Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([OH:16])=O)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.C(OCC)(=O)C>[CH3:3][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([NH:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:16])[CH3:1]
Reactant: NCc1ccccc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(=O)NCc2ccccc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 1.14 mmol) and 1,1'-carbonyldiimidazole (240 mg, 1.48 mmol) in 7 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and benzylamine (0.75 mL, 6.84 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:4 to 1:3) provides 3-(1-methylethoxy)-N-(phenylmethyl)-2-benzofurancarboxamide in 78% yield as a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:12][C@@H:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:1])=[CH:39][CH:40]=2
Reactant: C[C@@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3ccc([N+](=O)[O-])cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (R)-α-methyl-4-nitrobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 548 (M+H).
Reaction SMILES: CN(/[CH:4]=[C:5](/[C:10](=O)[CH3:11])\[C:6]([O:8][CH3:9])=[O:7])C.Cl.Cl.[CH2:15]([NH:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:22]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:10]([CH3:11])=[N:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)/C(=C\N(C)C)C(C)=O
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cn(Cc2ccccc2)nc1C
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 58.3 %

Procedure:
To a solution of (Z)-methyl 2-((dimethylamino)methylene)-3-oxobutanoate (15.8 g, 92.5 mmol) in ethanol (50 mL) was added 1-benzylhydrazine dihydrochloride (18 g, 92.3 mmol). The resulting solution was stirred for 3.5 h at 80° C., then concentrated under reduced pressure. The residue was dissolved in 200 mL of ethyl acetate. The organic layer was washed with 1×40 mL of water and 2×40 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as the eluent to furnish 12.4 g (58%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)[CH:9]=2)[CH:4]=1>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(-c3cccc([N+](=O)[O-])c3)ccc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Temperature: 25 °C
Yield: 20 %

Procedure:
To a solution of 2-methoxy-6-(3-nitrophenyl)naphthalene (200 mg, 0.71 mmol, 1 eq) in 100 ml of dry THF, Pd/C is added, and the mixture is stirred over night at RT under a hydrogen atmosphere. After filtration over Celite and purification by means of preparative thin-layer chromatograph, the product is obtained in a yield of 20% (36 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([C:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH:32]=2)[C:24]([N+:34]([O-:36])=[O:35])=[CH:23][C:21]=1[NH2:22].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CO>C1COCC1>[Cl:17][C:5]1[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([N+:34]([O-:36])=[O:35])[C:25]([C:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH:28]=3)=[CH:26][C:20]=2[O:19][CH3:18])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 21, 575 mg, 1.86 mmol) and 2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 490 mg, 1.86 mmol) was stirred in THF (30 mL) and cooled in an ice/water bath. Lithium bis(trimethylsilyl)amide (4.10 mL, 4.10 mmol, 1M in THF) was then added dropwise and the mixture was stirred for 1 h. CH3OH was added and the mixture was concentrated in vacuo. The crude material was suspended in CH3OH and the mixture was filtered. The collected solid was washed with CH3OH and diethyl ether and dried on the filter to give the title compound (660 mg, 72%) as a yellow powder; 1H NMR: 2.29 (3H, s), 2.30-2.38 (2H, m), 2.58 (2H, t), 2.97 (2H, dd), 3.96 (3H, s), 5.60-5.68 (1H, m), 7.00 (1H, s), 7.16 (1H, td), 7.36-7.45 (1H, m), 8.49-8.56 (3H, m), 8.87 (1H, d), 8.90 (1H, s), 8.97 (1H, s); m/z: ES+ MH+ 492.4.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[C:7]2[N:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C[C@H](N)c1nc2cccc(F)c2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(F)c2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 19.2 %

