Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][CH:50]=[C:51]([F:52])[C:46]=4[NH:45][C:44]3=[O:53])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:38][CH2:39][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][CH:50]=[C:51]([F:52])[C:46]=4[N:45]([S:59]([CH3:58])(=[O:61])=[O:60])[C:44]3=[O:53])[CH2:41][CH2:42]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4c(F)cccc43)CC2)CC1
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4c(F)cccc43)CC2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4yl)-piperidin-4-yl]-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 6 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26]C)=[O:25])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(Oc2cccc([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
A mixture of 3-nitrophenol (3.65 g, 26.2 mmol), potassium tert-butoxide (3.23 g, 28.8 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 min. After stirring, methyl 4-chloropyridine-2-carboxylate (3.00 g, 17.5 mmol) and potassium carbonate (10.9 g, 78.6 mmol) were added, and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (20 mL) and 8N aqueous sodium hydroxide solution (3 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (345 mg, 8.0%) as a white solid. A mixture of 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (339 mg, 1.24 mmol) thus-obtained, diphenylphosphoryl azide (333 μL, 1.55 mmol), triethylamine (215 μL, 1.55 mmol), N,N-dimethylformamide (5 mL) and water (5 mL) was stirred at 100° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (253 mg, 8.8%) as a white solid.
Reaction SMILES: C(O[C:4](=[O:36])[C@:5]([O:11][CH2:12][C@@:13]([C:28]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=1[F:35])([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:37]>CO>[Br:34][C:32]1[CH:31]=[CH:30][C:29]([F:35])=[C:28]([C@:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:8])([F:7])[F:9])[C:4]([NH2:37])=[O:36])[CH:33]=1
Reactant: CCOC(=O)[C@@](C)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Reactant: N
Solvent: CO
Product: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F

Procedure:
A solution of (R)-2-[(R)-2-(5-bromo-2-fluoro-phenyl)-2-(2-nitro-benzenesulfonylamino)-pro-poxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (26.6 g, 44.2 mmol) in 7N NH3 in MeOH (75 ml) was stirred for 16 h at 50° C. The solvent was removed under reduced pressure and the residual solid re-crystallized from Et2O to give the title compound as yellow crystals: TLC (hexane-EtOAc 1:1): Rf=0.35; UPLC RtH5=1.184 min; ESIMS: 589, 591 [(M+NH4)+]; 1H NMR (360 MHz, CDCl3): δ 7.85 (d, 1H), 7.64 (m, 3H), 7.44 (d, 1H), 7.41 (dd, 1H), 7.26 (m, 1H), 6.68 (br s, 1H), 6.57 (dd, 1H), 6.19 (s, 1H), 5.54 (br s, 1H), 4.24 (d, 1H), 3.93 (d, 1H), 1.79 (s, 3H), 1.67 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O>CS(C)=O>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:3]=[C:4]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: CSc1ncnc2c(N3CCCC3)nc(Cl)nc12
Solvent: O
Solvent: CS(C)=O
Product: CSc1ncnc2c(N3CCCC3)nc(N3CCNCC3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.8 g (0.01 mol) of 2-chloro-8-methylthio-4-pyrrolidino-pyrimido[5,4-d]pyrimidine is dissolved warm in 300 ml of dimethylsulphoxide and then a solution of 4.3 g (0.05 mol) of piperazine is added. After being stirred for 1 hour at ambient temperature the solution is poured into 1.5 liters of water. The precipitate obtained is suction filtered, washed with water and dried.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([NH2:14])=[C:9]([F:15])[CH:8]=1.[CH:16]([NH:19][C:20](=O)[CH3:21])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([NH:14][C:20](=[N:19][CH:16]([CH3:18])[CH3:17])[CH3:21])=[C:9]([F:15])[CH:8]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CC(=O)NC(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=NC(C)C)Nc1c(F)cc(Br)cc1F
Temperature: 15 °C
Yield: 84.7 %

Procedure:
Add phosphoryl chloride (16.0 kg) to a mixture of 4-bromo-2,6-difluoro-phenylamine (14.5 kg), N-isopropyl acetamide (8.5 kg), TEA (10.6 kg) in toluene (115 kg) at <20° C. Stir at 10-20° C. until complete by HPLC. Remove the solvent under vacuum and add MtBE (64 kg). Adjust the pH of the mixture with 10% aq. sodium carbonate (250 kg). Filter the mixture and rinse the cake with MtBE (11×2 kg). Separate the phases and wash the aqueous layer with MtBE (22×2 kg). Combine the organic layers and concentrate, filter and wash with cyclohexane (0.6 kg) and dry to afford 17.2 kg of the title compound. MS (ES+): m/z=292 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[O:10]=[C:11]([CH3:18])[CH2:12][C:13](OCC)=[O:14]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[CH2:12][C:11](=[O:10])[CH3:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(C)c(N)c1
Product: CC(=O)CC(=O)Nc1cc(C)ccc1C
Temperature: 25 °C

