Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:12][C:13]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)[CH:27]=3)=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][C@H:17]([CH3:46])[N:18]3[C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])[CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([O:12][C:13]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[CH:27]=3)=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][C@H:17]([CH3:46])[N:18]3[C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])[CH2:11][CH2:10][CH2:9]1
Reactant: C[C@H]1CCc2c(ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c2OC2CCC2)N1C(=O)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CCNCC4)c3)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a 0° C. solution of (S)-tert-butyl 4-(4-(5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.032 g, 0.060 mmol) in dichloromethane (2.0 mL). The ice bath was removed, and the mixture stirred at rt for 1.5 h. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-(5-cyclobutoxy-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.022 g, 85%) as an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.57-0.71 (m, 1H), 0.78-0.91 (m, 1H), 0.92-1.04 (m, 1H), 1.13 (d, J=6.45 Hz, 3H), 1.19-1.45 (m, 3H), 1.53-1.71 (m, 2H), 1.79-2.42 (m, 11H), 2.74-2.92 (m, 2H), 2.94-3.09 (m, 1H), 3.30 (br d, J=12.61 Hz, 2H), 4.04-4.21 (m, 1H), 4.28 (ddt, J=11.43, 7.62, 3.96, 3.96 Hz, 1H), 4.66-4.84 (m, 1H), 7.12 (d, J=8.21 Hz, 1H), 7.28 (d, J=8.21 Hz, 1H), 7.81 (s, 1H), 7.88 (s, 1H). MS (ESI, pos. ion) m/z 435 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CC(O)C>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: C1COCCN1
Solvent: CC(C)O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCOCC3)ncc2[N+](=O)[O-])CC1

Procedure:
A suspension of cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (100 mg, 0.293 mmol) and morpholine (0.256 mL, 2.93 mmol) in 2-propanol (1 mL) was irradiated in the microwave for 1 hour at 150° C. The reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-N-isopropyl-4-(2-morpholino-5-nitropyridin-4-ylamino)cyclohexanecarboxamide as a yellow powder (121 mg, quantitative yield). MS, m/z (C19H29N5O4): Calcd, 508.3. found, 509.1 [M+H].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1Br.[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.C1(C)C=CC=CC=1.CCOCC.O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:19]([CH:18]=1)[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1cccc(O)c1
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Yield: 7.1 %

Procedure:
2,4-Bis-trifluoromethylbromobenzene (5.86 g prepared by treatment of 2,4-di-carboxybromobenzene with hydrogen fluoride and sulphur tetrafluoride), 3-hydroxybenzoic acid (2.76 g) and anhydrous potassium carbonate (5.52 g) were heated in dimethylsulphoxide (5 ml) to 125°-130° for 14 hours. The mixture was cooled and poured into ice and water (500 ml). The mixture was acidified (HCl) and extracted with ether (300 ml). The extract was washed with water (2×300 ml), dried (MgSO4), and evaporated to give a solid. Further solid was obtained by re-extraction of the aqueous fractions with ether (250 ml). The solids were combined, taken up in hot toluene (60 ml) and diluted with petroleum (b.p. 60°-80°) to precipitate 3-hydroxybenzoic acid. The mixture was filtered and the filtrate evaporated to give a solid. This was washed with petroleum (b.p. 30°-40°). The washings were evaporated to give more solid. The solids were combined and re-crystallised from petroleum (b.p. 80°-100°) to give the required carboxylic acid (0.5 g) having a melting point of 133°-134°.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(OC(=O)C)C>CS(C)=O>[N:14]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(F)(F)F)c(N2CCCCC2)c1
Temperature: 55 °C
Reaction time: 43 h
Yield: 87.3 %

Procedure:
To a solution of 3-fluoro-4-(trifluoromethyl)benzonitrile (300 mg, 1.59 mmol) in DMSO (5.0 mL) was added piperidine (675 mg, 7.93 mmol), and the mixture was stirred for 43 hours at 55° C. After the mixture was cooled to room temperature, ethylacetate was added and washed with water then brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane:ethylacetate=10:1) to afford 3-piperidin-1-yl-4-(trifluoromethyl)benzonitrile (353 mg, 88% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[Se:25][C:24]=1[C:32]([NH2:34])=[O:33].CN(C=O)C.[OH-].[Na+]>>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:23]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:29])[CH3:30])[Se:25][C:24]=1[C:32]([NH2:34])=[O:33]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OCCOC

