Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:25][CH:26]([S:28]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)[C:35]([CH2:51][N:52]1[CH2:57][CH2:56][C:55](=O)[CH:54]([CH3:59])[CH2:53]1)=[C:34]2[C:60]([NH:62][C@H:63]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:64]([F:67])([F:66])[F:65])=[O:61])(=[O:30])=[O:29])[CH3:27]>ClCCl.O>[CH3:27][CH:26]([S:28]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)[C:35]([CH2:51][N:52]1[CH2:57][CH2:56][CH:55]([N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[CH:54]([CH3:59])[CH2:53]1)=[C:34]2[C:60]([NH:62][C@H:63]([C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1)[C:64]([F:67])([F:65])[F:66])=[O:61])(=[O:29])=[O:30])[CH3:25]
Reactant: C1COCCN1
Reactant: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)N[C@H](c2ccccc2)C(F)(F)F)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)N[C@H](c2ccccc2)C(F)(F)F)CCC1N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.6 %

Procedure:
Acetic acid (9.73 μL, 0.170 mmol), morpholine (0.030 g, 0.340 mmol), and sodium triacetoxyborohydride (0.048 g, 0.227 mmol) were added to a suspension of 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.080 g, 0.113 mmol) in dichloromethane (1.5 mL). The mixture was stirred at room temperature for 3 d. The solution was diluted with water (3 mL) and methylene chloride (5 mL) and poured into a hydrophobic frit to separate the phases. The organic phase was concentrated and the residue was purified via HPLC (Waters, Sunfire C18, 30×100 mm, 35-69% CH3CN/H2O with 0.1% TFA) to afford 6-[(1-methylethyl)sulfonyl]-3-{[3-methyl-4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.040 g, 45% yield) as a mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6) δ10.1250=4 Hz, 0.5H), 10.045 (br d, J=4 Hz, 0.5H), 8.38 (m, 2H), 8.14 (m, 2H), 7.97 (m, 2 H), 7.84 (d, J=8 Hz, 1H), 7.73 (m, 1H), 7.63 (m, 2H), 7.45 (br s, 2H), 6.24 (apparent q, J=6.8 Hz, 1H), 3.50 (m, 4H), 3.17 (m, 1H), 2.40-2.05 (m, 5H), 1.95-0.75 (m, 14H), 0.410 (d, J=6 Hz, 1.7H), 0.295 (br d, J=4 Hz, 1.3H). MS (m/z) 777.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10](COCC[Si](C)(C)C)[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=O)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH:41]1CCCN2CCCN=[C:42]12.CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl.O>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([NH:41][CH3:42])=[O:28])[N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CN=C2NCCCN2C1
Reactant: COC(=O)c1cccc(Cn2nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)c1
Temperature: 110 °C
Yield: 75 %

Procedure:
Methyl 3-{[3-[[(5-chloro-2-thienyl)sulfonyl]({[2-(trimethylsilyl)ethyl]oxy}methyl)amino]-4-(methyloxy)-1H-indazol-1-yl]methyl}benzoate (for a preparation see Intermediate 31) (70 mg, 0.112 mmol) in a Biotage microwave vial was added 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (Aldrich) (7.83 mg, 0.056 mmol) and methylamine solution in THF (2M, 1.125 mL). The reaction vessel was sealed and heated in a Biotage Initiator microwave oven using initial very high absorption level to 80° C. for 75 min. The reaction mixture was diluted with DCM (2 mL) and water (3 mL). The organic phase was separated, and the aqueous layer was further extracted with DCM (2 mL). The combined organic solutions were dried through an hydrophobic frit and concentrated under a nitrogen stream in a blowdown unit. The residue was treated TBAF in THF (1M, 1.125 mL, 1.125 mmol). The reaction vessel was sealed and heated in a Biotage Initiator at 110° C. for 15 min (very high absorption level). The solvent was removed under a nitrogen stream in a blowdown unit (T=35° C. overnight), dissolved in 1:1 MeOH-DMSO (2 mL) and purified by Mass Directed AutoPrep on standard C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus to give the title compound (41.7 mg, 75%) LCMS (System A) RT=1.03 min, ES+ve m/z 491/493 (M+H)+.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31]Br)[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31][N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: Clc1ccc(CCBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCc2ccc(Cl)c(Cl)c2)CC1)c1ccccc1
Temperature: 100 °C
Yield: 94.2 %

