Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.[Na].[SH:29][C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.O>COCCOC>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[S:29][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1)[C:12]#[N:13]
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Reactant: Sc1nc2ccccc2s1
Agent: [Na]
Solvent: O
Solvent: COCCOC
Product: N#CC(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
1.517 g of O-[p-toluenesulfonyl)-m-phenoxymandelonitrile was dissolved in 5 ml of DME, and the solution was stirred in an argon atmosphere under ice cooling. Sodium salt of 2-mercaptobenzothiazole (760 mg) was added, and the mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 1.5 hours. Water (20 ml) was added to the reaction mixture, and it was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene and methylene chloride) to afford 1.233 g (yield 85%) of alpha-(2-benzothiazolylthio)(m-phenoxyphenyl)acetonitrile as a colorless oil.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[N:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:16][CH:17]=1)=[C:10]=S.N=C=N.CO>C1COCC1.ClCCl>[CH3:32][NH:31][C:27]1[N:26]=[C:25]([C:24]2[C:19]([O:18][C:15]3[N:16]=[CH:17][C:12]([NH:9][C:10]4[NH:8][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=5[N:7]=4)=[CH:13][CH:14]=3)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N=C=S)cn2)n1
Reactant: Nc1ccccc1N
Agent: N=C=N
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nc4ccccc4[nH]3)cn2)n1

Procedure:
A mixture of benzene-1,2-diamine (0.091 g, 0.85 mmol), 4-(2-(5-isothiocyanatopyridin-2-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.237 g, 0.70 mmol), and polymer-supported carbodiimide (Argonaut technologies, 1.6 mmol/g, 1.3 g, 2.1 mmol) was heated for 14 h in anhydrous THF in a sealed vial. The reaction was cooled and was filtered, rinsing with 100 mL DCM. The filtrate was concentrated in vacuo to give an off-white solid. Sonication in dichloromethane gave a fluffy precipitate, which was filtered and collected to give an off-white solid. This material was adsorbed onto 0.8 g SiO2 from MeOH/MC, and purified by silica gel chromatography, 40 g, 0-10% MeOH/MC to give N-(6-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-3-yl)-1H-benzo[d]imidazol-2-amine as a white solid MS m/z=411 [M+H]+. Calc'd for C22H18N8O: 410.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:25]C(=O)C)=[C:6]2[C:10]=1[C:9](=[O:11])[C:8]([OH:23])([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[O:21][CH3:22])[C:7]2=[O:24]>Cl.CO.C(Cl)Cl>[NH2:25][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[C:10]2[C:6]=1[C:7](=[O:24])[C:8]([OH:23])([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[O:21][CH3:22])[C:9]2=[O:11]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2c(N)ccc(NC(C)=O)c2C1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2c(N)ccc(N)c2C1=O
Yield: 235 %

Procedure:
N-(7-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (45 mg, 0.10 mmol) was completely dissolved in 6M HCl (1.4 ml) and methanol (0.1 ml), followed by heating for 90 min at 80. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (80 mg, 200%).
Reaction SMILES: CN(OC)[C:3](=[O:19])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1.COCCOC.CCOC(C)=O>CCOCC>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:3](=[O:19])[CH2:4][CH2:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:25][CH:24]=1
Reactant: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 68.9 %