Procedure:
A mixture of (S)-1-(7-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 7 (367 mg, 1.44 mmol), 6-chloro-9H-purine (222 mg, 1.44 mmol) and DIPEA (0.74 mL, 4.31 mmol) in n-butanol (3.5 mL) was stirred in a sealed tube for 48 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The product thus obtained was further purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in EtOAc) followed by (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then sonicated in MeOH. The suspension was then diluted with diethyl ether and the solid collected by filtration affording 124 as a white solid (103 mg, 19%). LCMS: RT 3.40 min [M+H]+ 374.0. 1H NMR (DMSO, 400 MHz): δ 8.17-8.04 (2H, m), 7.98-7.86 (1H, br), 7.75-7.35 (6H, m), 7.19 (1H, td, J=8.09, 4.87 Hz), 7.02 (1H, dd, J=11.60, 8.02 Hz), 5.37 (1H, bs), 1.56 (3H, d, J=6.86 Hz)
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH2:30])=[C:20]([OH:31])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]4[NH:30][C:44](=[O:45])[CH2:43][O:31][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(N)cc3-c3ccccc3)cc2)CCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of tert-butyl(1-(4-(5-amino-6-hydroxy-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (1.8 g, 4.17 mmol), DIPEA (3.63 ml, 20 mmol) in DCM (100 ml) at 0° C. was added a solution of chloroacetyl chloride (0.465 ml) in DCM (20 ml). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added MIBK (120 ml) and saturated sodium bicarbonate (120 ml). The resulting mixture was heated at 115° C. for 16 h. After cooled down to room temperature, the MIBK was removed under reduced pressure. The residue was extracted with ethyl acetate (75 ml). The layers were separated and the aqueous phase extracted into ethyl acetate (2×50 ml). The combined organic phases were washed with water (150 ml) and brine (150 ml), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 2% methanol in DCM) to give the title compound (0.82 g, 42%). LCMS (Method A): RT=6.55 min, M+1=472. 1H NMR (500 MHz, CDCl3): 7.3-7.0 (10H, m), 4.96 (1H, br), 4.82 (2H, s), 2.55-2.25 (4H, m), 2.1-1.9 (1H, m), 1.8-1.65 (1H, m), 1.35-1.1 (9H, br).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH3:3].CN(C)C=O.O[NH:23][C:24](=[NH:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:16])[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[O:15][N:23]=[C:24]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:35]=2)=[CH:10][CH:11]=1)[CH3:3]
Reactant: COc1ccc(OCC(=N)NO)cc1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cc2nc(COc3ccc(OC)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
Add oxaxyl chloride (1.25 mL, 14 mmol) to 4-carboxymethyl-benzoic acid ethyl ester (365 mg, 1.75 mmol) in benzene (11 mL) and a drop of dimethylformamide at room temperature under argon gas over a 5 minute period. Stir the reaction mixture for 2 hours at room temperature. Concentrate the reaction mixture to an oil. Redissolve the oil in dimethylformamide (10 mL) and N-hydroxy-2-(4-methoxy-phenoxy)-acetamidine (380 mg, 1.9 mmol) is added. Stir the reaction mixture at room temperature for 3 hours. Heat the reaction mixture to 120° C. and stir for 7 hours. After cooling to room temperature, quench the reaction mixture with water and extract with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate. Purify the residue by flash column chromatography using 20% ethyl acetate/hexane to give the title compound (201 mg, 31%). LC-MS (m/e): 369 (M+1).
Reaction SMILES: C(O[CH:10]=[C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=O)C1C=CC=CC=1.[H][H]>C(O)(C)C.[Pt]=O>[CH3:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCC(=COC(=O)c1ccccc1)C2=O
Agent: O=[Pt]
Solvent: CC(C)O
Product: COc1ccc2c(c1)CCC(C)C2=O
Yield: 73.3 %

Procedure:
2-Benzoyloxymethylene-6-methoxy-1-tetralone (4.6 g, 0.015 mole) was hydrogenated over platinum oxide (160 mg) in isopropyl alcohol (150 mL) at 55 psi in a Parr hydrogenation apparatus. After about 90 minutes hydrogen uptake ceased and the reaction was stopped. The catalyst was removed by filtration and the solvents were removed in vacuo. The title compound (2.0 g, 0.011 mole, 70% yield) was obtained after purification by flash chromatography [gradient 10:1 to 5:1 EtOAc:Hexanes].
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=O.[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18]>C(O)(=O)C>[C:13]1([CH3:16])[CH:12]=[CH:11][C:10]([C:8]2[N:23]([CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[CH:2]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)NCCN
Reactant: Cc1ccc(C(=O)CCC2OCCO2)cc1
Solvent: CC(=O)O
Product: CC(=O)NCCn1cccc1-c1ccc(C)cc1
Yield: 69.5 %