Procedure:
The reaction of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale yellow color solid, mp 198-204° C. IR (KBr) vmax 3430, 3162, 2961, 1627, 1576, 1474, 1463, 1386, 1321, 1242, 1131, 1092, 937, 859 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.63 (1H, s, exchangeable with D2O), 8.67 (1H, s), 8.64 (1H, s), 7.66 (2H, br s, exchangeable with D2O), 7.40 (1H, s), 7.28 (1H, s), 4.25-4.33 (4H, m), 3.75-3.80 (4H, m), 3.37 (3H, s), 3.36 (3H, s), 1.41 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.2, 167.4, 153.9, 153.8, 153.0, 148.6, 147.0, 146.0, 120.8, 112.1, 108.7, 108.6, 101.5, 70.0 (2C), 68.2, 68.0, 58.4, 58.3, 36.5, 32.2; LC-MS (positive ion mode): m/z 521, 523 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a 0° solution of 15 g of 2-(aminomethyl)pyridine, 15.44 g of triethylamine and 150 ml of methylene chloride is added 17.48 g of methanesulfonyl chloride in 100 ml of methylene chloride. The mixture is stirred at 0° C. for 1 hour followed by stirring at room temperature for 3 hours. The reaction is poured into saturated sodium bicarbonate and extracted with methylene chloride. The combined extracts are washed with saturated sodium chloride and concentrated in vacuo. The residue is purified by chromatography (silica gel: 10% methyl alcohol/ethyl acetate) to give 19.84 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[C:11]([CH3:16])=[CH:10]2)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Product: CCOC(=O)C(Cc1ccc2c(c1)cc(C)n2Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-2-ethoxy-3-{2-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[F:13][CH2:14][C:15]([CH2:19][F:20])([OH:18])[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1/[CH:17]=[CH:16]/[C:15]([CH2:19][F:20])([OH:18])[CH2:14][F:13]
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Reactant: C=CC(O)(CF)CF
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: OC(/C=C/c1cc(C(F)(F)F)ccc1Cl)(CF)CF
Temperature: 80 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
A mixture of 3-bromo-4-chlorobenzotrifluoride (1.50 g), 1-fluoro-2-fluoromethyl-3-buten-2-ol (0.80 g), potassium carbonate (2.10 g), tetrabutylammonium bromide (325 mg), palladium acetate (56 mg) and N,N-dimethylacetamide (10 ml) was stirred under a nitrogen atmosphere at 80° C. for 14 hours. To the reaction mixture, 1 N HCl was added followed by extraction with a hexane/ethyl acetate mixed (1/1) solvent; the resulting organic layers were combined and washed with a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride; the mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=10/1) to give 4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-trans-buten-2-ol (1.53 g) having a melting point of 61-62° C.
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]1[NH:8][C:7](=O)[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1.[Cl-].[Na+].[S:18](=O)(=[O:21])([OH:20])[OH:19]>>[Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]1[NH:8][CH2:7][C:6]2[CH:10]=[C:11]([S:18]([OH:21])(=[O:20])=[O:19])[CH:12]=[CH:13][C:5]=2[O:4]1
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2c(c1)CNC(C(Cl)(Cl)Cl)O2
Temperature: 0 °C

Procedure:
A mixture of 3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (10 g.--obtained as described in Example 3) and concentrated sulphuric acid (100 ml.) was heated on a steam bath for 18 hours, and drowned into ice (400 g.). The resulting solution was saturated with sodium chloride and extracted with ethyl acetae (4×100 ml.) The extracts were combined and dried, the solvent was evaporated, and the residue was crystallised from glacial acetic acid to give 3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-sulphonic acid, m.p. > 260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:27]1([C:30]([NH:24][C:3]2[CH:4]=[C:5]([CH:8]3[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)[CH:6]=[CH:7][C:2]=2[F:1])=[O:31])[CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Reactant: O=C(O)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CC3)c1)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.3 %

