Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1>CN(C)C=O>[CH:13]1([CH2:16][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH2:15][CH2:14]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OCC2CC2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
A solution of 5.00 gm (37.6 mMol) 4-hydroxyindole in dimethylformamide was added dropwise over 30 minutes to a solution of 1.65 gm (41.3 mMol) sodium hydride (60% suspension in mineral oil) in 25 mL dimethylformamide at 0° C. The resulting black solution was stirred at room temperature for 2 hours and then a solution of 3.6 mL (37.6 mMol) cyclopropylmethyl bromide in 10 mL dimethylformamide was added dropwise. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then quenched by the addition of 100 mL water and the resulting mixture extracted well with ethyl acetate. The organic phases were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10% ethyl acetate in hexane. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 4.48 gm (64%) of the title compound as an amber oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.Cl.[NH2:17][C@@H:18]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:39][C:37]1[CH:38]=[C:33]([CH:34]=[C:35]([F:40])[CH:36]=1)[CH2:32][C@H:18]([NH:17][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1ccc(-c2nccs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(-c3nccs3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1,3-thiazol-2-yl)benzoic acid (110 mg, 0.6 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (220 mg, 0.6 mmol), and HATU (210 mg, 0.6 mmol) stirring in methylene chloride (5 mL) is added N,N-diisopropylethylamine (340 μL, 1.9 mmol). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is partitioned between methylene chloride and water. The organic layer is washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, gradient 95:5 to 92:8 methylene chloride/methanol) provides the title compound. ESI MS m/z 522.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[C:13]([NH2:21])[N:12]=3)[N:9]=[C:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:5]2=[N:6][CH:7]=1.[H][H]>N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:21])[N:12]=3)[N:9]=[C:8]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1N

Procedure:
196 mg (0.492 mmol) of the compound from example 7A were initially charged in pyridine (22 ml), 74 mg of palladium on carbon (10% by weight) were then added and the mixture was hydrogenated at standard hydrogen pressure overnight. The reaction mixture was then filtered through kieselguhr, the filter cake was washed with ethanol and the filtrate was concentrated. The residue was triturated with ethanol at 50° C., and the solid was filtered off and dried under high vacuum. This gave 107 mg (58% of theory) of the title compound.
Reaction SMILES: C([CH:3]([C:33]([OH:35])=[O:34])[N:4]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([C:31]#[N:32])[CH:20]=1)[C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6])C.[OH-].[Na+]>C(O)C>[C:31]([C:21]1[CH:20]=[C:19]([N:4]([C:5]([C:7]2[CH:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:11]=2)=[O:6])[CH2:3][C:33]([OH:35])=[O:34])[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])#[N:32]
Reactant: CCC(C(=O)O)N(C(=O)c1cnn(-c2ccc(F)cc2)c1)c1ccc(OCC(C)(C)C)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)COc1ccc(N(CC(=O)O)C(=O)c2cnn(-c3ccc(F)cc3)c2)cc1C#N
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
Ethyl N-(3-cyano-4-neopentyloxyphenyl)-N-[1(4-fluorophenyl)pyrazol-4-ylcarbonyl]glycine (1.5 g) was added to ethanol (15 ml). 10% aqueous sodium hydroxide solution (10 ml) was added and the mixture was stirred at a refluxing temperature for 30 min. The solvent was evaporated under reducer pressure. To the residue was added dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of chloroform-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous acetic acid to give the title compound (0.9 g), melting point: 274–275° C./decomposition
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc([N+](=O)[O-])cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].C(N(CC)CC)C.Cl[S:30]([C:33]1[CH:34]=[C:35]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]>C(#N)C>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:30]([C:33]1[CH:34]=[C:35]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNS(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1

