Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:1]1([CH2:6][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 1.28 g of 4-(pyrrolidin-1-ylcarbonyl)aniline obtained in stage b) below in 100 mL of tetrahydrofuran are added, under argon, 1.28 g of lithium aluminium hydride. The reaction mixture is stirred for one hour at room temperature and then cooled to 0° C. and treated successively with 1.28 mL of water, 1.28 mL of 15% (by weight) sodium hydroxide solution and 3.85 mL of water. The solid formed is filtered off and washed with ethyl acetate, and the filtrate is concentrated under reduced pressure to give 1.1 g of 4-(pyrrolidin-1-ylmethyl)aniline in the form of a dark yellow oil, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][NH:29][CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
Dissolve 4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.56 mmol; 680 mg) in DCM (10 mL) and add benzyl chloroformate (1.56 mmol; 0.23 mL) and DIPEA (3.11 mmol; 0.54 mL). Stir 15 min and evaporate. Purify the residue on 120 g silica gel with DCM to 20% EA/DCM to provide the title compound (741 mg; 83%). MS (ES): m/z=571 (M+H).
Reaction SMILES: [C:1](#[N:5])/[CH:2]=[CH:3]/[CH3:4].[NH:6]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[NH2:7].OCC[N+](C)(C)C>C(O)C>[NH2:5][C:1]1[CH2:2][CH:3]([CH3:4])[N:6]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[N:7]=1
Reactant: NNc1nc2ccccc2s1
Reactant: C/C=C/C#N
Agent: C[N+](C)(C)CCO
Solvent: CCO
Product: CC1CC(N)=NN1c1nc2ccccc2s1

Procedure:
A mixture of 20.1 g. of crotononitrile, 80 ml. of absolute ethanol, 4.87 g. of 2-hydrazinobenzothiazole and 1.5 ml. of 50% methanolic choline is refluxed for 16 hours. The solvent is removed in vacuo and water is added. The separated solid is collected by filtration, dissolved in dichloromethane, and passed through a short column of hydrous magnesium silicate. The effluent is refluxed with the gradual addition of hexane to give a crystalline product. The crystallization step is repeated to give 0.5 g. of the product of the Example as off-white plates, m.p. 212°-215° C.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)=[C:18]([CH2:27][CH3:28])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=C(CC)C(O)=CC=3OCCC)OC(=O)CC(=O)C2)CCCC1.[CH3:57][C:58]1[CH:59]=[N:60][C:61]2[N:62]([N:64]=[C:65]([CH:67]=O)[N:66]=2)[CH:63]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)=[C:18]([CH2:27][CH3:28])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:67][C:65]3[N:66]=[C:61]4[N:60]=[CH:59][C:58]([CH3:57])=[CH:63][N:62]4[N:64]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1-c1ncco1
Reactant: Cc1cnc2nc(C=O)nn2c1
Agent: CCCOc1cc(O)c(CC)cc1CCC1(C2CCCC2)CC(=O)CC(=O)O1
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(C)cn4n3)C(=O)O2)ccc1-c1ncco1

Procedure:
The title compound was prepared analogously to example A(1) where 6-cyclopentyl-6-{2-[3-ethyl-4-(1,3-oxazol-2-yl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (Example A(135)) was substituted in place of 6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-propoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione in that example and 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield (58 mg, 11%). 1H NMR (300 MHz, CDCl3): δ ppm 1.19 (t, J=7.44 Hz, 3H) 1.40 (d, J=4.33 Hz, 1H) 1.53-1.67 (m, 8H) 2.01-2.10 (m, 2H) 2.39 (s, 1H) 2.45-2.49 (m, 3H) 2.54-2.64 (m, 1H) 2.71 (dd, J=11.87, 5.46 Hz, 2H) 2.76-2.85 (m, 1H) 3.01 (q, J=7.47 Hz, 2H) 4.10 (s, 2H) 7.05-7.11 (m, 2H) 7.29 (s, 1H) 7.73 (s, 1H) 7.78 (d, J=7.91 Hz, 1H) 8.61 (s, 1H) 8.68 (d, J=2.07 Hz, 1H). MS (ESI): 528 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(O[CH:14]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)(=O)C>C1C=CC=CC=1>[CH:16]1[C:15]2[CH:14]([N:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C1CCNCC1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: c1ccccc1
Product: CN(C)C1CCN(C2c3ccccc3Oc3ccccc32)CC1