Procedure:
4-Benzamidopiperidine (204 mg.) and anhydrous potassium carbonate (138 mg.)were intimately ground together and added to 2-(3,4-dichlorophenyl)ethyl bromide (254 mg.). The resulting paste was heated at 100° C for 2 hours to give a hard solid. This was broken up, washed well with water andether and dried to give the title compound (355 mg.). Recrystallisation from ethanolic hydrogen chloride and ether gave the hydrochloride (237 mg.), m.p. 286.0° C. (Found: C, 58.2; H, 5.8; N, 6.8. C20H22Cl2N2O.HCl requires C, 58.05; H, 5.6; N, 6.8%).
Reaction SMILES: BrCCC1C2[C:7](=CC=CC=2)[NH:6][CH:5]=1.[C:13]1(=O)[O:17][CH2:16][CH2:15][CH2:14]1.Br[CH2:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:31])[NH:24][CH:23]=1.[C:32]1(=O)OC[CH2:34][CH2:33]1.C(OCC)(=O)CC(C)=O.CNC>>[Cl:31][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[C:22]1[CH2:21][CH2:20][CH2:32][C:33]([CH3:34])([CH:14]([CH2:13][N:6]([CH3:7])[CH3:5])[CH2:15][CH2:16][OH:17])[C:23]=1[NH:24]2
Reactant: Clc1cccc2[nH]cc(CCBr)c12
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=C1CCCO1
Agent: CNC
Solvent: CCOC(=O)CC(C)=O
Product: CN(C)CC(CCO)C1(C)CCCc2c1[nH]c1cccc(Cl)c21

Procedure:
By following the procedure of this example and using the appropriate compounds of formulae IV, V and VIII and amine of formula HNR5R6, other compounds of formula I are obtained. For example, by using 3-(2-bromoethyl)-4-chloroindole, ethyl acetoacetate γ-butyrolactone and dimethylamine, 5-chloro-γ-[(dimethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrocarbazole-1-propanol is obtained.
Reaction SMILES: Cl.CO[CH:4](OC)[CH2:5]Cl.[C:9]([O:15]CC)(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].[OH-].[Na+]>N1C=CC=CC=1.C(O)C.O>[CH3:13][C:11]1[O:12][CH:4]=[CH:5][C:10]=1[C:9]([OH:15])=[O:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(CCl)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1occc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a stirred solution of water (400 mL) and conc. hydrochloric acid (40 mL) is added chloroacetaldehyde-dimethylacetal (300 g) and brought to reflux. The homogenous solution was then added to a stirred cooled solution of ethyl acetoacetate (260 g. 2 mol) in pyridine (500 mL). This reaction mixture was allowed to stir overnight at ambient temperature. The lower layer of the reaction mixture was then removed and combined with the methylene chloride (2×100 mL) extract of the upper layer after dilution with an equal volume of water. The combined organics were washed with 1N HCl (200 mL), and evaporation of the solvent left the crude ester. Hydrolysis of this ester was accomplished by refluxing for 1 hour in ethanol (100 mL) and sodium hydroxide (50 g) in water (700 mL). The reaction mixture was then poured into water/ice (3 L) and acidified with hydrochloric acid to give a cream precipitate which was collected on a filter, washed with water and dried, to produce 180 g of 2-methyl-3-furoic acid, m.p. 105-106° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[O:13]=[C:14]1[CH:16]([C:17]([OH:19])=[O:18])[CH2:15]1.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[O:13]=[C:14]1[CH2:15][CH:16]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:1]1
Reactant: O=C(O)C1CC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C1CC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Carbonyldiimidazole (42.6 g, 263 mmol) was slowly added to a solution of 3-oxo-cyclopropane carboxylic acid (25.0 g, 219 mmol) in DCM (500 mL), stirred at RT for 2 h, treated with benzyl alcohol (24.17 g, 223 mmol) and stirred at RT for 16 h. The mixture was diluted with water, extracted with DCM (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to afford benzyl 3-oxocyclobutanecarboxylate (29.5 g, 66%) as a colorless syrup. 1H NMR (400 MHz, DMSO-d6): δ 7.38-7.35 (m, 5H); 5.14 (s, 2H); 3.62 (m, 5H); MS (ESI) m/z: 227.1 (M+Na+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:23]=[C:22]([CH3:24])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([CH3:25])[CH:9]=2)[N:4]=1.[CH3:28][S:29]([O:32]C)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O-:32])(=[O:31])=[O:30].[CH3:28][N+:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][CH2:14][CH2:13][O:12][C:11]2[C:22]([CH3:24])=[CH:23][C:8]([C:5]3[N:4]=[C:3]([C:2]([F:1])([F:26])[F:27])[O:7][N:6]=3)=[CH:9][C:10]=2[CH3:25])[CH:17]=1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1cccnc1
Reactant: COS(C)(=O)=O
Solvent: ClCCl
Product: CS(=O)(=O)[O-]
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc[n+](C)c1
Reaction time: 8 h
Yield: 157 %