Procedure:
To an ice-cold mixture of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.3 mmol, 1.0 eq.), cyclopropanecarboxylic acid (0.46 mmol, 1.5 eq.), N,N-diisopropylethylamine (0.6 mmol, 2.0 eq.) in dichloromethane (5 mL) was added a solution of phosphorus oxychloride (0.36 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 2.5 hours. LC-MS indicated that the starting material was consumed completely. The reaction was quenched by 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layer was concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford 105 mg of methyl 2-(3-(cyclopropanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 89%. MS (ESI+APCI) M+1=397.2.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)[CH2:11][CH2:10]1.BrB(C)C>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH2:11][CH2:10]1
Reactant: COc1ccccc1C1(c2ccccc2OC)CC1
Agent: CB(C)Br
Solvent: ClCCl
Product: Oc1ccccc1C1(c2ccccc2O)CC1

Procedure:
1,1-Bis(2-methoxyphenyl)cyclopropane (10.0 g, 0.039 mole) was combined with 60 ml of dichloromethane and the mixture was cooled in an ice bath and then treated with 10.0 ml of bromodimethylborane with cooling and stirring. The starting material was consumed in less than 1 hour as determined by gas-liquid chromatography. The mixture was then diluted with 500 ml of ether and the resulting solution was extracted twice with water and then with water saturated with ammonium chloride, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 9.0 g (101 percent of theory) of the title compound as a brownish-black solid: m.p., 158-160° C. This eluted as one clean peak in gas-liquid chromatography and had a proton NMR spectrum consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].[I-].[Na+].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>O.CN(C=O)C>[N+:9]([C:3]1[CH:4]=[C:5]([O:8][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OCc2ccccn2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
4-Amino-3-nitrophenol (5.00 g, 32.4 mMol), Cs2CO3 (22.8 g, 70 mMol), sodium iodide (476 mg, 3.20 mMol) and 2-picolyl chloride hydrochloride (11.2 g, 35 mMol) were added to 20 mL of anhydrous DMF under an atmosphere of dry N2. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture is then poured into water. The precipitate was collected via suction filtration. The precipitate was partitioned between DCM and 1.0 N aqueous NaOH. The organic layer was washed 2 more times with 1 N aqueous NaOH to remove any unreacted phenol. The organic layer was then washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 7.7 g of a dark red solid. The solid was chromatographed on flash silica gel eluting with EtOAc/DCM (2080) to give 3.7 g of the title compound 47A as an orange solid.
Reaction SMILES: [H-].[Na+].C(OC([NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)=O)(C)(C)C.[CH2:19]1OCCOCCOCCOCCOC1.CI>C1COCC1>[CH3:19][O:18][CH2:17][C@@H:14]1[CH2:13][CH2:12][C@H:11]([NH2:10])[CH2:16][CH2:15]1
Reactant: C1COCCOCCOCCOCCO1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H]1CC[C@@H](N)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (72 mg, 1.78 mmol, 60% by weight suspended in mineral oil) was washed three times with 10 mL portions of hexanes, and suspended in dry THF (12 mL). The suspension was cooled to 0° C. To this suspension, cis-(tert-butoxy)-N-[4-(hydroxymethyl)cyclohexyl]carboxamide (0.273 g, 1.20 mmol) and 15-crown-5 (0.250 mL, 1.25 mmol) were added. The reaction mixture was then stirred at 0° C. for about 30 min. Methyl iodide was then added dropwise (75 μL, 1.20 mmol). Since the reaction was not complete after overnight stirring at room temperature, the mixture was cooled to 0° C. and reacted with 100 mg of sodium hydride and 0.250 mL of 15-crown-5. After about 2 hours at room temperature, the reaction was complete. The reaction was quenched by the slow addition of water and the crude product was extracted with ethyl acetate. Purification was effected by column chromatography on silica gel using 20% ethyl acetate in hexanes as the eluent. ES-MS (m/z) 244. cis-(Tert-butoxy)-N-[4-(methoxymethyl)cyclohexyl]carboxamide was dissolved in ethanol (5 mL) and the solution was treated with 1 mL of acetyl chloride at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting solid was used without further purification. (79% yield) ES-MS (m/z) 144.
Reaction SMILES: C(Br)C=C.[C:5]([O-:8])([O-])=O.[K+].[K+].[CH2:11]([O:14][C:15]1[CH:22]=[CH:21][C:18](C=C)=[CH:17][CH:16]=1)[CH:12]=[CH2:13]>CC(C)=O>[CH2:11]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:5]=[O:8])=[CH:17][CH:16]=1)[CH:12]=[CH2:13]
Reactant: C=CCOc1ccc(C=C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C=CCBr
Product: C=CCOc1ccc(C=O)cc1

