Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:25]>CC(O)C.CO.ClCCl>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:25])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCCCc1nc(Cl)c2c(n1)c(I)cn2COCc1ccccc1
Solvent: CO
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCCc1nc(N)c2c(n1)c(I)cn2COCc1ccccc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
5-((Benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (1 g, 2.2 mmol) was suspended in 2-propanol (5 mL) and 35% (0.88) ammonia solution (4 mL). The reaction was stirred at 120° C. for 90 minutes in a Biotage Initiator microwave. A further 1 mL of 35% (0.88) ammonia solution was added to the reaction. The reaction was stirred at 120° C. for 90 minutes in a Biotage Initiator microwave. The reaction was evaporated in vacuo to yield a pale yellow oil. The oil was dissolved in the minimum volume of 20% methanol in dichloromethane and purified by chromatography on silica using a gradient of 0-100% ethyl acetate in cyclohexane gradient over 80 minutes. Fractions were combined and evaporated in vacuo to yield the title compound as a colourless oil (768 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].Cl.[CH3:13][NH:14][OH:15].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([CH:7]=[N+:14]([CH3:13])[O-:15])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: CNO
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cn1c(C=[N+](C)[O-])cnc1[N+](=O)[O-]

Procedure:
A mixture of 0.250 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde, 0.150 g. of N-methylhydroxylamine hydrochloride and 0.150 g. of sodium bicarbonate is refluxed in 80 ml. of anhydrous ethanol for 2 hours and after filtration is concentrated to small volume. The title compound crystallizes on cooling. Yield: 0.24 g. m.p. 208° -209° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[N:6][CH:7]=1.[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Br)cnc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1ncc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
To a solution of 10.68 g (56.2 mmol) 5-bromopyridine-2,3-diol in 290 mL MeOH was added 1(N) aqueous NaOH solution (56.2 mL). A solution of benzyl bromide (5.07 mL, 42.6 mmol) in MeOH (20 mL) was added dropwise to this mixture. After stirring at room temperature for 6 h, the reaction mixture was partitioned between water and EtOAc. Layers were separated and the aqueous phase was extracted with EtOAc (3×). Combined organic solutions were washed with brine (1×), dried over Na2SO4 and concentrated in vacuo. The resulting solid was recrystallized from MeOH-EtOAc to give 3-(benzyloxy)-5-bromopyridin-2-ol as a white solid (7.9 g, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5](=[O:17])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1.Br[CH:22]([CH3:26])[CH:23](Br)[CH3:24].C(=O)([O-])[O-].[K+].[K+].[K+].[Br-:34]>CC(C)=O>[Br:34][CH2:24][CH2:23][CH2:22][CH2:26][O:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5](=[O:17])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1
Reactant: [Br-]
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(O)c1
Reactant: CC(Br)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(OCCCCBr)c1