Procedure:
N-Methyl-N-methoxy-3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionamide (550 mg, 1.83 mmol, from Step B) was dissolved in 10 mL dry ether and the solution was cooled to 0° C. A solution of 4-fluorophenyl magnesium bromide (2 mL, 1.0 M in THF, 2.01 mmol) was added dropwise. A solid mass formed upon addition and 1 mL 1,2-dimethoxyethane was added. The mixture was warmed to room temperature and stirred for 45 min then poured into 100 mL EtOAc/10 mL 1 M aqueous HCl. The layers were separated and the organic phase was washed with water, then sat'd NaCl, then dried over Na2SO4 and concentrated. Flash chromatography (25 grams silica, 5/1 hexane/EtOAc eluant) afforded 423 mg (69%) of the title compound. 1H NMR (300 MHz, CDCl3) δ1.0-1.20 (m, 2H), 1.45 (s, 9H), 1.65-1.75 (m 4H), 2.6-2.75 (m 2H), 2.9-3.0 (t, 2H), 4.03-4.08 (m, 2H), 7.1-7.19 (m, 2H), 7.95-8.04 (m, 2H).
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:24])[NH:11][N:12]=[C:13]([OH:23])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[C:20](=[O:22])[CH3:21])[CH:6]=[CH:7][CH:8]=1.[C:25]([O:28][CH2:29]Cl)(=[O:27])[CH3:26]>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:24])[NH:11][N:12]=[C:13]([O:23][CH2:29][O:28][C:25](=[O:27])[CH3:26])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[C:20](=[O:22])[CH3:21])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OCCl
Reactant: CC(=O)c1ncccc1C(O)=NNC(=O)Nc1cccc(F)c1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=NNC(=O)Nc1cccc(F)c1)c1cccnc1C(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the sodium salt of compound 4 (1.0 g, 3.0 mmol) and chloromethyl acetate (0.4 g, 3.5 mmol) in 18 ml of DMF is stirred at RT for 3 days. The reaction mixture is poured onto ice. The solid which precipitates is collected by filtration, is washed with water and is air-dried. It is stirred in 50 ml of chloroform for 2 hours and is filtered. The filtrate is evaporated to give glass-like material, which is triturated with ether to give the crude product. Purification by prep. TLC gives acetyloxymethyl 2-acetylnicotinate 4-(3-fluorophenyl)semicarbazone, m.p. 159°-160° (compound 54, Table C).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F)C1CC1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F)C1CC1

Procedure:
The title compound was prepared from [2-amino-5-(cyclopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J15) (259 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (393 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18]N=CC=2)[CH:13]=1)=[O:7].O=[C:27]1[C:32](C(O)=O)=CC(C2C=CC=CN=2)=N[NH:28]1.C(Cl)(=O)C(Cl)=O.ClC1C=C(Cl)C=CC=1CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:32]=[CH:27][N:28]=2)[CH:13]=1)=[O:7]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: O=C(O)c1cc(-c2ccccn2)n[nH]c1=O
Agent: NCc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccccn2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-2-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 1 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.21 cm3 of 2,4-dichlorobenzylamine and 0.22 cm3 of triethylamine, 0.22 g of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at a temperature above 260° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)(O)[C:4]([F:7])([F:6])[Cl:5].S(Cl)([Cl:22])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]([Cl:22])([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)[C:4]([F:7])([F:6])[Cl:5]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(O)(C(F)(F)F)C(F)(F)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccc(C(Cl)(C(F)(F)F)C(F)(F)Cl)cc1

Procedure:
A mixture of 1,1,1,3,3-pentafluoro-2-(4-ethoxyphenyl)-3-chloropropan-2-ol (28 g), thionyl chloride (45 cm3) and pyridine (3 cm3) was heated at the reflux temperature for 4 hours, diluted with toluene and the volatile components removed by evaporation under reduced pressure. The residual oil was dissolved in chloroform, washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure yielded 1,1,1,3,3-pentafluoro-2,3-dichloro-2-(4-ethoxyphenyl)propane (29.5 g) as a residual oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19](Cl)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCC1CCNCC1