Procedure:
4-allyloxybenzaldehyde was prepared by reaction of allyl bromide on 4-hydroxybenzaldehyde in refluxing acetone in the presence of K2CO3. The distilled product was used as a precursor for 4-allyloxystyrene synthesis.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17](=[O:23])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:16][C:11]3=[N:10][C:9]=2[C:24]([OH:26])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.Cl.[CH3:51][NH:52][O:53][CH3:54].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH:1]1([CH2:7][C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17](=[O:23])[N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:16][C:11]3=[N:10][C:9]=2[C:24]([N:52]([O:53][CH3:54])[CH3:51])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNOC
Reactant: CCN(CC)C(=O)c1ccn2c(CC3CCCCC3)c(C(=O)O)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccn2c(CC3CCCCC3)c(C(=O)N(C)OC)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
3-Cyclohexylmethyl-7-(N,N-diethylcarbamoyl)imidazo[1,2-a]pyridine-2-carboxylic acid (181 mg, 0.506 mmol) obtained in step 1 of Example 2 was dissolved in DMF (1.8 mL), and the solution was stirred at room temperature for 2 hours after adding EDC.HCl (146 mg, 0.760 mmol), HOBt.H2O (116 mg, 0.760 mmol), N,O-dimethylhydroxylamine hydrochloride (74.0 mg, 0.760 mmol), and pyridine (0.0610 mL, 0.760 mmol). Under ice-cooled condition, a saturated sodium hydrogen carbonate aqueous solution was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0→95/5) to give 3-cyclohexylmethyl-7-(N,N-diethylcarbamoyl)-N-methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide (200 mg, yield 99%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[CH3:36][CH:37]1CCN[CH2:39][CH2:38]1>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([N:3]1[CH2:39][CH2:38][CH:37]([CH3:36])[CH2:2][CH2:1]1)=[O:5]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: CC1CCNCC1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)N4CCC(C)CC4)C(O)C3O)c2n1

Procedure:
The title compound was prepared according to the method of example 39, step a) using the product from example 1, step c) and 4-methyl-piperidine, followed by deprotection according to the method of example 39, step b).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][N:10]=[CH:9][C:8]=2[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.O.C(O)(=O)C.N>[Fe].C(O)CC>[NH2:1][C:4]1[C:12]2[S:11][N:10]=[CH:9][C:8]=2[C:7]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c2cnsc12
Agent: [Fe]
Agent: N
Solvent: O
Solvent: CC(=O)O
Solvent: CCCO
Product: Nc1ccc(OCc2ccccc2)c2cnsc12
Yield: 98 %

Procedure:
28.6 g of 7-nitro-4-benzyloxy-1,2-benzisothiazole are added in portions to a boiling mixture of 67 ml of water, 30 g of iron powder, 3 ml of glacial acetic acid and 167 ml of n-propanol and the mixture is then refluxed for a further hour. When it has cooled, it is neutralized with concentrated ammonia solution and filtered. The filter residue is washed with methylene chloride and the combined wash solutions are dried over magnesium sulfate and freed from the solvent under reduced pressure. 25.1 g (100% of theory) of 7-amino-4-benzyloxy-1,2-benzisothiazole of melting point 126°-128° C. are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([B:32]([OH:34])[OH:33])=[CH:28][CH:27]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:4]1[C:3]([CH2:2][S:25][C:26]2[CH:31]=[CH:30][C:29]([B:32]([OH:34])[OH:33])=[CH:28][CH:27]=2)=[C:7]([CH:8]([CH3:10])[CH3:9])[O:6][N:5]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: OB(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(B(O)O)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 131.2 %

Procedure:
A mixture of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (152 mg, 0.5 mmol), cesium carbonate (489 mg, 1.5 mmol) and 4-mercaptophenyl boronic acid (75 mg, 0.5 mmol) in dimethylformamide (5 mL) was allowed to stir for 24 hours in a 60° C. oil bath. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated to yield 277 mg of crude [4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]boronic acid and dimethylformamide. 1H NMR (400 MHz, d6-DMSO): δ 7.63-7.59 (m, 4H), 7.55-7.51 (m, 1H), 7.17 (d, J=8 Hz, 2H), 3.86 (s, 2H), 3.12 (septet, J=7 Hz, 1H), 1.13 (d, J=7 Hz, 6H).