Procedure:
To a solution of 3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine (1 g, 2.6 mmol, 1.1 eq) in 10 ml of methylene chloride was added methyl methanesulfonate (0.32 g, 2.9 mmol) and the mixture was gently refluxed overnight. After adding 0.5 eq of methyl methanesulfonate, the mixture was allowed to reflux an additional 24 h. The mixture was concentrated in vacuo and a solid residue was washed with ether to afford 1.11 g (85.3%) of 1-methyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridinium methanesulfonate, as a white powder.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[O:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH:17]2[CH2:18][CH2:19][O:15][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OC1CCOC1
Product: N#Cc1c(OC2CCOC2)cccc1[N+](=O)[O-]
Yield: 50 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and tetrahydrofuran-3-ol in 50% yield as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 1H), 2.32 (m, 1H), 3.81 (td, J=8.3, 4.6 Hz, 1H), 3.89 (m, 2H), 3.98 (dd, J=10.8, 4.5 Hz, 1H), 5.36 (m, 1H), 7.75 (dd, J=8.1, 1.5 Hz, 1H), 7.91 (t, J=8.2 Hz, 1H), 7.95 (dd, J=8.2, 1.6 Hz, 1H).
Reaction SMILES: C([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([N:21]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([N:34]1[C:46]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:40]3[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:13]=2)C1C=CC=CC=1.C(=NC1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].CN(C=O)C>O>[CH:45]1[C:46]2[N:34]([C:12]3[CH:11]=[CH:10][C:9]4[NH:8][C:20]5[C:15]([C:14]=4[CH:13]=3)=[CH:16][C:17]([N:21]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:18][CH:19]=5)[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]=2[CH:42]=[CH:43][CH:44]=1
Reactant: c1ccc(Cn2c3ccc(-n4c5ccccc5c5ccccc54)cc3c3cc(-n4c5ccccc5c5ccccc54)ccc32)cc1
Agent: C(=Nc1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc2[nH]c3ccc(-n4c5ccccc5c5ccccc54)cc3c2c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
Under a nitrogen atmosphere, a suspension of N-benzyl-3,6-di(N-carbazolyl)carbazole (2.06 g, 3.5 mmol), benzylideneaniline (1.27 g, 7.0 mmol) and t-BuOK (5.06 g, 50 mmol) in a dried DMF (30 mL) was stirred at 75° C. for 4 hours. Water (about 150 mL) was added and black tar precipitated was filtrated. The tar-like material was dissolved in hot chloroform, to which anhydrous magnesium sulfate and activated carbon were added to be stirred for 30 minutes with heating. The mixture was filtrated, the filtrated liquid was concentrated, and then the residuum was recrystallized with chloroform/ethanol to give the compound in the title, (3,6-di(N-carbazolyl)carbazole) as beige powder. The yield was 29%. The melting point was 185 to 187° C. NMR data are shown in FIG. 17 (1H NMR) and FIG. 18 (13C NMR).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][C:12]([OH:14])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15]([O-])([O-])=O.[Na+].[Na+].CN([CH:24]=[O:25])C>CCOC(C)=O>[Si:1]([O:8][CH2:9][C:10]#[C:11][C:12]([O:25][CH2:24][CH3:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)O
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C#CCO[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
To a solution/suspension of 2.0 g of 4-(t-butyldimethylsilyloxy)-2-butynoic acid and 1.48 g Na2CO3 in 37 mL DMF under N2 was added slowly 1.58 mL Et2SO4. After stirring overnight, the reaction was diluted with EtOAc and washed several times with H2O. The organic extract was then washed with brine and dried over MgSO4. Filtration, evaporation and flash chromatography with a 5%-10% Et2O/hexanes gradient provided 1.58 g of pure product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][O:10][C:11]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1.[C:35]1([C@@H:41]2[CH2:43][C@H:42]2[N:44]2[C:52](=[O:53])[CH:47]3[CH2:48][NH:49][CH2:50][CH2:51][N:46]3[C:45]2=[O:54])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[O:53]=[C:52]1[CH:47]2[CH2:48][N:49]([C:28]([NH:12][C:11]3[O:10][N:9]=[CH:8][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:29])[CH2:50][CH2:51][N:46]2[C:45](=[O:54])[N:44]1[C@H:42]1[CH2:43][C@@H:41]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1C2CNCCN2C(=O)N1[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1oncc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1oncc1-c1ccccc1)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)C2C1
Reaction time: 2 h
Yield: 30 %