Procedure:
3-(1,3-Dioxolan-2yl)-4'-methylpropiophenone (10.2 g) was dissolved in 20 ml of acetic acid and added under argon and while stirring to a solution of 9.4 g of N-acetylethylenediamine in 100 ml of acetic acid. The reaction mixture was heated to reflux overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 200 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 150 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 100 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 14.0 g of dark brown oil were chromatographed on 550 g of silica gel with ethyl acetate/hexane (2:1) as the eluent. 7.8 g (70%) of N-[2-(2-p-tolylpyrrol-1-yl)ethyl]acetamide were isolated as a brown oil. MS: m/e=242 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].C([O:13][B:14](OCC)[O:15]CC)C.S(=O)(=O)(O)O>C(OCC)C.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:14]([OH:15])[OH:13])=[CH:3][CH:4]=1
Reactant: CCOB(OCC)OCC
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethyl ether is added dropwise under reflux to a suspension, under inert gas, of 1.3 g of magnesium turnings in 5 ml of anhydrous diethyl ether, and the mixture is left under reflux for 2 hours. The reaction medium is then poured into a solution of 9.02 ml of triethylborate in 60 ml of anhydrous ether cooled down to −70° C. After agitation for 1 hour at −70° C., then for 1 hour at ambient temperature, the solution is poured into a mixture comprising 11 ml of sulphuric acid and 50 g of ice and water followed by agitation for 1 hour. The organic phase is extracted with 100 ml of an aqueous solution saturated in sodium bicarbonate, the aqueous phases are combined, then reacidified with 6N hydrochloric acid, extracted with ether, dried and evaporated under reduced pressure. 3.9 g of expected product is obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([CH:11]=O)=[N:2]1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH2:27])=[C:22]([NH2:28])[CH:21]=1>CCO>[CH3:26][C:24]1[C:23]2[NH:27][C:11]([C:3]3[CH2:4][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[O:1][N:2]=3)=[N:28][C:22]=2[CH:21]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])[CH:25]=1
Reactant: Cc1cc(-c2ccccc2F)cc(N)c1N
Reactant: O=CC1=NOC2(CCCCC2)C1
Solvent: CCO
Product: Cc1cc(-c2ccccc2F)cc2nc(C3=NOC4(CCCCC4)C3)[nH]c12
Temperature: 80 °C
Yield: 44 %

Procedure:
1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (167 mg, 1.00 mmol, as prepared in Example 19, step B) was placed in a 25 mL round-bottom flask equipped with a magnetic stir bar. 2′-Fluoro-5-methyl-biphenyl-3,4-diamine (218 mg, 1.01 mmol, as prepared in the previous step) was added as a solution in EtOH (10 mL). The flask was fitted with a reflux condenser (top open to air), and the mixture was heated to 80° C. for 6 h. The cooled mixture was concentrated under reduced pressure. The residue was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min, yielding 159 mg (44%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.57 (br. s., 1H), 7.50 (td, J=7.8, 1.9 Hz, 1H), 7.31-7.37 (m, 1H), 7.08-7.28 (m, 4H), 2.64 (s, 3H), 2.31 (s, 2H), 1.69-1.89 (m, 6H), 1.47-1.64 (m, 4H).
Reaction SMILES: [NH2:1][C:2](=[O:22])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14](F)[CH:13]=2)[N:9]=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=1)[CH3:4].[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C>[NH2:1][C:2](=[O:22])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:13]=2)[N:9]=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=1)[CH3:4]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(-c2ccnc(F)c2)n1)C(N)=O
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccnc(Oc3ccc(F)cc3)c2)n1)C(N)=O
Temperature: 160 °C
Yield: 50.5 %