Procedure:
The compound obtained in Example 2-3 step (ii) (240 mg), triethylamine (0.12 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (204 mg) were dissolved in acetonitrile (5 ml), and the same manner to Example 2-13 step (iii) was conducted to give the titled compound as a white solid. Yield: 35 mg (9%); mp 218-219° C., MS APCI+ve 493 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:12]2(O)[CH3:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:12]2=[CH2:24])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCN1C(=O)OC2(CCN(Cc3ccccc3)CC2)C1(C)O
Solvent: O
Solvent: OCc1ccccc1
Product: C=C1N(CCCCCCC)C(=O)OC12CCN(Cc1ccccc1)CC2
Yield: 81 %

Procedure:
The solution of 18.7 g of 8-benzyl-3-n-heptyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 40 ml of benzyl alcohol is heated at 160° C. for 5 hours while the water formed in the reaction is azeotropically distilled off. Thereafter, the mixture is evaporated under reduced pressure. After taking up the residue in chloroform the solution is dried over anhydrous magnesium sulfate, filtered off and evaporated under reduced pressure. The crude product obtained is recrystallized from n-hexane under clarifying by activated carbon to obtain the title compound in 81% yield, m.p.: 47°-48° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:16])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-tert-Butyl-2-methyl-6-nitro-phenol (209 mg, 1 mmol) was dissolved in 3 mL acetone. 552 mg K2CO3 (4 eq) was added, followed by addition of MeI (0.33 mL, 5 mmol). The reaction mixture was stirred vigorously at 60° C. overnight. After removal of the acetone, the residue was shaken with DCM. Filtration and evaporation of the solution yielded 221 mg product which was used as such.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1.C(OCC)(=O)C>CN(C=O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[N:17][CH:18]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(Oc2ccc(Br)cn2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 4-trifluoromethoxyphenol (4.4 ml) and sodium hydride (60% dispersion in mineral oil, 1.35 g) in dry DMF (3 ml) was added a solution of 2,5-dibromopyridine in dry DMF (3 mL). The mixture was heated at 60° C. for 8 h. Upon cooling, ethyl acetate was added and the mixture was washed with NH4Cl 1N. The organic layer was dried (Na2SO4) and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent:AcOEt/Hexane 1:10) to afford 1.08 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[C:35]([NH2:38])(=[O:37])[CH3:36]>>[C:35]([N:38]([CH2:9][CH2:10][CH2:11][O:14][CH3:15])[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)(=[O:37])[CH3:36]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CC(N)=O
Product: COCCCN(C(C)=O)c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Method D, 0238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.128 g of N-(3-chloromethylphenyl)-N-3-methoxypropyl)acetamide are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.20 (2:1 EtOAc-heptane); Rt=5.80.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:20][N:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH3:29])[CH3:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Reactant: CN(C)CCCCCCN
Solvent: Cc1ccccc1
Product: CN(C)CCCCCCNc1nc2cc(Cl)c(Cl)cc2nc1-c1ccccn1
Yield: 60.9 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and 6-dimethylamino-hexylamine (0.46 g) in toluene (25 mL) was refluxed under nitrogen atmosphere for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as a fluffy yellow powder (0.41 g); mp 88-90° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:14]3[C:9](=[N:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=3)[NH:8][N:7]=2)=[O:5])[CH2:3][CH2:2]1>CCOC(C)=O.C(=O)(O)[O-]>[NH2:15][C:12]1[CH:13]=[C:14]2[C:6]([C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])=[N:7][NH:8][C:9]2=[N:10][CH:11]=1
Reactant: O=C(c1n[nH]c2ncc([N+](=O)[O-])cc12)C1CC1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: Nc1cnc2[nH]nc(C(=O)C3CC3)c2c1
Yield: 77.3 %

Procedure:
SnCl2 dihydrate (0.24 g, 1.1 mmol) was added to cyclopropyl(5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (0.050 g, 0.22 mmol) in EtOAc (1 mL). The reaction mixture was heated to reflux for 6 hours. The mixture was then cooled, diluted with EtOAc (5 mL), aqueous bicarbonate (5 mL) and filtered through celite. The organic layers were extracted with EtOAc (3×5 mL), dried over sodium sulfate, and concentrated to provide (5-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)(cyclopropyl)methanone (0.035 g, 0.17 mmol, 80% yield).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].C(Br)C>>[CH2:16]([O:15][P:14]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1cc(-c2ccccc2)no1
Solvent: CCBr
Product: CCOP(=O)(Cc1cc(-c2ccccc2)no1)OCC

