Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:19]([CH3:21])[CH3:20])[C:7]([N:9]1[C@H:14]([C:15](O)=[O:16])[CH:13]2[CH2:18][CH:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].C([N:25](C(C)C)CC)(C)C.[OH-].[NH4+]>C(#N)C.O>[C:15]([C@@H:14]1[CH:13]2[CH2:18][CH:10]([CH2:11][CH2:12]2)[N:9]1[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:19]([CH3:21])[CH3:20])(=[O:16])[NH2:25]
Reactant: COC(=O)N[C@H](C(=O)N1C2CCC(C2)[C@H]1C(=O)O)C(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N1C2CCC(C2)[C@H]1C(N)=O)C(C)C
Reaction time: 1 h

Procedure:
(3S)-2-((S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.78 g, 5.97 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (2.49 g, 5.56 mmol), and diisopropylethylamine (2.61 mL, 14.92 mmol) were dissolved in acetonitrile (30 mL) at ambient temperature and treated by dropwise addition with 28% ammonium hydroxide solution (2.49 g, 17.98 mmol). The resulting mixture was stirred for 1 hour and then diluted with water and extracted into dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give methyl (2S)-1-((3S)-3-carbamoyl-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a white waxy solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:1]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCCCC2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of piperidine (2.98 g) and methyl 6-chloronicotinate (5.00 g) in N,N-dimethylformamide (75 ml) was added potassium carbonate (12.08 g). The mixture was stirred at 100° C. for 3 hours. After cooling to ambient temperature, to the reaction mixture was added water (100 ml) and then the mixture was stirred for 15 minutes at ambient temperature. The resulting precipitates were filtered, washed with water, and dried to give methyl 6-(1-piperidyl)nicotinate (5.55 g), as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2].CN([CH:16]=[O:17])C>C1COCC1>[C:1]([NH:4][C:5]1[C:10]([F:11])=[C:9]([CH:16]=[O:17])[C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)cc1F
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(Cl)c(C=O)c1F
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 2-acetylamino-5-chloro-3-fluoropyridine (50 mg, 0.27 mmol) and DMF (123 μL, 1.6 mmol) were dissolved in THF (0.5 mL) at room temperature. The solution was cooled to −20° C., a 24 wt % lithium hexamethyldisilazide THF solution (492 μL, 0.61 mmol) was added dropwise, and the mixture was stirred for 3 hours at that temperature. The reaction mixture was subjected to HPLC analysis under the same conditions as Example 8, and the purity and conversion rate were calculated from the area ratio of the title compound and the starting compound (2-acetylamino-5-chloro-3-fluoropyridine). The formula used was: Conversion rate (%)=100−(area ratio of starting compound).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:24]([O:23][C:21](=[O:22])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:8]=1)[CH:25]=[CH2:26]
Reactant: CC(C)(C)NCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(C)(C)C
Yield: 61 %

Procedure:
tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-amine from the above reaction (1.33 g, 4.84 mmol) was treated with allyl chloroformate (0.77 mL) in methylene chloride (15 mL) with diisopropyl ethylamine (1.7 mL) at room temperature for 3 hours. The mixture was diluted with methylene chloride (50 mL), washed with water (2×), brine, dried over Na2SO4, filtered. Removal of the solvent followed by chromatography on silica gel (1:4 ethyl acetate:hexane eluent) afforded product in 61% yield. LC-MS showed the product had the expected M+H+ of 360. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.6 (d, 1H) 7.9 (d, 2H) 7.6 (d, 1H) 7.4 (m, 2H) 5.9 (m, 1H) 5.2 (m, 2H) 4.7 (s, 2H) 4.6 (d, 2H) 1.4 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][NH:28][CH2:27][CH2:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCCCCCC(=O)NOCc1ccccc1)CC2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.3 g, 1.3 mmol) was reacted with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.43 g, 1.3 mmol) in the presence of potassium carbonate (0.18 g, 1.4 mmol) and DMF as solvent to give 8-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.28 g, 49%; purified by column chromatography using silica gel and ethyl acetate: methanol 9:1 as an eluent). MS (M+H+)=441.
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1.CN(C)C=O>O>[CH3:29][O:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:20]([O:1][C:2]2[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[N:21]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: COC(=O)c1ccc(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C)nc1Oc1nc(OC)cc(OC)n1
Yield: 8 %

