Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:11][C:5]2[N:6]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: ClCc1ccccn1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3Cc2ccccn2)c1=O
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
0.20 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione was added at room temperature to an N,N -dimethylformamide solution (5 ml) having suspended therein 0.05 g of sodium hydride (purity: 55%). After standing for 20 minutes, the solution was added with 0.09 g of 2-chloromethylpyridine hydrochloride and stirred for 4 hours. Then N,N-dimethylformamide was distilled off and the residue was extracted with ethyl acetate by adding water. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This product was purified by preparative thin-layer chromatography using hexane/ethyl acetate (2:3) as developing solvent to obtain 0.09 g of the objective compound as pale yellow crystals.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:37]1([N:43]2[C:47]([SH:48])=[N:46][N:45]=[N:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][S:48][C:47]2[N:43]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:44]=[N:45][N:46]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](CSc2nnnn2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [trans-4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-methanol (prepared as described in J. Med. Chem. (2001), 44, 531, 9.0 g, 34.8 mmol) in THF (100 mL) were added PPh3 (13.7 g, 1.5 eq.), 1-phenyl-1H-tetrazole-5-thiol (6.2 g, 1 eq.) and DIAD (10.3 mL, 1.5 eq.). The reaction mixture was stirred at rt overnight. After evaporation to dryness, the residue was chromatographed over SiO2 (Hex-EA 8-1) to afford the title sulfide (11.4 g) contaminated with some PPh3.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[C:14]1([C:24]2[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[CH3:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:27]2[CH:28]=[CH:29][C:24]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:25][CH:26]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(-c2cccc3ccccc23)cc1
Reactant: COc1ccc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(-c3cccc4ccccc34)cc2)c2ccccc12
Temperature: 25 °C
Yield: 52.4 %

Procedure:
1-Bromo-4-methoxynaphthalene (25 g, 0.105 mol), 4-(naphthalen-1-yl)phenylboronic acid (30.4 g, 0.137 mol), potassium carbonate (21.9 g, 0.16 mol), tetrakis(triphenylphosphine)palladium(0) (2.4 g, 0.01 mol), water (25 mL), tetrahydrofuran (75 mL) and toluene (75 mL) were stirred in a 250 mL round-bottom flask for 12 hours under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (300 mL) and water (1000 mL). The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to obtain a solid. The solid was dissolved in hot toluene (400 mL) and then filtered. The filtrate was recrystallized in methanol (800 mL). The resultant solid was filtered and washed with hexane (300 mL) to obtain a product (20 g, 0.055 mol, 52.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9].C(Cl)(Cl)Cl.O.[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9]
Reactant: Cc1cccc(C)[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Yield: 76 %

Procedure:
A solution of 2.23 g (18.1 mmol) of 2,6-dimethylpyridine 1-oxide (Alfa Aesar) in 7 mL of H2SO4 and 2.7 mL of HNO3 was stirred at 130° C. for 23.5 h. The solution was added to ice with CHCl3 and H2O, and the aqueous layer was extracted with CHCl3 (2×). The combined extracts were washed with 75 mL of saturated NaHCO3 solution, and the aqueous layer was extracted with CHCl3. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give 2.3 g of 2,6-dimethyl-4-nitropyridine 1-oxide in 76% yield which was used without further purification.
Reaction SMILES: [CH2:1]([O:9][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14]CCCCCC[Si](C)(C)O[Si](C)(C)C)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC(=O)CCCCCCCCC=C)CC1C=CC=CC=1.[CH3:51][SiH:52]([CH3:58])[O:53][Si:54]([CH3:57])([CH3:56])[CH3:55]>>[CH2:1]([O:9][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][Si:52]([CH3:58])([CH3:51])[O:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)O[Si](C)(C)CCCCCCCCCCC(=O)OCCc1ccccc1
Reactant: C[SiH](C)O[Si](C)(C)C
Agent: C=CCCCCCCCCC(=O)OCCc1ccccc1
Product: C[Si](C)(C)O[Si](C)(C)CCCCC(=O)OCCc1ccccc1