Procedure:
A mixture of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(2-fluoropyridin-4-yl)pyrimidine-4-carboxamide (60 mg, 0.2 mmol), 4-fluorophenol (40 mg, 0.2 mmol) and Cs2CO3 (76 mg, 0.2 mmol) in DMF (1 mL) was placed in a microwave reaction vial and heated in a microwave oven at 160° C. for 20 minutes. The reaction was worked up with DCM then dried and evaporated. The residue was subjected to C18 flash chromatography using acetonitrile/H2O/0.1 TFA as the eluent and neutralized to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(2-(4-fluorophenoxy)pyridin-4-yl)pyrimidine-4-carboxamide as white solid (40 mg, yield 50%). 1H NMR (CD3OD): 7.90-8.21 (3H, m), 6.90-7.2 (5H, m), 4.4 (1H, m), 1.35 (3H, d, J=7.0 Hz). LC/MS: m/z=398 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]>CN(C=O)C>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[OH:8])[NH:1][C:17](=[O:18])[O:19][CH:20]([CH3:22])[CH3:21]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Nc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-amino-2-chlorophenol (21.45 grams, 0.15 mole) in dry DMF (150 ml.) and pyridine (11.8 grams) is added at 0°C. slowly dropwise with stirring isopropyl chloroformate (16.5 grams, 0.016 mole). After 4 hours at 0° C. to 5°C., a further one gram of isopropyl chloroformate is added. The mixture is stirred at 25°C. for 16 hours, then poured into ice-dilute hydrochloric acid. After 4 hours stirring and scratching, a solid separates out and is filtered off. Crystallization from methanol gives 14.5 grams, 42%, melting point 89°C. to 90°C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][S:21][CH2:20][CH2:19]1>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][S:21][CH2:20][CH2:19]1)([O-:10])=[O:9]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1N1CCSCC1
Temperature: 25 °C

Procedure:
A solution of 1-fluoro-2-nitro-benzene (2.0 mmol, 0.21 mL), triethylamine (3.0 mmol, 0.42 mL) and thiomorpholine (3.0 mmol, 0.30 mL) in dioxane (2 mL) was irradiated using microwave for 15 minutes at a temperature of 160° C. The solution was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel to provide 4-(2-Nitro-phenyl)-thiomorpholine. To the solution of this nitro compound in MeOH (10 mL) was added Pd on carbon (5% Pd, 100 mg). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide compound 39A. HPLC-MS RT=1.06 minutes, mass calculated formula C10H14N2S 194.09, observed LCMS m/z 195.10 (M+H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[C:20]([NH2:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]([CH3:26])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:11][C:10]=2[C:20](=[O:21])[NH:22][C:24]1([CH3:26])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: NC(=O)c1sc(-c2ccncc2)cc1NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1Cc1ccccc1
Temperature: 70 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
A mixture of 3-(benzylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.124 g, 0.400 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate), then triturated with ethyl acetate/hexanes (1:1), and the precipitate was collected by filtration to afford the title compound (0.0841 g, 60%) as a yellow solid:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[Br:10]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[CH3:9][O:8][C:1](=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][Br:10]
Reactant: C/C=C/C=C/C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Solvent: Clc1ccccc1
Product: COC(=O)C=CC=CCBr
Yield: 64.9 %

Procedure:
A mixture of methyl sorbate (1.26 g, 10 mmol) and N-bromosuccinimide (1.98 g, 11.0 mmol) in chlorobenzene was irradiated with a 250 W sunlamp so as to achieve a state of reflux for 4 hours. The (cooled) mixture was then evaporated under reduced pressure to give a brown oil which was purified by column chromatography (9:1 60-80° C. petroleum ether:diethyl ether) to give the title compound (1.33 g, 65%) as a clear oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][C:10](=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:13]1([N:19]2[C:10]([CH2:9][OH:8])=[N:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: O=C1COC(c2ccccc2)=N1
Solvent: CCO
Product: OCc1nc(-c2ccccc2)nn1-c1ccccc1
Yield: 60.9 %

Procedure:
A mixture of 2-phenyloxazol-4(5H)-one (600 mg, 3.35 mmol) and phenylhydrazine (420 mg, 382 μL, 3.69 mmol) in ethanol (10 mL) was refluxed for 2 h. The reaction mixture was concentrated in vacuo. The obtained suspension was filtered, washed with EtOH and dried in vacuo to give 513 mg of a light yellow solid which proofed to be product. The filtrate was evaporated to give 430 mg of a yellow solid which also contained a considerable amount of product. Thus, the product was obtained after purification of the evaporated filtrate by flash chromatography (using silica gel and an ethyl acetate/dichloromethane gradient) and combination with the precipitated product as light yellow solid (711 mg, 2.83 mmol, 84.4%). MS: M=252.2 (M+H)+