Procedure:
A solution of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate (10.5 g) in ethanol (20 ml) is catalytically hydrogenated over 10% Palladium-carbon (5 g, 50% wet) as a catalyst at ordinary temperature under atmospheric pressure. After the absorption of hydrogen ceases, the catalyst is removed by filtration and the filtrate is concentrated in vacuo to yield ethyl 4-(4-piperidyl)butyrate, which is dissolved in a mixture of ethyl acetate (200 ml) and water (100 ml). To the solution is added sodium bicarbonate (6 g), and the resulting mixture is stirred at room temperature. Benzyloxycarbonyl chloride (6 ml) is added dropwise to the stirred mixture, and the stirring is continued for 1.5 hours at room temperature. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography using hexane:ethyl acetate (3:1) as an eluent to yield ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)butyrate (5.3 g) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:23]([O:22][C:20]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@]1(C)CN(Cc2ccccc2)C[C@H]1C
Product: COC(=O)[C@@]1(C)CN(C(=O)OCc2ccccc2)C[C@H]1C

Procedure:
The procedure of Reference Example 2 was repeated by using the thus synthesized methyl(3R*,4S*)-1-benzyl-3,4-dimethylpyrrolidine-3-carboxylate crude product (12.28 g) and benzyl chloroformate (21.3 mL, 149.3 mmol) to obtain 4.23 g (14.52 mmol, 2 steps, 15%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[O:15]=[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1COCC1>[F:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[C:16]1([OH:15])[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: Fc1ccc(F)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1(O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-bromo-1,4-difluorobenzene (5.15 g, 25.9 mmol) in dry THF (77 ml, 15 v) at −78° C. was added i-PrMgCl (2M, 19.5 ml, 38.8 mmol) drop wise and stirred for 1 h at room temperature then cooled again to −78° C. and added tert-butyl 2-oxopiperidine-1-carboxylate (dissolved in dry THF) (6.0 g, 31.0 mmol) drop wise and reaction mixture was stirred for 2 h at room temperature. After completion of reaction, quenched with sat.NH4Cl solution and diluted with ethyl acetate. Organic layer was separated and water layer was extracted with ethyl acetate. Combined organic layer were washed with water, brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude Int-17 (9.4 g) which was directly used for the next step.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[CH2:22]([CH:24]1[CH2:32][C:27]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:26][CH:25]1[C:33](O)=[O:34])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:22]([CH:24]1[CH2:32][C:27]2([O:28][CH2:29][CH2:30][O:31]2)[CH2:26][CH:25]1[C:33]([NH:2][NH:1][C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[C:6]2=[N:7][CH:8]=1)=[O:34])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CCC1CC2(CC1C(=O)O)OCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCC1CC2(CC1C(=O)NNc1cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A 50 mL round bottom flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.350 g, 1.16 mmol, Example #1, Step D), 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid (0.250 g, 1.25 mmol), and DCM (6.0 mL). To the reaction mixture was added HATU (0.483 g, 1.27 mmol) and TEA (0.64 mL, 4.6 mmol) and the resulting yellow suspension was stirred at rt for about 3 h. To the reaction solution was added DCM (25 mL) and the solution was washed with water and brine (20 mL each). The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a brown oil. The crude product was purified by silica gel chromatography eluting with a gradient of: 0-10% MeOH in DCM. The product containing fractions were concd under reduced pressure to give 8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide as a foam (0.50 g, 89%): LC/MS (Table 1, Method c) Rt=1.49 min; MS m/z: 486 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](OC)[CH:16]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[C:24]1([Mg]Cl)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C[O:35][CH2:34]C1>>[CH2:1]([O:3][C:4]([C:5]1[C:6]([OH:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:24]2[C:29]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:28][CH:27]=[C:26]([O:35][CH3:34])[CH:25]=2)=[O:23])[CH3:2]
Reactant: Cl[Mg]c1ccccc1
Reactant: C1CCOC1
Reactant: CCOC(=O)C(Cc1cccc(OC)c1)C(=O)c1ccccc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