Procedure:
A mixture of 2,5-dimethylaniline (1.00 g, 8.25 mmol) and ethyl 3-oxobutanoate (1.0 mL, 1.0 eq) was microwaved at 180° C. for 5 minutes. After the reaction mixture was cooled to room temperature, it was triturated with hexane. The resulting precipitate was filtered and dried under high vacuum to yield the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.28 (s, 3 H) 2.32 (s, 3 H) 2.34 (s, 3 H) 3.63 (s, 2 H) 6.88 (d, J=7.62 Hz, 1 H) 7.07 (d, J=7.62 Hz, 1 H) 7.75 (s, 1 H) 9.00-9.12 (m, 1 H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[C:13](O)=[C:12]([Cl:19])[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[C:13]([O:4][CH3:1])=[C:12]([Cl:19])[CH:11]=1
Reactant: CCc1cc(Br)cc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cc(Br)cc(Cl)c1OC
Reaction time: 20 h
Yield: 90.5 %

Procedure:
Potassium carbonate (3.9 g, 28 mmol) followed by methyl iodide (0.58 mL, 9.3 mmol) were added to a solution of 4-bromo-2-chloro-6-ethyl-phenol (2.2 g, 9.3 mmol) in DMF (10 mL). The mixture was stirred for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (0% to 3% EtOAc in hexanes) to give the desired product (2.1 g, 91%) 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.6 Hz, 3H), 2.66 (q, J=7.6 Hz, 2H), 3.82 (s, 3H), 7.22 (s, 1H), 7.37 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3].[CH3:16][C@H:17]1[C:25]2[C:24]([C:26]3[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([NH:15][C:31]([C:29]1[S:30][C:26]([C:24]2[C:25]3[C@H:17]([CH3:16])[CH2:18][CH2:19][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:27][CH:28]=1)=[O:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3]
Reactant: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)O)s3)c21
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N[C@H](CN=[N+]=[N-])Cc4ccc(Cl)cc4Cl)s3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
(S)-1-Azido-3-(2,4-dichlorophenyl)propan-2-amine (33 mg, 0.134 mmol) was added to a solution of (R)-5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylic acid (35 mg, 0.134 mmol) in DCM (0.7 mL). HBTU (56 mg, 0.148 mmol) was added, followed by DIPEA (0.23 mL, 1.34 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS of the reaction mixture showed no more starting material. The solvent was removed, and the resulting residue was purified on silica gel (0%-50% EtOAc/hexanes) gradient elution to yield N-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide as an oil (59 mg, 90%). m/z 486 (MH+).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([OH:18])=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:25][NH2:26]>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([NH:26][CH3:25])=[O:18])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CN
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)O)(CC1)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Carboxylic acid 10-4 (810 mg, 2.96 mmol) was dissolved in 12 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 4.4 mL, 8.8 mmol) and subsequently with 5 drops of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 mnin. The acid chloride was dissolved in anhydrous methylene chloride (12 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 8.9 mL, 17.8 mmol). Upon addition of the amine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 200 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to chromatography on silica gel eluting with a gradient from 0 to 3.5% methanol in methylene chloride to give 4-[2-(ethylsulfonyl)ethyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide 10-5 as a white powder. MS (ESI+)=288 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]1[C@H:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][S:17][C@@H:16]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:14]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([N:15]2[C@H:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][S:17][C@@H:16]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)SC[C@H]2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.8 cm3 of 3-methylphenyl isocyanate is added to a solution of 2.0 g of tert-butyl (2R,4R)-3-(2-aminoacetyl)-2-phenyl-4-thiazolidinecarboxylate in 25 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 12 hours at a temperature in the vicinity of 25° C., then diluted with 100 cm3 of ethyl acetate. The organic phase is washed with 2 times 40 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The crude product obtained is purified by chromatography on silica [eluent: methylene chloride/methanol (98/2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in heptane, 0.5 g of tert-butyl (2R,4R)-3-{2-[3-(3-methylphenyl)ureido]acetyl}-2-phenyl-4-thiazolidinecarboxylate is thus obtained in the form of a white amorphous powder ([α]D20 =+70.0°±1.3° (C=1.02%; CHCl3)) [proton NMR (200 MHz, CDCl3, δ in ppm), 2 rotamers at room temperature, description for the preponderant rotamer at 25° C.: 1.45 (bs, 9H, (CH3)3); 2.2 (s, 3H, CH3); 3.2 (A2X, 2H, CH2S); 3.2 and 4.3 (ABX, 2H, CH2N); 4.9 (t, 1H, CHN); 6.1 (bdd, 1H, NH); 6.2 (s, 1H, SCHN); 6.8 to 7,7 (m, 9H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3375, 2975, 2930, 1735, 1650, 1610, 1595, 1560, 1490, 1455, 1370, 1150, 780, 730, 695].
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[C:11]([Cl:18])[N:10]=2)[CH2:5][CH2:4]1.[Br:19][C:20]1[CH:21]=[C:22]([C:26](O)=[O:27])[NH:23][C:24]=1[CH3:25]>>[C:15]([C:13]1[CH:12]=[C:11]([Cl:18])[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([NH:2][C:26]([C:22]3[NH:23][C:24]([CH3:25])=[C:20]([Br:19])[CH:21]=3)=[O:27])[CH2:4][CH2:5]2)[CH:14]=1)(=[O:17])[CH3:16]
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Reactant: CC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: CC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)c1