Procedure:
A solution of 2.14 g. of 4-dimethylaminopiperidine and 4.0 g. of 9-acetoxyxanthene in 100 ml. of sieve dried benzene was refluxed for 24 hours. The mixture was then washed with a 5 percent aqueous solution of sodium carbonate, dried and the solvent removed in vacuo. The residue was recrystallized three times from hexane to afford 1-(9-xanthenyl)-4-dimethylaminopiperidine, m.p. 92°-93°C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:34][CH2:33]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:34][CH2:33]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 86.9 %

Procedure:
3-Methyl-4-nitrophenol (1.74 g, 11.4 mmol), triphenylphosphine (5.98 g, 22.8 mmol), and phenylmethyl 4-hydroxy-1-piperidinecarboxylate (3.99 g, 17.0 mmol) were dissolved in DCM with stirring and cooled to 0° C. Diisopropyl azodicarboxylate (3.35 mL, 17.0 mmol) was added via syringe. The reaction was stirred for 10 min and allowed to warm to rt. The reaction was stirred overnight and adsorbed onto silica gel. The crude material was purified by flash chromatography, and fractions containing product were concentrated in vacuo. The material was contaminated with 3-methyl-4-nitrophenol. The material was dissolved in diethyl ether and washed with 2N NaOH solution (3×), H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide 3.67 g (87%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=9.0 Hz, 1H), 7.42-7.24 (m, 5H), 7.06 (d, J=2.4 Hz, 1H), 7.01 (dd, J=9.1, 2.7 Hz, 1H), 5.07 (s, 2H), 4.76 (ddd, J=7.7, 4.2, 4.0 Hz, 1H), 3.81-3.64 (m, 2H), 3.31 (br. s., 2H), 2.52 (s, 3H), 2.01-1.88 (m, 2H), 1.63-1.49 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=4[NH2:31])[CH2:20][CH:19]3[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[CH:35]1(C(Cl)=O)[CH2:37][CH2:36]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH:31][CH:35]4[CH2:37][CH2:36]4)[CH2:20][C:19]3=[O:32])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:7])=[CH:33][CH:34]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccc(F)cc3)CCCCC2)C(O)C1
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3NC3CC3)CC2=O)CCCCC1)c1ccc(F)cc1

Procedure:
In accordance with the same procedure as in Example 87, except that 4-[N-[1-[N-(4-fluorobenzoyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol and cyclopropylcarbonyl chloride was used instead of methoxyacetyl chloride in Step 3 thereof, 1.5 g of the titled compound was prepared.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>C(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]3[CH2:19][CH2:20]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1)C1CC1
Agent: [Pd]
Solvent: ClCCl
Product: Nc1ccc(Oc2cc(NC(=O)C3CC3)ncn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Dissolve N-[6-(4-nitrophenoxyl)pyrimidin-4-yl]cyclopropanecarboxamide (2.2 g, 7.33 mmol) in DCM (50 mL), add Pd/C (10%, 340 mg), flush with H2, and stir at room temperature under H2 for 2 hrs. After the reaction is complete, flush with N2, and then filter, concentrate the filtrate, purify the crude product by chromatography (silica gel, EtOAc:PE=1:1) to provide the title compound (1.8 g, 91%). MS: (M+1): 271.
Reaction SMILES: [F:1][C:2]([F:27])([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2.[BH4-].[Na+]>CO>[F:27][C:2]([F:1])([CH:22]([OH:26])[CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2
Reactant: CCCC(=O)C(F)(F)CCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(O)C(F)(F)CCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.17 h

Procedure:
To a solution of (1S,5R,6R,7R)-6-(4,4-difluoro-5-oxooctyl)-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]octan-3one (32) (5.48 g) in methanol was added sodium borohydride (0.800 g) at 0° C. and the resulting mixture was stirred for 10 minutes. The reaction mixture was treated in the conventional manner and the obtained crude product was subjected to column chromatography to give the title compound (33). Yield: 5.46 g (99.5%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Zn]>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][NH:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccccc1CNc1ccccc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1CNc1ccccc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of 2-fluoro-N-(2-nitrobenzyl)aniline (9.8 g, 40 mmol) in ethanol (200 mL) was treated with a solution of ammonium chloride (11 g, 66 mmol) in H2O (200 mL) and zinc dust (40 g, 66 mmol), and the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was filtered, diluted with ethyl ether (1 L), washed with H2O (1 L) and evaporated to provide N-(2-aminobenzyl)-2-fluoroaniline (8 g) as a pink solid:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[CH:16]=[O:17]
Reactant: Cc1cc(CO)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C=O)cc(C(F)(F)F)c1