Procedure:
According to the same procedure, 11-(1,1,3,3,3-pentamethyl-disiloxanyl)-undecanoic acid phenethyl ester was prepared from undec-10-enoic acid phenethyl ester and pentamethyldisiloxane.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][C:19]([O:21]C)=O)=[C:13]([CH3:23])[CH:12]=1.[Si]([O:31][C:32]([O:34][CH3:35])=[CH2:33])(C(C)(C)C)(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH3:23])[C:14]([CH2:18][CH:19]([OH:21])[CH2:33][C:32]([O:34][CH3:35])=[O:31])=[C:15]([CH3:17])[CH:16]=1
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)Cc1c(C)cc(Br)cc1C
Agent: CC(C)C[AlH]CC(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CC(O)Cc1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
DIBAL-H (8.66 mL, 12.99 mmol) was added dropwise to a solution of methyl 2-(4-bromo-2,6-dimethylphenyl)acetate (3.18 g, 12.37 mmol) in CH2Cl2 (60 mL) at −78° C. and stirred for 1 h. 1-(tert-Butyldimethylsilyloxy)-1-methoxyethene (4.05 mL, 18.55 mmol) followed by BF3.OEt2 (1.959 mL, 15.46 mmol) were added. The reaction was stirred at −78° C. for 20 min and then allowed to warm to rt. The reaction was quenched by the addition of 10 mL of 1.0 M HCl, extracted with dichloromethane. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% ethyl acetate in hexane over 15 min using a 40 g silica gel cartridge) to yield 2A (2.5 g, 8.30 mmol, 67.1% yield) as a clear oil. 1H NMR (500 MHz, chloroform-d) δ ppm 7.18 (2H, s), 4.20-4.28 (1H, m), 3.72 (3H, s), 2.91 (1H, dd, J=14.03, 8.25 Hz), 2.72-2.78 (2H, m), 2.53-2.57 (2H, m), 2.55 (2H, dd, J=40.03, 6.19 Hz), 2.33 (6H, s), 1.58 (2H, br. s.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].N1CCCCC1.O>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)c1cccc(/C=C/N(C)C)c1[N+](=O)[O-]

Procedure:
A solution of methyl 3-methyl-2-nitrobenzoate (43 g, 0.22 mole), dimethylformamide dimethyl acetal (52.5 g, 0.44 mole) and piperidine (18.7 g, 0.22 mole) in dimethylformamide (120 ml) was heated under reflux for 24 hours, cooled and poured into water to give the crude product.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][N:8]=2)(=O)[CH3:2].Cl.Cl.[CH2:24]([NH:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(O)(=O)C>[CH2:24]([N:31]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5](=[O:21])[C:4]=2[C:1]([CH3:2])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1nn(Cc2ccccc2)c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 25 °C
Yield: 61.5 %

Procedure:
Compound 102 obtained in Example 2, 3.0 g (10.7 millimoles), was suspended in 20 ml of glacial- acetic acid, and 3.1 g (16.1 millimoles) of benzylhydrazine dihydrochloride and 9.0 ml (64.2 millimoles) of triethylamine were added to the suspension. The mixture was heated under reflux for 10 hours. The reaction solution was cooled to room temperature, and the precipitate was collected by filtration and recrystallized from DMF-water to give 2.4 g (61.5%) of Compound 5.
Reaction SMILES: N[C:2]([NH2:4])=[O:3].[F:5][C:6]1[CH:7]=[C:8]2C(=O)O[C:10](=[O:11])[C:9]2=[CH:15][CH:16]=1>>[F:5][C:6]1[CH:16]=[C:15]2[C:2](=[O:3])[NH:4][C:10](=[O:11])[C:9]2=[CH:8][CH:7]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NC(N)=O
Product: O=C1NC(=O)c2cc(F)ccc21
Temperature: 160 °C
Reaction time: 3 h