Procedure:
5.0 g (0.03 mol) of methyl 2-hydroxy-6-methylnicotinate, 5.0 g (0.03 mol) of potassium carbonate, 5.7 g (0.03 mol) of 2-chloro-4,6-dimethoxypyrimidine and 50 ml of N,N-dimethylformamide were weighed, and were reacted at 100° C. for 4 hours. The reaction mixture was then poured into water, and was extracted with 100 ml of ethyl acetate. The organic layer was then washed with water and a saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.73 g of the aimed product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)=[CH:11][CH:10]=1.[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1>C1COCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:23][C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)O1
Reactant: O=[N+]([O-])c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Nc1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Reaction time: 4 h
Yield: 20.8 %

Procedure:
A mixture of 2,4-difluoro-4′-(3-nitro-benzyloxy)-biphenyl (28 mg, 0.082 mmol), succinic anhydride (8.2 mg, 0.083 mmol) and 10% Pd/C (4.4 mg) in THF (3 mL) was hydrogenated at 45 psi for 4 hrs. The reaction mixture was filtered and evaporated. The crude product was purified by flash chromatography with a 0-50% gradient of ethyl acetate in hexanes to yield 7 mg (20.7%) of N-[3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-phenyl]-succinamic acid as a solid. LC-MS (ES) calculated for C23H19F2NO4, 411.41; found m/z 410.2 [M−H]−.
Reaction SMILES: F[C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H:5]([C:17]2N(C)N=[CH:19][C:18]=2[N+]([O-])=O)[O:4]C1.N[C:27]1[S:31][C:30]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])=[N:29][C:28]=1[C:40]([NH:42][C:43]1[CH:44]=[N:45][N:46]([CH3:57])[C:47]=1[CH:48]1[CH2:54][CH2:53][C@@H:52]([NH2:55])[C@H:51]([F:56])[CH2:50][O:49]1)=[O:41]>>[NH2:55][C@H:52]1[C@H:51]([F:56])[CH2:50][O:49][C@H:48]([C:47]2[N:46]([CH3:57])[N:45]=[CH:44][C:43]=2[NH:42][C:40]([C:28]2[N:29]=[C:30]([C:32]3[C:33]([F:39])=[CH:34][C:35]([CH:18]4[CH2:17][CH2:5][O:4][CH2:19]4)=[CH:36][C:37]=3[F:38])[S:31][CH:27]=2)=[O:41])[CH2:54][CH2:53]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@@H](N)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cc(C4CCOC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2,6-difluoro-4-(tetrahydrofuran-3-yl)phenyl)thiazole-4-carboxylic acid (Intermediate 145) gave 216. The product was isolated as a mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.61 (s, 1H), 7.80 (s, 1H), 7.27 (d, J=10.0 Hz, 2H), 4.81 (dd, J=10.8, 3.7 Hz, 1H), 4.46-4.22 (m, 1H), 4.24-4.09 (m, 1H), 4.08-3.89 (m, 3H), 3.86-3.75 (m, 4H), 3.63 (dd, J=8.4, 6.9 Hz, 1H), 3.58-3.45 (m, 1H), 3.34-3.16 (m, 3H), 2.42-2.29 (m, 1H), 2.11-1.91 (m, 2H), 1.87-1.79 (m, 1H), 1.72-1.62 (m, 4H). LCMS (ES+) m/z 522 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].C[O:10][C:11]1[CH:28]=[CH:27][C:14]2[CH:15]([CH3:26])[CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19][C:13]=2[CH:12]=1.Cl>ClCCl.C(Cl)(Cl)Cl.O>[OH:7][C:5]1[C:28]([C:11](=[O:10])[CH3:12])=[CH:27][C:14]2[CH:15]([CH3:26])[CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])[CH2:18][CH2:19][C:13]=2[CH:6]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc2c(cc1O)CCN(C(=O)C(F)(F)F)CC2C