Procedure:
4-Phenylisoxazol-5-amine (2 eq) was dissolved in THF (0.1M) and treated with LiHMDS (0.1N, 2 eq), after stirring for 1 h CDI (1 eq) was added. The suspension was stirred for a further 2 h and then A5 (1 eq, 0.1 M) was added and the reaction stirred 5 h. The reaction was quenched with sat. aq. NH4Cl solution and then extracted with EtOAc. Organic layers were washed with brine, dried and concentrated under reduced pressure. The crude material was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 30% yield. 1H NMR (400 MHz, DMSO, 300K) δ 9.68 (1H, s), 9.00 (1H, s), 7.54 (2H, m), 7.43 (2H, m), 7.30 (3H, m), 7.23 (3H, m), 4.35 (1H, m), 4.16-4.06 (2H, m), 3.17-2.88 (3H, m), 2.69 (1H, m), 2.42-2.31 (1H, m), 1.61-1.49 (1H, m), 1.45-1.39 (1H, m). MS (ES+) C25H23N5O4 requires 457, found: 458 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:10]=[CH:11][CH:12]=1.[CH3:26]OCOC.C(Cl)Cl>C1(C)C=CC=CC=1.CCOCC>[Br:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[CH2:26][N:15]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:14][CH2:13]2
Reactant: COCOC
Reactant: Cc1ccc(S(=O)(=O)NCCc2cccc(Br)c2)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCc3cc(Br)ccc3C2)cc1
Reaction time: 15 h
Yield: 90 %

Procedure:
To a stirred solution of sulfuric acid (60% w/w, 20 g) in 32 mL of toluene at r.t. was added 7.60 g of N-[2-(3-bromo-phenyl)-ethyl]-4-methyl-benzenesulfonamide, followed by 32 mL of dimethoxymethane. The reaction mixture was heated over an oil bath set at 50° C. externally with stirring under nitrogen for 15 h. LC/MS: retention time=4.549 min, MS 366/368. TLC (DCM): SM Rf=0.35, product Rf=0.65. The reaction was complete as judged by TLC. The reaction mixture was cooled to r. t. and diluted with ether (100 mL). The two layers were separated and the aqueous layer was extracted with ether (25 mL). The combined ethereal solution was washed with water (25 mL), saturated sodium bicarbonate (25 mL) and brine (20 mL), sequentially. Then, the ethereal solution was dried over anhydrous granular potassium carbonate, filtered, and concentrated in vacuo. The crude product, a solid after standing, was re-crystallized from ether (75 mL) and pentane (100 mL). The material was collected by suction filtration and dried under vacuum to obtain 6.6 g (90%) of the title compound as a white crystalline solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2.[H-].[Na+].[CH3:20]OCCOC.CI>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:20])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2
Reactant: COCCOC
Reactant: COC(=O)Cc1ccc2cc(OC)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCO
Product: COC(=O)C(C)c1ccc2cc(OC)ccc2c1