Procedure:
5-Bromomethyl-3-phenylisoxazole (7.14 g, 30 mmol) and triethyl phosphite (10.4 ml, 60 mmol) were heated at 150° C. until no more ethyl bromide distilled, then the temperature maintained for a further 1 h. The mixture was then distilled under reduced pressure to give 5-diethylphosphonomethyl-3-phenylisoxazole bp 190°-192° C. at 0.5 mm Hg (8.15 g, 27.6 mmol, 92%); νmax (film) 2980, 2900, 1605, 1580, 1465, 1440, 1410, 1250, 1160, 1020, 970, 770, 690, 670 cm-1 ; δH (CDCl3) 1.30(6H, t, J 7 Hz, OCH2CH3), 3.45(1H, d, JH-P 22 Hz, CH2 -P), 4.10(4H, m, OCH2CH3), 6.55(1H, d, J 3 Hz, CH-4), 7.40(3H, m, Ph), 7.65(2H, m, Ph); δC (CDCl3) 16.3, 16.4(OCH2CH3), 24.7, 26.9(CH2 -P), 62.8, 62.9(OCH2CH3), 101.5, 101.6 (C-4), 126.8, 128.9, 130.0 (Ph), 162.8 (C-3), 164.3, 164.4 (C-2).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[N:3][C:2]=1[CH2:14][OH:15])=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1[N:5]2[C:6]3[C:11]([N:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH2:14][OH:15])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: OCc1cn2c(n1)CNc1ccccc1-2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: OCc1cn2c(cnc3ccccc32)n1
Reaction time: 6 h
Yield: 90.2 %

Procedure:
A solution of 3 g of 4,5-dihydro-imidazo-[1,2-a]-quinoxaline-2-methanol in 500 ml of chloroform and 9 g of manganese dioxide was refluxed with stirring for 6 hours and the mixture was filtered hot and concentrated. The mixuture was cooled and filtered to obtain 2.68 g of a imidazo-[1,2-a]-quinoxaline-2-methanol and imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde mixture and the latter was chromatographed over silica gel. Elution with a 97.5% chloroform--2.5% methanol mixture yielded first 0.23 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde and then 1.42 g of imidazo-[1,2-a]-quinoxaline-2-methanol melting at 217°-220° C. Evaporation of the filtrate yielded 0.43 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde for a total yield of 0.66 g melting at 214°-215° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)\[CH2:7][Br:17])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(C)c1
Yield: 43.8 %