Procedure:
A solution fo oxalyl chloride (2.8 ml) in 20 ml of CH2Cl2 is treated with a solution of dimethyl sulfoxide (DMSO)(5.0 ml) in 15 ml of CH2Cl2 at -60° C. as in Example 11 To this mixture is added the 3-trifluoromethyl-5-methylbenzyl alcohol (5.4 g) in CH2Cl2 (20 ml) followed by 20 ml of triethlyamine. Appropriate reaction conditions and work-up as in Example 11 afforded 3-trifluoro- methyl-5-methylbenzaldehyde.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>O1CCOCC1>[CH2:34]([O:33][C:31]([N:17]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)CCNC(CO[Si](C)(C)C(C)(C)C)CC(=O)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CCN(C(=O)OCc1ccccc1)C(CO[Si](C)(C)C(C)(C)C)CC(=O)OCC
Temperature: 25 °C
Yield: 72.9 %

Procedure:
To the amine 3B (7.80 g, 21.6 mmol) and NaHCO3 (2.82 g, 33.6 mmol, 1.55 eq) in 40 mL anhydrous dioxane was added benzyl chloroformate (4.80 g, 28.1 mmol, 1.3 eq) at 0° C. over 5 mins. The ice bath was removed, and the mixture was allowed to warm to RT overnight. Solvents were removed in vacuo; the residue was diluted with 50 mL of water and 100 mL of EtOAc. The organic phase was separated, and the aqueous phase was further extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over Na2SO4, and concentrated. The residue was chromatographed on SiO2 to afford 7.8 g (73%) of product 3C as a colorless liquid along with the recovery of 1.02 g starting material. ESI-MS:m/z 496.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:11]([O-])=O>C(O)C.Cl>[NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: Nc1c([N+](=O)[O-])ccc2[nH]nnc12
Agent: Cl
Solvent: CCO
Product: Nc1ccc2[nH]nnc2c1N
Yield: 117.3 %

Procedure:
A suspension of 4-amino-5-nitrobenzotriazole (0.72 g, 4 mmol) in 100 ml of ethanol and 1 ml of conc. hydrochloric acid was hydrogenated at atmospheric pressure and room temperature for 6 h in the presence of 100 mg of 5% palladiumon-charcoal. The mixture was filtered and the catalyst was washed with about 50 ml of water. The combined filtrate was evaporated to dryness giving 0.70 g of the 4,5-diamino-benzotriazole as an hydrochloride. A solution of the crude diamino compound in 40 ml of 4M hydrochloric acid was refluxed with oxalic acid dihydrate (0.50 g, 4 mmol) for 3 h. The mixture was cooled on ice, and pH was adjusted to 5-6 with 2N sodium hydroxide. The precipitate was filtered off and washed with water and ethanol. It was then dissolved in 10ml of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. After adjustment to pH 6-7 With 4M hydrochloric acid the reprecipitated product was isolated, washed with water and ethanol, and dried at 100° C. affording 0.12 g (15%) of pure title compound; m.p.>300° C.; IR (KBr): 3200-2000, 1670 cm-1 ; 1H-NMR (DMSO-d6) 6.9 (broad s, 3H, NH +20H); 7.03 (d,J =8 Hz, lH, ArH); 7.43 (d,J =8 Hz,1H, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1cccc(Br)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C)(C=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of tert-butyl 2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (CD1; R4=Me) (1.5 g, 4.6 mmol) in EtOAc (150 mL) at reflux was added IBX (3.82 g, 13.6 mmol, 3 eq). Reflux was continued for another 2 h and then the mixture was cooled to RT. The white precipitate was filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel by eluting with EtOAc/hexanes to give 1.0 g (66%) of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate (CD2; R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 9.42 (s, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.55-7.40 (m, 2H), 5.85 (bs, 1H), 1.96 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:11]1[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([S:9][C:11]2[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Fc1cc(F)cc(S)c1
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2cc(F)cc(F)c2)c1
Reaction time: 16 h