Procedure:
8.2 parts (0.137 mole) of urea are added to 185 parts of the distillate (containing 43.4 parts (0.261 mole) of 4-fluorophthalic anhydride). The mixture is stirred for 3 hours at 135°-140° C., after which the evolution of gas is complete, and is finally heated for a further 10 minutes at 160° C. The solvent is distilled off (144.2 parts) at 115°-130° C. and under 0.3 mbar. According to gas chromatography, it contains 9.6 parts of 4-fluorophthalimide. The distillation residue is stirred with water, and the product is filtered off under suction, washed and dried, 31 parts of 4-fluorophthalimide of melting point 174°-176° C. being obtained. The total yield is 40.6 parts (94.2% of theory) of 4-fluorophthalimide.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:13].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:13][C:12]1[CH:7]=[C:8]([CH2:4][CH2:3][CH2:2][CH2:1][O:5][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:13])[CH:9]=[CH:10][CH:11]=1
Reactant: CCCCO
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: BrCCCCCCOCCCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred mixture of 4-3-bromophenyl) butan-1-ol (18 g) (EP 0 995 752A1), 1,6 dibromohexane (48 ml), tetrabutylammonium bromide (1.5 g) and 50% aqueous sodium hydroxide solution (500 ml) was stirred for 2 days at ambient temperature. The mixture was poured into water (1000 ml) and extracted into ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated. The residual oil was purified on the biotage eluting with light petroleum (40-60° C.), and then light petroleum (40-60° C.)-ether (9:1). The appropriate fractions were evaporated to give the title compound (18 g) LCMS RT=4.34 min.
Reaction SMILES: COC1C=CC(C(NC2COCC(C3C=CC=C(Br)C=3)(C)N=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.C(=[N:52][C:53]1[CH:54]=[C:55]([C:59]2([CH3:89])[CH2:64][O:63][CH2:62][C:61]([NH:65][C:66]([C:81]3[CH:86]=[CH:85][C:84]([O:87][CH3:88])=[CH:83][CH:82]=3)([C:73]3[CH:78]=[CH:77][C:76]([O:79][CH3:80])=[CH:75][CH:74]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[N:60]2)[CH:56]=[CH:57][CH:58]=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Pd]>[NH2:52][C:53]1[CH:54]=[C:55]([C:59]2([CH3:89])[CH2:64][O:63][CH2:62][C:61]([NH:65][C:66]([C:73]3[CH:74]=[CH:75][C:76]([O:79][CH3:80])=[CH:77][CH:78]=3)([C:81]3[CH:86]=[CH:85][C:84]([O:87][CH3:88])=[CH:83][CH:82]=3)[C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[N:60]2)[CH:56]=[CH:57][CH:58]=1
Reactant: COc1ccc(C(NC2=NC(C)(c3cccc(N=C(c4ccccc4)c4ccccc4)c3)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: COc1ccc(C(NC2=NC(C)(c3cccc(Br)c3)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=NC(C)(c3cccc(N)c3)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
Following the general procedure described below the palladium-catalyzed amination of (RS)-[bis-(4-methoxy-phenyl)-phenyl-methyl]-[5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-amine followed by the hydrolysis of the intermediate (RS)-{5-[3-(benzhydrylidene-amino)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl}-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine yielded the title compound. Mass (calculated) C32H33N3O3 [507.64]; (found) [M+H]+=508.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([F:18])=[CH:11][C:5]=1[O:6][CH2:7][C:8](O)=[O:9])([O-])=O.[H][H]>C(O)C.[Pt](=O)=O>[F:18][C:12]1[C:13]([NH2:15])=[CH:14][C:4]2[NH:1][C:8](=[O:9])[CH2:7][O:6][C:5]=2[CH:11]=1
Reactant: O=C(O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1cc2c(cc1F)OCC(=O)N2
Yield: 91.4 %

Procedure:
A suspension of 2,4-dinitro-5-fluorophenoxyacetic acid (0.25 g) and platinum dioxide (80 mg) in ethanol (10 ml) was subjected to catalytic reduction at room temperature under an ordinary pressure until 130 ml of hydrogen was absorbed. The reaction mixture was filtered, and the filtrate was concentrated to give 7-fluoro-6-amino-2H-1,4-benzoxazin-3(4H)-one (0.16 g; yield, 91.4%). M.P., more than 300° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][C:18]([NH2:20])=[N:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][C:18]([NH:20][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=3)=[N:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(NCc3ccccc3)c2)c1
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2nc(NC(=O)c3cccnc3)sc2-c2ccnc(NCc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 41.9 %

Procedure:
To a solution of [5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.52 g, 1.4 mmol) and 4-dimethylaminopyridine (0.051 g, 0.42 mmol) in N,N-dimethylacetamide (10 mL) was added nicotinoyl chloride hydrochloride (0.37 g, 2.1 mmol), and the mixture was stirred at 80° C. for 14 hrs. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The resulting crystals were crystallized from isopropyl ether to give the title compound (0.28 g, yield 59%).
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20](O)=[O:21])[CH2:4]1.C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[ClH:26].[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20]([Cl:1])=[O:21])[CH2:4]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H]1CN(CC(=O)Cl)C[C@H](C)N1c1ncnc2sccc12

Procedure:
A mixture of the product from Example 9 step (ii) (1.15 g) and oxalyl chloride (1.2 ml) in dichloromethane (100 ml) was treated with 2 drops of dimethylformamide. After 24 hours at room temperature a further aliquot of oxalyl chloride (3.6 ml) was added and the mixture heated under reflux for 48 hours. The solvent was evaporated under reduced pressure. Toluene was added to the residue and then evaporated under reduced pressure to give the subtitle product as a yellow oil (0.95 g).
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:14]I>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][CH:4]=[N:3]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cccnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of sodium hydride (5.5 g, 137.50 mmol, 60%) in N,N-dimethylformamide (150 ml) was added quinolin-7-ol (8 g, 55.11 mmol). The reaction was stirred for 1 h at 0° C. in a water/ice bath. Then CH3I (7.84 g, 55.23 mmol) was added and the solution was stirred for an additional 1 h at room temperature. The reaction was then quenched by the addition of water/ice (700 ml) and extracted with ethyl acetate (3×200 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by a silica gel column with 6% ethyl acetate in petroleum ether to afford 7-methoxyquinoline as a red oil (5.5 g, 63%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH3:2].[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27])([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:14]([O:18][C:19]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:28])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)CCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.6 %