Procedure:
To a stirred mixture of (E)-3-m-tolyloxy-but-2-enoic acid ethyl ester (6.41 g, 0.029 mol) in carbon tetrachloride (30 mL) under a nitrogen atmosphere was added N-bromosuccinimide (7.78 g, 0.044 mol) and benzoyl peroxide (704 mg, 0.003 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-m-tolyloxy-but-2-enoic acid ethyl ester (3.80 g, 44%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[CH3:12][CH:13]([CH3:16])[CH2:14][SH:15].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[S:15][CH2:14][CH:13]([CH3:16])[CH3:12]
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Reactant: CC(C)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)CSc1nc(C(=O)O)ccc1Br
Temperature: 150 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
5-Bromo-6-chloropicolinic acid (2 g, 8.46 mmol; CAN 959958-25-9), 2-methylpropane-1-thiol (915 mg, 1.1 mL, 10.2 mmol) and cesium carbonate (6.89 g, 21.1 mmol) were suspended in DMSO (100 mL). The reaction mixture was heated to 150° C. and stirred for 1 d and was poured onto icewater/1N HCl (100 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined extracts were washed with icewater/brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (2.49 g, 51%) as an orange solid which was used in the next step without further purification. MS (EI): m/e=288.4 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[NH3:30]>CO.C(OCC)(=O)C>[NH2:30][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28]
Reactant: N
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)NC(=O)c2ccc(-c3ccc(F)cc3)cc2)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of Example 1D (1.0 g) in methanol (10 mL) and concentrated aqueous ammonia (3 mL) was heated in a sealed pressure tube to 60° C. for 16 hours, cooled to 0° C., diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([S:12]([NH:15][CH2:16][CH2:17][N:18]([C:23](=[O:34])[CH2:24][N:25]3[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]3=[O:27])[CH2:19][C:20]([OH:22])=O)(=[O:14])=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O>O1CCCC1>[C:1]1([C:7]2[S:11][C:10]([S:12]([N:15]3[CH2:16][CH2:17][N:18]([C:23](=[O:34])[CH2:24][N:25]4[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]4=[O:27])[CH2:19][C:20]3=[O:22])(=[O:14])=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cn(CC(=O)N(CCNS(=O)(=O)c2nnc(-c3ccccc3)s2)CC(=O)O)c(=O)[nH]c1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3nnc(-c4ccccc4)s3)C(=O)C2)c(=O)[nH]c1=O
Temperature: -20 °C
Yield: 90 %

Procedure:
To a solution of N-[2-(5-phenyl-1,3,4-thiadiazole-2-sulfonylamino)-ethyl]-N-[(thymin-1-yl)-acetyl]-glycine (1.02 g, 2 mmol) in tetrahydrofuran (50 mL) was added N-methylmorpholine (3.3 mL, 3 mmol) and then the mixture was cooled to −20° C. After stirring for 5 min at the same temperature, isobutyl chloroformate (3.4 mL, 26 mmol) was added to the reaction mixture. The resulting mixture was slowly warmed to 0° C. for 1 hour. Then the reaction mixture was evaporated in vacuo and dissolved in a mixture of ethyl acetate and acetonitrile. The solution was washed with brine and dried over sodium sulfate and filtered. The filtrate was evaporated in vacuo and triturated with tetrahydrofuran-ethyl ether (1/1, v/v) to precipitate solid. The solid was filtered off, washed with ethyl ether, and dried in vacuo to give the titled compound (883 mg, 90%). 1H NMR (500 MHz; DMSO-d6) δ 11.30 (s, 0.6H), 11.29 (s, 0.4H), 8.10 (d, 2H), 7.68–7.57 (m, 3H), 7.33 (s, 0.6H), 7.27 (s, 0.4H), 4.66 (s, 1.2H), 4.58 (s, 0.8H), 4.43 (s, 0.8H), 4.30 (s, 1.2H), 4.17 (t, 1.2H), 4.02 (t, 0.8H), 3.95 (t, 1.2H), 3.85 (t, 0.8H), 1.73(s, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[C:35]([F:43])[CH:34]=1>>[F:43][C:35]1[CH:34]=[C:33]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)[CH:38]=[CH:37][C:36]=1[S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)c(F)c4)ccc3o2)CC1
Yield: 27.5 %

Procedure:
Following the General Procedure-1, the titled compound (30 mg) was prepared from Intermediate 8 (100 mg, 0.23 mmol) and 4-bromo-2-fluoro-1-(methylsulfonyl)benzene (70 mg, 0.37 mmol) as an off-white solid. M.P.: 174.3-177.5° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.03 (t, J 7.9, 1H), 7.88 (d, J 1.6, 1H), 7.61-7.51 (m, 3H), 7.46 (dd, J 1.6, 11.1, 1H), 4.15 (d, J 11.2, 2H), 3.26 (s, 3H), 3.20-3.11 (m, 1H), 3.00 (t, J 12.2, 2H), 2.20-2.12 (m, 2H), 1.98-1.84 (m, 2H), 1.48 (s, 9H).