Procedure:
To a mixed liquid of 9.3 g of aluminum chloride in 30 ml of dichloromethane was added dropwise 1.6 ml of acetyl chloride under ice-cooling, followed by stirring. Then, a solution of 5 g of 7-methoxy-1-methyl-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine in 70 ml of dichloromethane was added thereto, followed by stirring for 13 hours while slowly elevating the temperature to room temperature. The reaction mixture was ice-cooled, and 30 ml of 1 M hydrochloric acid was added dropwise thereto, followed by addition of water and extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (elution solvent: HEX-EtOAc) to obtain 5.137 g of 1-[8-hydroxy-5-methyl-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl]ethanone as a pale brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:19][O:18][C:12]([CH:13]([CH:7]([C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:13]([C:12]([O:18][CH3:19])=[O:17])[C:14](=[O:15])[CH3:16])[C:14](=[O:15])[CH3:16])=[O:17]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)C(C(C)=O)C(c1cccc([N+](=O)[O-])c1)C(C(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
To a mixture of 72.1 g of zinc chloride in 200 ml of ethyl acetate was added dropwise a mixture of 40.0 g of m-nitrobenzaldehyde and 61.5 g of methyl acetoacetate at room temperature over 50 minutes. The mixture was stirred at room temperature for further 15 minutes, and further stirred while heating at 60°-65° C. for 6.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, then 800 ml of ether and 800 ml of water were added thereto, and the desired product was extracted with ether. The aqueous layer was extracted again with 300 ml of ether, which was combined with the first ether layer. The combined layer was washed with 200 ml of a 5% aqueous sodium bicarbonate solution, and then with 200 ml of saturated saline. This substance was dried over anhydrous magnesium sulfate, and the ether was distilled off to obtain 92.7 g of crude crystals. The crystals were recrystallized from methanol to obtain 47.7 g (yield 49.3%) of 3,5-bis(methoxycarbonyl)-4-(3-nitrophenyl)-2,6-heptanedione.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.Cl.[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:44][CH2:45][OH:46])[CH:41]([CH3:43])[CH3:42])(=[O:17])[CH3:16].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH2:39][N:40]([CH:41]([CH3:43])[CH3:42])[CH2:44][CH2:45][O:46][CH2:12][O:11][CH3:10])(=[O:17])[CH3:16]
Reactant: COc1ccc(OCCCN(CCO)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: COCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCN(CCCOc1ccc(OC)cc1C1Sc2cc(Cl)ccc2N1C(C)=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 51.5 %

Procedure:
N,N-Diisopropylethylamine (0.18 ml, 1.01 mmol) and chlorodimethyl ether (0.05 ml, 0.55 mmol) were added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline hydrochloride (235 mg, 0.46 mmol) in methylene chloride (2.0 ml) under ice-cooling. The mixture was stirred at room temperature for 3.5 hours, then a saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated brine (50 ml) and dehydrated with anhydrous magnesium sulfate, and ethyl acetate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol=20/1) to give 124 mg (52%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:19](=O)[C:20]#[CH:21])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N+]([O-])([O-])=O.[C:27]1([NH:33][C:34]([NH2:36])=[NH2+:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.CCOCC>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:19]3[CH:20]=[CH:21][N:36]=[C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:35]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=[NH2+])Nc1ccccc1
Reactant: C#CC(=O)c1c(-c2cccc(OC)c2)nc2c(Cl)cccn12
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: O
Product: COc1cccc(-c2nc3c(Cl)cccn3c2-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 140 °C
Yield: 49.2 %

Procedure:
To a solution of 1-[8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-one (58 mg, 0.19 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added N-phenylguanidinium nitrate (185 mg, 0.94 mmol) and potassium carbonate (129 mg, 0.94 mmol). The mixture was heated at 140° C. for 1.25 hours and then cooled to room temperature. Water was added then ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes-ethyl acetate) provided 4-[8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl]-N-phenylpyrimidin-2-amine (40 mg, 50%) as a yellow solid. 1H NMR (CDCl3 with 2 drops CD3OD): δ 9.45 (d, 1 H), 8.16 (d, 1 H), 7.60–7.58 (m, 2 H), 7.39 (d, 1 H), 7.34–7.29 (m, 3 H), 7.17–7.15 (m, 2 H), 7.07 (t, 1 H), 6.95 (m, 1 H), 6.75 (t, 1 H), 6.58 (d, 1 H), 3.79 (s, 3 H); MS m/z 428 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)(=[O:4])=[O:3].[NH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[C:23]=1[Br:28]>>[Br:28][C:23]1[C:24]([CH3:27])=[N:25][O:26][C:22]=1[NH:21][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccsc1CCc1ccc2c(c1)OCO2
Product: Cc1noc(NS(=O)(=O)c2ccsc2CCc2ccc3c(c2)OCO3)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 2. By reacting 3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene with 5-amino-4-bromo-3-methylisoxazole and purifying the crude product by HPLC, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide was obtained in a 30% yield, m.p. 180° (dec.).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([CH2:11][N+:12]([O-])=O)[CH2:7][CH2:8][CH2:9][CH3:10])C.[H][H]>CO.[Ni]>[CH2:7]([CH:6]1[CH2:11][NH:12][C:4](=[O:3])[CH2:5]1)[CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCC(CC(=O)OCC)C[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCCCC1CNC(=O)C1
Yield: 90.7 %

