCCl)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCCCI)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Yield: 89.4 %

Procedure:
To a solution of 6-chlorohexyl-(4,4,5,5,5-pentafluoropentyl)malonic acid diethyl ester (743 mg, 1.69 mmol) in acetone (5 ml) was added sodium iodide (761 mg, 5.08 mmol), which was then refluxed for 4 h. When the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. Then, the organic layer was washed with wafer and saturated sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=15:1) to give the title compound (801 mg, yield: 89%) as a colorless liquid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[OH2:14]>C(Cl)(Cl)(Cl)Cl.CC#N>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[C:11]([CH3:13])[N:12]=[C:3]([C:2]([OH:14])=[O:1])[CH:4]=1)=[O:7]
Reactant: COC(=O)c1cc(C)nc(CO)c1
Reactant: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(C)nc(C(=O)O)c1
Reaction time: 2 h

Procedure:
To a stirring mixture of 51.6 mg (0.283 mmol) of methyl 2-(hydroxymethyl)-6-methylisonicotinate in 1.6 mL of CCl4, 1.6 mL of CH3CN, and 2.4 mL of H2O was added 348 mg (1.63 mmol) of NaIO4, and 8.8 mg (0.0424 mmol) of RuCl3.(H2O)n. After 2 h, 6 mg of RuCl3.(H2O)n was added, and after 2.5 h the mixture was filtered through Celite twice with EtOAc and MeOH. The solution was concentrated and then reconcentrated with MeOH (2×) to remove H2O. Crude 4-(methoxycarbonyl)-6-methylpicolinic acid was used in the next reaction without further purification.
Reaction SMILES: C[O:2][C:3]1([CH3:10])O[CH:8]2[CH:5]([CH2:6][CH2:7]2)[O:4]1.C[Si](C)(C)[Br:13]>C(Cl)Cl>[Br:13][C@@H:8]1[CH2:7][CH2:6][C@H:5]1[O:4][C:3](=[O:2])[CH3:10]
Reactant: C[Si](C)(C)Br
Reactant: COC1(C)OC2CCC2O1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CC[C@H]1Br
Yield: 92.7 %

Procedure:
107.0 g (0.743 mol) of 3-methoxy-3-methyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 122.0 g (0.8 mol) of trimethylbromosilane are heated under reflux in 400 ml of methylene chloride for 15 hours. Concentration and distillation in vacuo give 132.9 g (93%) of trans-1-bromo-2-acetoxy-cyclobutane. Boiling point11 78°, nD20 1.4748.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: Cc1ccc(B(O)O)cc1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(C)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.[Li]CCCC>C1COCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([B:14]([OH:15])[OH:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-bromo-2-methoxypyridine (8.25 g, 43.9 mmol) and triisopropylborate (10.3 g, 55.0 mmol) in THF (110 mL) at −80° C. was dropwise added n-BuLi (1.6M in hexanes, 30.1 mL, 48.2 mmol). The reaction mixture was gradually warmed to RT over 1 h and then stirred at RT for 16 h. The reaction mixture was quenched by addition of 1N aqueous HCl solution and stirred for 1 h. The aqueous layer was basified with 6N aqueous NaOH to pH=9, extracted with a mixture of EtOAc and Et2O. The aqueous layer was acidified to pH=7 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. This material was used in the next step without further purification.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)=[C:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].CO>C(Cl)Cl>[CH:1]([C@H:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)=[C:2]=[CH2:3]
Reactant: C=C=CC1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C=C=C[C@@H]1CCC(=O)N1
Yield: 97.1 %