Procedure:
This compound (41) was prepared from 3′-hydroxy-3,4-methylenedioxy-chalcone, 12 (2.7 g, 10 mmol), dibromo butane (3.6 mL, 30 mmol) and potassium carbonate (2.76 g, 20 mmol) in dry acetone (100 mL) using the identical procedure as described for 39. Yield 3.6 g (89%); mp 97-98° C.; MS (FAB) 403/405 (M++1); IR (KBr) 1654; 1H NMR (200 MHz, CDCl3) δ 7.73 (d, J=15.6 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.51 (s, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.34 (d, J=15.6 Hz, 1H), 7.16 (s, 1H), 7.14-7.07 (m, 2H), 6.84 (d, J=7.9 Hz, 1H), 6.02 (s, 2H), 4.07 (t, J=5.6 Hz, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.16-1.94 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[C:17](=S)=[S:18].Cl>O.CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:17]([SH:18])=[N:14][N:13]=3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: S=C=S
Reactant: Cn1ccc2ccc(C(=O)NN)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ccc2ccc(-c3nnc(S)o3)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 1-methyl-1H-indole-6-carboxylic acid hydrazide (2.8 g, 14.8 mmol), potassium hydroxide (0.91 g, 16.3 mmol) and methanol (50 ml) was stirred at room-temperature for 30 min. Carbon disulfide (2.25 g, 29.6 mmol) was added and the mixture was stirred for 15 h at reflux. The mixture was allowed to cool to room-temperature, water was added, pH was adjusted to 3 by adding concentrated aqueous hydrochloric acid. The crystalline product was isolated by filtration and washed with water. Yield 2.75 g (80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].N1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]1(C)[CH:22]=CC(S(Cl)(=O)=O)=C[CH:18]=1.[NH4+].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8]([C:13]([C:14]3[CH:22]=[CH:17][CH:18]=[CH:16][CH:15]=3)=[CH:12][N:7]=[CH:6]2)=[CH:9][CH:10]=1
Reactant: c1ccncc1
Reactant: COc1cccc(CN)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc2c(-c3ccccc3)cncc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxybenzylamine (15 g) and pyridine (15 mL) in CH2Cl2 (100 mL) at 0° C. was added p-toluenesulfonyl chloride (21 g) portionwise. After addition was complete, the mixture was stirred at r.t. for 2 h and then saturated NH4Cl was added. The mixture was extracted with Et2O and the extracts were washed with H2O, brine, dried (MgSO4) and concentrated. The residue, 2-bromoacetophenone (23 g) and Cs2CO3 (45 g) in acetone (400 mL) were stirred at r.t. for 20 h. The acetone was evaporated and saturated NH4Cl was added. The mixture was extracted with EtOAc and the organics were washed with H2O, brine, dried (MgSO4) and concentrated. The residual solid was swished in Et2O for 3 h and then mixed with TFA (17 mL). After heating at 75° C. for 2.5 h, the mixture was cooled to r.t., EtOAc and H2O were added and the aqueous phase was made basic by the careful addition of solid K2CO3. The organic phase was washed with saturated NaHCO3, H2O, brine and dried (MgSO4). Concentration and chromatography (silica gel; hexane/EtOAc (3:2 to 1:1) provided the title compound as a solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([CH:26]2[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]2)[C:19](=[O:34])[C:18]=1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:38][CH:37]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([CH:26]2[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]2)[C:19](=[O:34])[C:18]=1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[NH:3][C:4](=[O:7])[O:5][N:49]=2)=[CH:38][CH:37]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(OC)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogen carbonate (0.54 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[7-butyl-4-(4-methoxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.16 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.063 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.053 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.069 g, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[N:30]=5)=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[CH:32]=[CH:33][C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:22]3[CH:21]=[N:20][N:17]4[CH:18]=[CH:19][C:14]([N:9]5[C@@H:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)[CH2:12][O:11][C:10]5=[O:13])=[N:15][C:16]=34)=[CH:28][CH:27]=2)=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ccc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cc5)nc34)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2ccc(F)cc2)N1c1ccn2ncc(-c3ccc(-c4cc[nH]n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
To (S)-4-(4-fluorophenyl)-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (80 mg, 0.14 mmol) in DCM (4 mL) was added TFA (1 mL) and the reaction was stirred for 4 hours at ambient temperature. The reaction was concentrated to dryness, and 7N ammonia in methanol was added to the residue. After concentration to dryness, the residue was purified by reverse phase chromatography (SP4, 12M, water/CH3CN 100:0 to 0:100, 20 column volumes) to yield (S)-3-(3-(4-(1H-pyrazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(4-fluorophenyl)oxazolidin-2-one (35 mg, 57% yield) as a white solid. LCMS (APCI+) m/z 441.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12]([NH:15][CH3:16])(=[O:14])=[O:13].Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH3:18][N:19]([CH3:20])[C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[C:2]([F:1])[CH:7]=1
Reactant: CNS(=O)(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CNS(=O)(=O)c1cc([N+](=O)[O-])c(N(C)C)cc1F
Reaction time: 1 h
Yield: 45.7 %

Procedure:
A solution of 2,4-difluoro-N-methyl-5-nitrobenzenesulfonamide (8.0 g, 31.6 mmol) in CH2Cl2 (200 mL) at −20° C. was treated with dimethylamine hydrochloride (2.56 g, 31.6 mmol). The resulting mixture was treated dropwise with triethylamine and stirred for 1 hour before being treated with 15% aqueous HCl to adjust the pH to 3, diluted with water, and extracted with EtOAc. The organic extract was dried (sodium sulfate), concentrated, and subjected to flash chromatography (20-50% EtOAc-petroleum ether) to give 4-(dimethylamino)-2-fluoro-N-methyl-5-nitrobenzenesulfonamide (4.0 g, 46%) as a yellow solid. MS (m/z) 278.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.N1C(C)=CC=CC=1C.[CH3:38][S:39]([NH:42][C:43]1[S:44][C:45]([CH2:48][C:49](O)=[O:50])=[CH:46][N:47]=1)(=[O:41])=[O:40].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.O>[CH3:38][S:39]([NH:42][C:43]1[S:44][C:45]([CH2:48][C:49]([NH:2][CH:3]2[C:28](=[O:29])[N:5]3[C:6]([C:12]([O:14][CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]23)=[O:50])=[CH:46][N:47]=1)(=[O:40])=[O:41]
Reactant: CS(=O)(=O)Nc1ncc(CC(=O)O)s1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cnc(NS(C)(=O)=O)s3)[C@H]2SC1
Reaction time: 3.5 h
Yield: 29.4 %