Procedure:
In an open flask, cuprous oxide (0.6 g., 4 mmoles) and 3,5-difluorothiophenol (0.76 g., 4 mmoles) were combined with 25 ml. of dimethylformamide and heated in an oil bath maintained at 150°-160° C. for 2 hours. 5-Bromofuran-3-carboxylic acid was added, the flask was equipped with a reflux condenser, and heating at 150°-155° C. was continued for 16 hours. The reaction mixture was cooled, filtered, the filtrate diluted with 150 ml. of water and product extracted into two 30 ml. portions of ethyl acetate. The combined ethyl acetate extracts were back-washed with water, evaporated to an oil, the oil taken up in ether, product extracted into 12 ml. of 1 N sodium hydroxide, the basic extract acidified with conc. hydrochloric acid and the product extracted back into fresh ether and evaporated to yield crude product as an oil. The oil was chromatographed on approximately 100 ml. of silica gel with hexane/5% acetic acid as eluant, clean fractions (Rf 0.2 on thin layer chromatography with the same eluant) were combined, concentrated to dryness, and crystallized by trituration with hexane to yield purified 5-(3,5-difluorophenylthio)furan-3-carboxylic acid (127 mg., m.p. 128°-130° C., m/e 256).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:46][C:47]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:48]=1[NH2:49]>CN(C=O)C>[CH3:46][C:47]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:48]=1[NH:49][C:10]([C:8]1[S:7][C:3]2=[N:4][CH:5]=[CH:6][N:1]=[C:2]2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1cc2nccnc2s1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)c1cc2nccnc2s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (250 mg, 1.387 mmol), HATU (633 mg, 1.665 mmol) and DIPEA (0.459 mL, 2.77 mmol) in DMF (5 mL) was stirred for 15 min. 2-methyl-5-nitroaniline (211 mg, 1.387 mmol) was added and stirred at 60° C. for 4 h. Quenched in citric acid solution and the resulting precipitate was collected to give N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carboxamide 75 (400 mg, 92%). (m/z)=315 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[OH:1][CH2:2][C:3]1[N:25]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7](=[O:9])[CH:8]=1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: NCc1ccccc1
Solvent: O
Product: O=c1cc(CO)n(Cc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one (10.5 g, 45.3 mmol) in benzylamine (40 ml) and water (60 ml) was refluxed for four hours and then stirred overnight at room temperature. The resulting precipitate was collected and washed thoroughly with water to give 9.17 g (28.6 mmol) of 2-(hydroxymethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)pyridinone (melting point 146°-147° C.) upon drying. The supernatant was diluted with water to a total volume of 450 ml, and after standing for one hour at room temperature, the resulting precipitate was collected to yield 2.47 g (7.69 mmol) of additional 2-(hydroxymethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone upon drying.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]2[O:20][C:21]([C:24]3[N:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]2[O:20][C:21]([C:24]3[N:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)nc1
Yield: 81.7 %

Procedure:
Methyl 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylate (46 mg, 0.10 mmol) was dissolved in THF/H2O (3:2, 10 mL) and LiOH (7 mg, 0.3 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 15 min before the addition of 1 N HCl to adjust the solution to an acidic pH to quench the reaction. The reaction solution was diluted with EtOAc and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3×). The organic phases were combined and washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylic acid as a white solid (35 mg, 79%): 1H NMR (THF-d8, 600 MHz) δ 9.18 (d, 1H, J=1.3 Hz), 8.41 (dd, 1H, J=8.2, 2.0 Hz), 7.97 (s, 1H), 7.94 (d, 1H, J=8.2 Hz), 7.35 (d, 2H, J=7.9 Hz), 7.28 (d, 2H, J=7.8 Hz), 7.22 (t, 2H, J=8.0 Hz), 6.95 (d, 2H, J=8.1 Hz), 6.87 (t, 1H, J=7.3 Hz), 2.09 (s, 2H), 3.43 (t, 2H, J=7.6 Hz), 3.06 (t, 2H, J=7.6 Hz); 13C NMR (THF-d8, 150 MHz) δ 187.1, 166.1, 160.1, 158.9, 153.5, 152.2, 150.3, 141.5, 139.2, 136.4, 130.0, 129.3, 129.1, 128.4, 127.5, 121.3, 120.1, 115.5, 70.2, 41.4, 30.1; HR ESI-TOF m/z 429.1443 (M+H+, C25H20N2O5, requires 429.1445).