Procedure:
A solution of (5S)-N-((2S)-2-(1,1-dimethylethyl)dimethylsilyloxy)propanoyl)-5-(1,2-propadienyl)pyrrolidin-2-one (2.70 g, 8.7 mmol), K2CO3 (0.6 g, 4.4 mmol), and MeOH (40 mL) was stirred at room temperature for 1.5 hours. The solvent was removed by rotary evaporation (≤30° C.) to give a yellow gum. This gum was dissolved in CH2Cl2 (20 mL), filtered to remove salts and applied to a silica gel plug (50 g). This plug was rinsed with 10% MeOH/CH2Cl2, discarding the initial eluent which contains the chiral auxiliary, to give (5S)-5-(1,2-Propadienyl)pyrrolidin-2-one (1.04 g, 97%) as a clear oil: TLC (Eluent A) Rf =0.45; 1H NMR: δ6.6 (br s, 1 H, NH); 5.17 (ddd, 3J64 ≃4J68 ≃4J68 ≃6.6 Hz, 1 H, H6); 4.88 (d, 4J68 ≃6.7 Hz, 1 H, H8); 4.88 (d, 4J68' =6.4, 1 H, H8'); 4.21 (m, 1 H, H5); 2.35 (m, 3 H, H3, H4, H4'); 1.93 (m, 1 H, H3'); Cl Mass spec: m/z 124 (MH+), 84 (MH+ --C3H4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[F:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][C:15]2[C:16](=[O:31])[NH:17][N:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1.N>>[Br:8][C:4]1[CH:3]=[C:2]([N:17]2[C:16](=[O:31])[C:15]([O:14][C:13]3[CH:32]=[CH:33][C:10]([F:9])=[CH:11][CH:12]=3)=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH:19]=[N:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Br)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1,3-dibromobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 260 mg, 50.5%). mp 208–210° C. 1H NMR (300 MHz, CDCl3) δ 3.09 (s, 3H), 6.89–7.04 (m, 4H), 7.34 (t, J=9 Hz, 1H), 7.53 (br d, J=9 Hz, 1H), 7.64 (br d, J=9 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 7.87 (t, J=1.5 Hz, 1H), 8.08 (d, J=9 Hz, 2H), 8.09 (s, 1H). MS (DCI/NH3) m/z 517 (M+H)+, 534 (M+NH4)+. Anal. calc. for C23H16BrFN2O4S: C, 53.7; H, 3.11; N, 5.45. Found: C, 53.46; H, 2.88; N, 5.18.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:15][C:12]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([N:20]4[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]4)[C:3]2=[N:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CN1CCNCC1
Reactant: Cc1cnc2c(Cl)nc3ccccc3n12
Product: Cc1cnc2c(N3CCN(C)CC3)nc3ccccc3n12

Procedure:
By reaction of 4-chloro-1-methylimidazo[1,2-a]quinoxaline (example 2) with N-methylpiperazine, according to a procedure that is similar to that followed in example 3, there is obtained 1-methyl-4(N'-methylpiperazinyl)imidazo[1,2-a]quinoxaline. m.p. (DSC)=108.0° C.(onset); IR (KBr): 2928, 1535, 1510 cm-1 ; 1H-NMR (CDCl3): δ8.1 (1H,dd), 7.7 (1H,dd), 7.4÷7.0 (3H,m), 4.35 (4H,t), 2.85 (3H,s), 2.6 (4H,t), 2.3 (3H,s); UV (EtOH): λmax =228, 248, 279, 309, 325 nm. Elementary analysis for C16H19N5 (m.w. 281.36): calcd. C 68.30, H 6.81, N 24.89%; found C 68.37, H 7.15, N 25.05%.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[I:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc(I)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-(iodo)benzaldehyde (2.00 g, 8.62 mmol) (BioNet Research) in DCM (20 mL) was added 2-methylpropane-2-sulfinamide (2.09 g, 17.2 mmol) (AK Scientific) and copper (II) sulfate (2.75 g, 17.2 mmol) (Fluka). The suspension was stirred at rt under N2 for 17 h. The suspension was then filtered through Celite® brand filter agent, and the solids were washed with DCM (2×20 mL). The filtrates were concentrated and purified by ISCO (80 g, SiO2, 0-100% EtOAc/hexanes) to give the title compound as a yellow solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:9]([CH3:10])=[C:8]([CH2:11][C:12]([CH3:14])=[CH2:13])[C:7]([OH:15])=[C:6]([CH3:16])[C:5]=1[CH3:17])=[O:2].C([O-])(=O)C.[Na+].[Br:23]Br>C(O)(=O)C>[Br:23][CH2:13][C:12]1([CH3:14])[CH2:11][C:8]2[C:9]([CH3:10])=[C:4]([NH:3][CH:1]=[O:2])[C:5]([CH3:17])=[C:6]([CH3:16])[C:7]=2[O:15]1
Reactant: BrBr
Reactant: C=C(C)Cc1c(C)c(NC=O)c(C)c(C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CBr)O2
Temperature: 0 °C
Yield: 67.1 %