Procedure:
To a mixture of 22 g. of methyl 2-(6-methoxy-2-naphthyl)acetate (prepared by treating 20.5 g. of 2-(6-methoxy-2-naphthyl)acetic acid with 4.5 g. of diazomethane in ether), and 2.5 g. of sodium hydride in 150 ml. of 1,2-dimethoxyethane; 25 g. of methyl iodide are added. The reaction mixture is allowed to stand for several hours; then it is diluted with ethanol followed by water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered and evaporated to yield methyl 2-(6-methoxy-2-naphthyl)propionate.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O.O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1(C)C=CC=CC=1>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Nc1ccccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12 g (0.1 mole) of 4-tolualdehyde and 10.9 g (0.1 mole) of 2-aminophenol in toluene is heated at reflux with azeotropic removal of water. After 20 hours at reflux, the reaction is cooled to room temperature, 44.3 g (0.1 mole) of lead tetraacetate is added, and the mixture is stirred at room temperature overnight. The solids are removed by filtration, and the filtrate is swirled with basic alumina. Removal of the solvent in vacuo affords the solid product which is then purified by recrystallization from benzene.
Reaction SMILES: O.[NH2:2][C:3]1[C:8]([C:9](=[S:17])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][C:19]([OH:21])=[O:20].[Na].[CH2:23](I)[CH3:24].O>CN(C)C=O>[NH2:2][C:3]1[C:8]([C:9](=[S:17])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][C:19]([O:21][CH2:23][CH3:24])=[O:20]
Reactant: Cc1ccc(C(=S)c2cccc(CC(=O)O)c2N)cc1
Reactant: CCI
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(C(=S)c2ccc(C)cc2)c1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Seventeen grams (0.05 mole) of sodium 2-amino-3-(4-methylthiobenzoyl)phenylacetic acid monohydrate are dissolved in approximately 150 ml of dimethylformamide and the solution treated with 33 g ethyl iodide. The solution is stirred at room temperature for 2.5 hrs. and added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate and concentrated to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:16])=[N-]>CO>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: C=[N+]=[N-]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1N

Procedure:
To a solution of 2-amino-3-nitro-benzoic acid (6 g, 33 mmol) in methanol (20 mL), an ethereal solution of diazomethane gas was added until the staring material is completely consumed. The reaction mixture was then evaporated under reduced pressure and the crude resulting solid was purified by flash column chromatography using 5% ethylacetate & hexane as an eluent, to obtain 2 g of the required product as a yellow coloured solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])=[CH:20][C:19]=1[Cl:30].CC(=O)OCC>CN(C=O)C>[Cl:30][C:19]1[CH:20]=[C:21]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: C=C(c1ccc(Cl)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4ccc(Cl)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
To a solution of (Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (397 mg, 1.66 mmol) and 1,2-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (400 mg, 1.66 mmol) in DMF (5 mL) at rt was added TEA (168 mg, 1.66 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (6:1) to give the final title compound 5-(5-(3,4-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (180 mg; yield 24.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.83-7.60 (m, 5H), 4.45 (d, J=18.8 Hz, 1H), 4.26 (d, J=18.4 Hz, 1H), 1.48 (s,6H) ppm; HPLC purity: 96.8% at 220 nm and 97.5% at 254 nm; MS: m/z=444.3 (M+, ESI+).