Procedure:
To a suspension of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.3 g) in methylene chloride (100 ml) was added 2,6-lutidine (1.08 g) at 8° C., and the mixture was stirred for a while. To the resultant solution were added 2-(2-methanesulfonamidothiazol-5-yl)acetic acid (2.6 g) and dicyclohexylcarbodiimide (2.06 g) under ice-cooling with stirring, and the stirring was continued at the same temperature for an hour and then at ambient temperature for additional 3.5 hours. After addition of water, the precipitated substance was removed by filtration. The filtrate was washed with 10% hydrochloric acid, and the organic layer was separated out, and washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain benzhydryl 7-[2-(2-methanesulfonamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (1.8 g). The same product (1.8 g) was recovered from the removed substance obtained above. Total yield: 3.6 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[CH2:17][C:16]2([F:19])[F:18])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>CCCCCC.C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([O:13][CH2:14][C@H:15]2[CH2:17][C:16]2([F:19])[F:18])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CC2(F)F)cc1
Solvent: CCO
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1

Procedure:
A racemate (48.4 g) of (2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate was resolved by HPLC (column: CHIRALPAK AD (trade name), 50 mmID×500 mL, DAICEL CHEMICAL INDUSTRIES, LTD., mobile phase:hexane/ethanol=50:50) to give the title compound having a shorter retention time (18.4 g). The steric configuration was determined by X ray structure analysis.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][C:14](=[C:17]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH:24]=[CH:23][C:22]3[S:21][C:20]([CH:31](C)C(O)=O)=[CH:19][C:18]2=3)[CH2:13][CH2:12]1.C[C:37]([CH3:39])=[O:38]>>[C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][C:14](=[C:17]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH:24]=[CH:23][C:22]3[S:21][C:20]([CH2:31][CH2:39][C:37]([OH:8])=[O:38])=[CH:19][C:18]2=3)[CH2:13][CH2:12]1
Reactant: CC(C(=O)O)c1cc2c(s1)C=Cc1ccccc1C2=C1CCNCC1
Reactant: CC(C)=O
Agent: O=S(=O)(O)c1ccccc1
Product: O=C(O)CCc1cc2c(s1)C=Cc1ccccc1C2=C1CCNCC1
Temperature: 25 °C
Yield: 30 %

Procedure:
3-(4-Piperidin-4-ylidene-4H-1-thiabenzo[f]azulen-2-yl-propionic acid benzenesulfonate of 99.6% purity (1.0 g) was dissolved in acetone (50 mL) by heating and allowed to cool down to room temperature and the crystals deposited therefrom were filtered to give 0.30 g (recovery rate: 30%) of 3-(4-piperidin-4-ylidene-4H-1-thiabenzo[f]azulen-2-yl) propionic acid benzenesulfonate of 100% purity.
Reaction SMILES: [CH3:1][CH:2]([NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1)[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.Cl>O.O1CCCC1>[CH3:1][CH:2]([NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1)[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc(C(C)Nc3nc(-c4ccccc4)cs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Nc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CC(=O)O)cc2)cc1

Procedure:
A mixture of methyl 4-[4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyloxy]phenylacetate (510 mg), a 1N aqueous sodium hydroxide solution (2.5 mL), methanol (5 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 1 hr. Water was added to the reaction mixture, 1N hydrochloric acid (3 mL) was added to the mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 4-[4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyloxy]phenylacetic acid. The crystals were recrystallized from diethyl ether-hexane to give colorless prism crystals (427 mg, 87%). melting point: 116-118° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[F:10][C:11]([F:19])([F:18])[C:12](=O)[C:13](OC)=[O:14]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:9][C:13](=[O:14])[C:12]([C:11]([F:19])([F:18])[F:10])=[N:8]2
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: Nc1cccc(Br)c1N
Solvent: CCO
Product: O=c1[nH]c2c(Br)cccc2nc1C(F)(F)F
Yield: 29 %