Procedure:
4-Formylamino-2,3,5-trimethyl-6-(2-methyl-2-propenyl)phenol (50 g, 0.21 mol) and sodium acetate (30.5 g, 0.37 mol) were added to acetic acid (500 ml). Bromine (16.5 ml, 0.21 mol) was added dropwise to the mixture with stirring. After the reaction mixture was stirred for 30 minutes, the mixture was poured into ice water and the product was extracted with ethyl acetate. The extract was washed with aqueous saturated sodium bicarbonate solution, dried and then concentrated. The residue was dissolved in ethyl acetate again and insoluble materials were filtered off. The filtrate was concentrated and isopropyl ether was added to the residue. The crystals precipitated were filtered off to obtain the desired compound (44.0 g, yield: 65.7%), m.p. 157°-158° C.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1nc(Cc2ccccc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of methyl 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoate (5.2 g, 21.1 mmole) in methanol (30 ml) was added 50 ml of 1N NaOH. The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to PH=3-4 under ice bath, and extracted with EtOAc (3×). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to yield the desired product (4.8 g, 98%) as colorless oil. LCMS calculated for C12H13N2O3 (M+H): 233.1. found 233.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[Cl:20])=[O:8].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=1[Cl:20])=[O:8]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(Br)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(Br)ccc1OC(=O)N1CCOCC1
Yield: 93.5 %

Procedure:
Using 5-bromo-N-[2-chloro-4-(trifluoromethyl)phenyl]-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([O:17][CH2:18][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][OH:21])[C:13]=2[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:35]=[C:36]=[O:37])(=O)=O.O>C(Cl)Cl>[C:36]([O:21][CH2:20][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][O:17][C:14]1[C:13]2[CH:30]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:10]=[CH:11][C:12]=2[O:16][N:15]=1)(=[O:37])[NH2:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(CO)NC(=O)OC(C)(C)C)c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of 0.47 g of 5-tert-butoxycarbonylamino-3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 10 ml of methylene chloride is added 0.21 g of chlorosulfonyl isocyanate at -45° to -40° C., and the temperature is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. Subsequently, 10 ml of water is added, and they are subjected to reaction at 20°-25° C. for one hour. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the crystals obtained are collected by filtration, to obtain 0.47 g of colorless, crystalline 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-tert-butoxycarbonylamino-1,2-benzoisoxazole.
Reaction SMILES: C[Si](C)(C)C#C[C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[C:9]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:8]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:7][C:6]=1[CH2:28][OH:29].[CH2:32]1COC[CH2:33]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:32]([CH:28]([C:6]1[CH:5]=[C:10]([C:11]([CH3:13])([CH3:14])[CH3:12])[C:9]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[C:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:7]=1)[OH:29])#[CH:33]
Reactant: CC(C)(C)c1cc(CO)c(C#C[Si](C)(C)C)c(C(C)(C)C)c1OCOCC[Si](C)(C)C
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C#CC(O)c1cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.5 g (40 mmol) of α-trimethylsilylethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol and 50 ml of THF are introduced into a round-bottomed flask and 40 ml (44 mmol) of tetrabutylammonium fluoride solution (1.1 M in THF) are added dropwise. The mixture is stirred at room temperature for one hour, the reaction medium is poured into water and extracted with ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and hexane (5/95 by volume). After evaporation of the solvents, 13.5 g (86%) of α-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol are collected in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:4][CH2:5][O:6][CH3:7].[H][H]>[Pd].C1COCC1>[F:1][C:2]([F:31])([F:32])[C@H:3]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:4][CH2:5][O:6][CH3:7]
Reactant: [H][H]
Reactant: COCC[C@@H](OC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: COCC[C@@H](OC(=O)c1ccc(-c2ccc(O)cc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.93 g (6.60 mmol) of the 4'-benzyloxy-4-biphenylcarboxylic acid (R)-1-trifluoromethyl-3-methoxypropyl ester obtained in the second stage and 0.4 g of 5% palladium/carbon as catalyst was added to 50 ml of THF. The solution was placed in a hydrogen atmosphere, using a hydrogen baloon, and was stirred at room temperature overnight. After filtering out the catalyst and concentrating the filtrate, there was obtained approximately quantitatively 4'-hydroxy-4-biphenylcarboxylic acid (R)-1-trifluoromethyl-3-methoxypropyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br>CCO.O.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([Br:18])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccn3ccnc23)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-benzyloxy-imidazo[1,2-a]pyridine (25.46 g) in EtOH (250 mL) was added Br2 (7.03 mL) in water (7 mL) dropwise at RT. The resulting dark orange suspension was stirred at RT for 1 h. The reaction mixture was diluted with NaOH (90 mL, 1 N) and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The product crashed in the column and tubing during attempted purification. Recovered product provided 8-benzyloxy-3-bromo-imidazo[1,2-a]pyridine (21 g).