The compound (300 mg, 0.97 mmol) obtained in Step 1 was dissolved in THF and 1.5 equivalents of phenylmagnesium chloride were added thereto, followed by stirring for 1 hr at 0° C. Then, the resulting mixture washed with saturated saline, and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 285 mg of the titled compound (yield: 76%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18]C)=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][N:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2c(F)cccc2F)cnc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of methyl 3-amino-6-(2,6-difluorophenyl)pyrazine-2-carboxylate (258 mg, 0.973 mmol) and lithium hydroxide monohydrate (200 mg, 4.8 mmol) in THF (4.0 mL) and water (2.0 mL) was heated at 60° C. in a sealed vial for 2 h. The reaction mixture was allowed to cool to ambient temperature and neutralized by the addition of 1.0 M hydrogen chloride in water (4.8 mL, 4.8 mmol) to form a precipitate. The precipitate was collected by filtration, washed with EtOAc (5 mL), and dried under vacuum to afford the sub-title compound (170 mg). The filtrate was diluted with EtOAc (15 mL) and the layers were separated. The organic layer was washed with H2O (3 mL) and the combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide additional sub-title compound. The crude product was used in the subsequent reaction without further purification (70 mg). LC/MS (ESI) calc. for C11H8F2N3O2(M+H)+: m/z=252.1. found: 251.9.
Reaction SMILES: [C:1]([N:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:19]([F:32])[CH:18]=1)[C:5]1[CH:6]=[C:7]([O:12]C(=O)C)[CH:8]=[CH:9][C:10]=1Br)(=[O:3])[CH3:2].C1(C)C(C)=CC=CC=1.C([Sn](CCCC)(CCCC)[C:46]1[S:47][C:48]2[CH:54]=[CH:53][CH:52]=[CH:51][C:49]=2[N:50]=1)CCC.C(=O)([O-])[O-].[K+].[K+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[S:47]1[C:48]2[CH:54]=[CH:53][CH:52]=[CH:51][C:49]=2[N:50]=[C:46]1[C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[CH:6][C:5]=1[N:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:19]([F:32])[CH:18]=1)[C:1](=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: CC(=O)Oc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CO
Product: CC(=O)N(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A mixture of acetic acid 3-{acetyl-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}-4-bromophenyl ester (50 mg) and dichlorobis(triphenylphosphine)palladium (II) (7 mg), xylene (1 ml) and 2-tributylstannylbenzothiazole (84 mg) was refluxed for 1.5 hours. The reaction mixture was cooled at room temperature, methanol (2 ml), water (1 ml) and potassium carbonate (50 mg) was added thereto, and the solution was vigourously stirred for 15 minutes at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, then dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (20 mg).
Reaction SMILES: [O:1]=[O+][O-].C([C:6](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:7]([C@@H:9]([NH:14][C:15](=[O:30])[O:16][C:17]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])#N.[CH3:50][C@H:51]([NH2:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl>[O:1]=[C:6]([NH:58][C@@H:51]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:50])[C:7]([C@@H:9]([NH:14][C:15](=[O:30])[O:16][C:17]1([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:8]
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCCC1)C(=O)C(=O)N[C@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
Ozone was bubbled through a solution of 393.0 mg (623.0 μmol) of 1-benzylcyclohexyl (1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate in 12 mL of dichloromethane at −78° C. for 15 min. The solution was purged with nitrogen for 5 min, then 80.3 μL (623.0 μmol) of (S)-α-methylbenzylamine was added and the solution was stirred at −78° C. for 15 min. The solution was concentrated and 5 mL of a 1 M solution of silver nitrate in tetrahydrofuran:water (4:1) was added and the mixture was stirred for 66 h at room temperature. The solution was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:4) to give 115.6 mg (39%) of 1-benzylcyclohexyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate. Rf=0.30 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.18 (d, J=8 Hz, 1H), 7.36-7.06 (m, 11H), 4.98 (p, J=8 Hz, 1H), 4.82-4.74 (m, 1H), 3.10 (s, 2H), 2.01 (d, J=12 Hz, 2H), 1.80-1.10 (m, 14H), 1.42 (d, J=7 Hz, 3H), 0.82 (t, J=7 Hz, 3H); HRMS C29H38N2O4+Na m/z 501.2729 (M+Na)Cal; 501.2711 (M+Na)Obs.