Procedure:
To a solution of 3-nitromethylheptanoic acid ethyl ester (10 g, 49.2 mmol) in methanol (100 mL) under argon was added Raney Ni (5 g). The mixture was stirred under 50 psi of hydrogen for 48 h, flushed with argon, filtered through a Celite pad, and concentrated under vacuum to afford 4-butylpyrrolidin-2-one as a colorless oil (6.3 g, 91%). MS(ES) m/e 142 [M+H]+.
Reaction SMILES: [NH:1]1[C:18](=[O:19])[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH:4]([CH3:6])[CH3:5].N[C@H](C(N[C@H](C(O)=O)CC1C=CC=CC=1)=[O:27])CC(C)C>>[NH2:9][C@H:10]([C:18]([NH:1][C@H:2]([C:7]([OH:27])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@@H]1NC(=O)[C@H](Cc2ccccc2)NC1=O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O

Procedure:
As a result, it was confirmed that 6.8 mg/l cyclo(L-Leu-L-Phe), 28.7 mg/l L-Leu-L-Phe and 18.5 mg/l L-Phe-L-Leu were formed. No cyclodipeptide or dipeptide was detected in the reaction mixture when without ATP incubated in the same manner.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:20]2[C:28]3[C:27](Cl)=[N:26][CH:25]=[N:24][C:23]=3[N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH:21]=2)=[O:19])[C:12]=1[F:40])C1C=CC=CC=1.[OH-:42].[K+].Cl.[CH3:45]O>>[NH2:10][C:11]1[C:12]([F:40])=[C:13]([C:18]([C:20]2[C:28]3[C:27]([O:42][CH3:45])=[N:26][CH:25]=[N:24][C:23]=3[NH:22][CH:21]=2)=[O:19])[C:14]([F:17])=[CH:15][CH:16]=1
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c3c(Cl)ncnc32)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: COc1ncnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c12
Temperature: 70 °C

Procedure:
{3-[4-Chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl}-carbamic acid benzyl ester (35, 152 mg, 0.255 mmol) is combined with 15 mL of methanol and potassium hydroxide (1.06 g, 18.9 mmol) is added. The mixture is heated at 70° C. for 36 hours, then 6 N aqueous hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (36, 0.03 mg). MS (ESI) [M+H]+=305.1.
Reaction SMILES: C1(C[O:5][C:6](=[O:31])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:14]([Cl:30])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[Cl:30][C:14]1[CH:13]=[C:12]([CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:31])=[O:5])[CH:17]=[C:16]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:15]=1[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc(Cl)cc2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc(Cl)cc2)c(OCC2CC2)c1
Yield: 102.3 %

Procedure:
2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.18 g, 0.36 mmol) was dissolved in a mixture of EtOH and H2O (9 mL /1 mL) and KOH (0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5 and the reaction mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure to give 2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid as a yellowish solid (0.15 g, 93%). M.p.=52-53° C. 1H NMR (300 MHz, CDCl3/TMS): δ 10.60 (br s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.75 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 1.99-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.40 (m, 2H), 0.22-0.12 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.7, 157.2, 139.7, 134.0, 133.4, 133.1, 131.8, 128.5, 127.9, 121.6, 111.3, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>C(#N)C>[O:21]=[C:19]([CH3:20])[CH2:18][O:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: NC(=O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)COc1cccnc1C(N)=O

Procedure:
A mixture of 27.6 g of 3-hydroxy-2-pyridinecarboxylic acid amide and 31 g of potassium carbonate in 600 ml of acetonitrile is heated to the boil for two hours, whilst stirring well. 22.2 g of chloroacetone are added dropwise to the resulting thick paste in the course of 30 minutes. The reaction mixture is stirred for 20 hours whilst boiling under reflux. The undissolved material is filtered off after cooling and the filtrate is evaporated under reduced pressure. The residue is stirred with water, whereupon unconverted 3-hydroxy-2-pyridinecarboxylic acid amide remains as an undissolved residue. The aqueous solution is evaporated under reduced pressure and the residue is extracted with methylene chloride. Evaporation of the organic solution under reduced pressure gives crude 3-(2-oxo-propyloxy)-2-pyridinecarboxylic acid amide, which melts at 135°-140° C. after crystallisation from ethanol.