Procedure:
The title compound was synthesized by an analogous method to Example 42 starting from 1-1-[2-(4-aminopiperidin-1-yl)-6-chloropyridin-4-yl]ethanone hydrochloride salt (Intermediate 197) and 4-Bromo-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 18).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[C:16]([F:17])=[C:15]2[C:10]([C:11](=O)[CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:14]2)=[CH:9][CH:8]=1>C(#N)C>[Br:3][C:11]1[C:10]2[C:15](=[C:16]([F:17])[C:7]([Cl:6])=[CH:8][CH:9]=2)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1cc(-c2ccccc2)[nH]c2c(F)c(Cl)ccc12
Solvent: CC#N
Product: Fc1c(Cl)ccc2c(Br)cc(-c3ccccc3)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Phosphorus oxybromide (19 g, 0.066 mole), 7-chloro-8-fluoro-2-phenyl-1H-quinolin-4-one (6.2 g, 0.022 mole) and acetonitrile (40 mL) were combined in a 150 mL pressure bottle with a magnetic stir bar. The flask was heated at 100° C. and stirred overnight. Heat was removed, and an ice-water bath was installed. After 10 minutes, the bottle was opened, and water (60 mL) was added to the cooled stirring reaction. The quenching was exothermic to ca. 50° C. After stirring 10 minutes, a nice, filterable solid had formed, however, the reaction was extracted with 100 mL, then 3×50 mL methylene chloride. The extracts were combined, washed with saturated sodium bicarbonate solution (100 mL), and suction filtered through a small pad of silica gel, rinsing with methylene chloride. The filtrate was concentrated in vacuo, and put under high vacuum at 45° C. for 1 h to afford the crude product, which was recrystallized from 100 mL of ethanol, suction filtered to collect, and washed with ethanol. The purified product was vacuum oven dried for 1 h at 45° C. to afford the title compound as a white solid. A second crop was taken. The mother liquor was concentrated then chromatographed on silica gel with hexanes/methylene chloride 1:1 and combined with the second crop to afford additional material; 1H NMR (CDCl3, 400 MHz) δ 7.49-7.55 (m, 4H), 7.87-7.90 (dd, 1H, J=1.7 Hz & J=8.9 Hz), 8.15-8.18 (dd, 2H, J=1.5 Hz & J=7.9 Hz), 8.21 (s, 1H); HPLC tR=4.15 min (OpenLynx, nonpolar—5 min).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([OH:44])(=[O:43])[CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]([NH:27][CH2:28][C@@H:29]2[NH:40][C:39]3[C:37](=[O:38])[NH:36][C:34]([NH2:35])=[N:33][C:32]=3[NH:31][CH2:30]2)=[CH:25][CH:24]=1)=[O:22])[C:17]([OH:19])=[O:18].C(O)=O>CN(C)C=O>[CH:1]([N:40]1[C@@H:29]([CH2:28][NH:27][C:26]2[CH:25]=[CH:24][C:23]([C:21](=[O:22])[NH:20][C@H:16]([C:17]([OH:19])=[O:18])[CH2:15][CH2:14][C:13]([OH:44])=[O:43])=[CH:42][CH:41]=2)[CH2:30][NH:31][C:32]2[N:33]=[C:34]([NH2:35])[NH:36][C:37](=[O:38])[C:39]1=2)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2c(c(=O)[nH]1)N[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Solvent: O=CO
Solvent: CN(C)C=O
Product: Nc1nc2c(c(=O)[nH]1)N(C=O)[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2