Procedure:
A solution of 3-bromobenzene-1,2-diamine (1.00 g, 5.35 mmol, CombiBlocks, Inc., San Diego, Calif.) and methyl 3,3,3-trifluoro-2-oxopropanoate (0.655 mL, 6.42 mmol; Alfa Aesar, Ward Hill, Mass.) in EtOH (15 mL) was stirred at reflux under argon for 17 h. The mixture was concentrated in vacuo. Purification by silica gel (0-70% EtOAc/Hexanes) provided 8-bromo-3-(trifluoromethyl)quinoxalin-2(1H)-one (224b, 29% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (1H, br. s.), 8.04 (1H, d, J=7.8 Hz), 7.95 (1H, d, J=8.2 Hz), 7.38 (1H, t, J=7.9 Hz). 19F NMR (377 MHz, DMSO-d6) δ ppm −68.44 (3F, br. s.). MS (ESI, pos. ion) m/z: 293.0 (M+1).
Reaction SMILES: [CH3:1][C@H:2]([C:7](=O)[C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:10]=2[CH:9]=1)[CH2:3][C:4](O)=[O:5].O.[NH2:25][NH2:26]>C(O)C>[CH3:1][C@@H:2]1[C:7]([C:8]2[CH:22]=[CH:21][C:11]3[N:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:14][C:10]=3[CH:9]=2)=[N:26][NH:25][C:4](=[O:5])[CH2:3]1
Reactant: NN
Reactant: C[C@@H](CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Solvent: CCO
Solvent: O
Product: C[C@H]1CC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
177 mg (572 μmol) (S)-3-methyl-4-oxo-4-(2-phenyl-benzoxazol-6-yl)-butyric acid are combined with 10 ml of ethanol and 350 μl (7050 μmol) hydrazine hydrate. The reaction mixture is refluxed for 3 h. The solvent is eliminated by rotary evaporation in vacuo and the residue is separated through silica gel (eluant cyclohexane/EA).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)=[CH2:2].BrN1C(=[O:17])CCC1=O.[OH-].[Na+]>O.CC(O)(C)C>[O:17]1[CH2:2][CH:1]1[C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(C#N)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C2CO2)nc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 6-ethenylpyridine-3-carbonitrile (0.742 g, 5.70 mmol) in a 2:1 ratio of H2O:t-BuOH (30 mL) was treated with N-bromosuccinimide in portions over 5 min (1.07 g, 5.99 mmol) and stirred at 40° C. for 1 h. After cooling to 5° C., the reaction was basified with drop wise addition of solution of sodium hydroxide (0.684 g in 5 mL of H2O, 17.1 mmol) and stirred for another 1 h. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with saturated aqueous NaCl (1×30 mL) and dried over MgSO4. Evaporation of the solvent and purification over SiO2 (0-30% EtOAc/hexanes as eluent) provided 6-(oxiran-2-yl) pyridine-3-carbonitrile.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C:18](O)=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:21])[O:5][N:4]=1)[CH3:2].S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C:18]([Cl:24])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:21])[O:5][N:4]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1CC(=O)O
Solvent: Cc1ccccc1
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1CC(=O)Cl

Procedure:
A mixture of 10.3 g. (0.036 mole) 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetic acid and 22.0 g. (0.185 mole) thionyl chloride in 100 ml. toluene is stirred at room temperature for 18 hours. The toluene is removed in vacuo to give 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C[Li].Cl[C:13]1C(Cl)=C(O)C(C#N)=C(C#N)C=1O.[OH-].[Na+]>C(OCC)C.O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:13])[N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(Cl)n1
Reactant: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N
Agent: [Li]C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CSc1nc(C)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.93 mL of 4-chloro-2-methylthiopyrimidine was dissolved in 50 mL of diethyl ether, and 100 mL of a 1 M diethyl ether solution of methyllithium was gradually added to the solution at −78° C. The reaction solution was stirred at 0° C. for 1 hour, and then a solution prepared by mixing 2.3 mL of water and 15 mL of tetrahydrofuran was added to the reaction mixture. The reaction mixture was stirred at the same temperature for 10 minutes, and then 50 mL of a tetrahydrofuran solution containing 13.7 g of 2,3-dichloro-5,6-dicyanohydroquinone was added to the reaction solution. The reaction solution was stirred at the same temperature for 1 hour, and then 100 mL of a 1 N aqueous solution of sodium hydroxide was added to the reaction solution. The obtained reaction solution was extracted with hexane, and the organic phase was washed with a 1 N aqueous solution of sodium hydroxide and saturated brine. The resultant solution was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 5.1 g of 4-chloro-6-methyl-2-methylthiopyrimidine product [1-9] as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:21])[CH:3]=1.Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:23][OH:24])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:21])[CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2F)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)cc2F)cc1
Yield: 85.6 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(4′-chloro-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (1.100 g, 0.00359 mol) was allowed to react with hydroxylamine hydrochloride (0.300 g, 0.00432 mol) in the presence of sodium carbonate (0.458 g, 0.00432 mol) in absolute ethanol (20 mL) to give 0.989 g of 4-(4′-chloro-2′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as an off-white solid; mp 147.5-149.5° C.