Procedure:
To a solution of 7-ethoxy-7-oxoheptanoic acid (7.23 g, 385 mmol) in DMF (150 mL) was added tert-butyl(2-aminophenyl)carbamate (8 g, 385 mmol), HBTU (14.6 g, 385 mmol), DIEA (20 mL, 1155 mmol). The mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted by EtOAc (200 mL×3). The organic layers were combined and washed with saturated aqueous solution of Na2CO3, dried over Na2SO4 and then concentrated to give the desired compound (14 g, yield 96.3%).
Reaction SMILES: O[C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[CH:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)C>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:33]=[C:34]([OH:39])[C:35]([CH3:38])=[CH:36][C:37]=2[C:2]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:11])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1Nc2ccccc2C1(O)c1ccccc1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Product: Cc1cc(C2(c3ccccc3)C(=O)Nc3ccccc32)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1O
Temperature: 25 °C
Yield: 89.4 %

Procedure:
As another non-limiting example, 4-tert-butyl-N-[5-hydroxy-4-methyl-2-(2-oxo-3-phenyl-2,3-dihydro-1H-indol-3-yl)-phenyl]-benzenesulfonamide (compound 1430) was synthesized by adding dropwise 4-tert-butyl-benzenesulfonyl chloride (8 g, 34 mmol) in 5 mL dichloromethane to a stirring solution of 5-Amino-2-methyl-phenol (4 g, 32 mmol) in 20 mL pyridine and letting the mixture spin overnight at room temperature. The resulting mixture was concentrated in vacuo and the product was purified by column chromatography to yield 8 g (78%) of 4-tert-butyl-N-(3-hydroxy-4-methyl-phenyl)-benzenesulfonamide. A mixture of 3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (3.9 g, 17 mmol), 4-tert-butyl-N-(3-hydroxy-4-methyl-phenyl)-benzenesulfonamide (7 g, 22 mmol) and p-toluenesulfonic acid (6.5 g, 32 mmol) in dichloroethane was refluxed for 12 hours. The resulting mixture was cooled to room temperature to yield a colorless solid. The solid was filtered and purified using column chromatography to yield 8 g (88%) of the desired product (compound 1430).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27]O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:12])([F:13])[F:14])=[C:8]([CH:9]=1)[O:10][CH2:27][C@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:20]([O:19][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:21])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-nitro-2-trifluoromethylphenol (2.83 g, 13.7 mmol), (R)-(+)-(tert-butoxy-carbonyl)-2-pyrrolidinemethanol (2.75 g, 13.7 mmol), and PPh3 (3.58 g, 13.7 mmol) in 24 mL THF, cooled at −20° C. was added dropwise over 1.5 h a 12 mL THF solution containing DEAD (2.43 g, 13.9 mmol). The mixture turned a deep red. The reaction was warmed gradually to RT and stirred for 18 h. The reaction was concentrated in vacuo and treated with a small mixture of hexanes and Et2O. After sonication, the solids were filtered off, and the filtrate was concentrated in vacuo. The crude was dissolved in a very small amount of EtOAc and Et2O then diluted with hexanes, which were washed once with 0.1N HCl, 3 times with 2N NaOH, and once with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using 5% EtOAc in hexanes to yield the title compound as a clear thick oil.
Reaction SMILES: CC1ON=C(C2C=CC=CC=2)C=1C1N=C2C=CC(C(O)=O)=CN2C=1.C(OC(=O)[NH:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([C:41]3[C:42]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[N:43][O:44][C:45]=3[CH3:46])[N:40]=2)[CH:37]=1)(C)(C)C>>[CH3:46][C:45]1[O:44][N:43]=[C:42]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:41]=1[C:39]1[N:40]=[C:35]2[CH:34]=[CH:33][C:32]([NH2:31])=[CH:37][N:36]2[CH:38]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)OC(C)(C)C)ccc2n1
Agent: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)O)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Yield: 74.8 %

Procedure:
As described for Example 46, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-6-carboxylic acid (1.62 g, 5.1 mmol) instead of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid, was converted to [2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-yl]-carbamic acid tert-butyl ester (910 mg, 46% MS: m/e=389.5 [M+H]+) and then to the title compound (506 mg, 78%) which was obtained as a light grey foam. MS: m/e=291.0 [M−H]−.