Procedure:
The method of claim 1 wherein said treating comprises adding 1,1'-carbonyl-diimidazole to a solution of (6S)-tetrahydrofolic acid and formic acid in substantially dry N,N-dimethyl-formamide, whereby N5-Formyl-(6S)-tetrahydrofolic acid is produced.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[Cl:16])[CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19].N1C=CC=CC=1>O>[Cl:16][C:10]1[CH:11]=[C:12]([NH:15][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(Oc2cccc(Cl)n2)c(Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc(Oc2cccc(Cl)n2)c(Cl)c1
Reaction time: 18 h

Procedure:
4-((6-Chloro-2-pyridinyl)oxy)-3-chlorobenzeneamine (7.1 grams; 0.028 mole) and propionyl chloride (2.6 grams; .028 mole) were contacted in the presence of 40 ml. of dry pyridine and the resulting reaction mixture allowed to stand at ambient temperatures for a period of about 18 hours. The reaction mixture was then poured into 250 ml. of cold water and allowed to stand for about 15 minutes. The resulting product precipitate was recovered by filtration and taken up in boiling benzene and the resulting solution dried, treated with Norite and filtered. Hexane was then added to the filtrate which was then cooled to precipitate the desired N-(3-chloro-4-((6-chloro-2-pyridinyl)oxy)phenyl)propionamide compound as a white crystalline solid having a melting point of 166°-168° C. The product was found to have carbon, hydrogen, nitrogen and chlorine contents of 55.0, 3.9, 9.0 and 22.5, respectively, as compared with the theoretical contents of 54.0, 3.9, 9.0 and 22.8, respectively, calculated for the named structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[C:14](=[O:15])[O:13][C:12]([CH3:17])([CH3:16])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH:19]([Mg]Br)=[CH2:20]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:9]2[C:10](=[O:18])[O:11][C:12]([CH3:16])([CH3:17])[O:13][C:14]2=[O:15])[CH:19]=[CH2:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.1 (6.0 g, 24.17 mmol) in THF, was added vinylmagnesium bromide (available from Aldrich) (207.2 mL, 145.0 mmol) via cannula at 0° C. The resulting heterogeneous mixture was warmed to room temperature, stirred for 30 minutes, and quenched with 1 N aq. HCl. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to provide 15.1 as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[N:7]=1
Reactant: Cc1coc(-c2nc(N)nc(S(C)=O)c2C#N)c1
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1coc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-(2-pyridyl)ethylmercaptan and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([OH:34])=O)=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:53]1C=CC=CC=1.C(=O)([O-])O.[NH4+]>C(#N)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([NH2:53])=[O:34])=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:36])[CH3:37])[O:11][N:10]=1
Reactant: c1ccncc1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(N)=O)cccc3c2)cc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid (97 mg, 0.180 mmol), di-tert-butyl dicarbonate (60 mg, 0.273 mmol), and pyridine (0.021 mL, 0.273 mmol) were combined into anhydrous acetonitrile (5 mL). The mixture was stirred at ambient temperature for half an hour. Ammonium hydrogen carbonate (25 mg, 0.273 mmol) was then added to the mixture and the reaction was stirred at ambient temperature for 48 hours. The solvent was then removed on a rotary evaporator and the crude residue was dissolved in ethyl acetate. The organic solution was then washed with water three times, followed by saturated sodium bicarbonate, and then brine. The crude organic extract was then dried over magnesium sulfate, filtered, and then evaporated to dryness. The residue was washed with hexanes several times to remove the residual di-tert-butyl dicarbonate, and the solids were removed via filtration to give the title compound as a white solid (94 mg, 98%) 1H NMR (CDCl3): 8.48 (d, J=9 Hz, 1H), 7.88-8.00 (m, 2H), 7.75 (d, J=9 Hz, 1H), 7.68 (d, J=9 Hz, 1H), 7.58 (d, J=9 Hz, 2H), 7.36-7.51 (m, 3H) 7.25 (d, J=9 Hz, 1 H), 6.88 (d, J=9 Hz, 2H), 6.42 (broad s, 1H), 6.13 (broad s, 1H), 4.81 (s, 2H), 3.26-3.44 (m, 1H), 1.37-1.47 (m, 6H). ESI-LCMS m/z 531 (M+H)+.