Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:47][C:48]1[N:52]=[C:51]([CH2:53][O:54][CH2:55][C@H:56]([NH:64][CH3:65])[CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:50][N:49]=1>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:12])[N:64]([CH3:65])[C@@H:56]([CH2:55][O:54][CH2:53][C:51]1[O:50][N:49]=[C:48]([CH3:47])[N:52]=1)[CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@@H](COCc1nc(C)no1)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(COC[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
(2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (701 mg, 2.68 mmol) was dissolved in dichloromethane (4 mL) and N,N-dimethylformamide (4 mL). The solution was cooled to 0° C. 1-Hydroxy-7-azabenzotriazole (365 mg, 2.68 mmol) and N-(3- dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (617 mg, 3.22 mmol) were successively added. The solution was stirred for 15 min at 0° C. A solution of 3-methyl-5-(((2R)-2-(methylamino)-3-phenylpropoxy)methyl)-1,2,4-oxadiazole (701 mg, 2.68 mmol) in dichloromethane (4 mL) was added. The reaction mixture was stirred for 16 hours, while the temperature slowly rose to room temperature. It was diluted with ethyl acetate (100 mL) and extracted with a mixture of saturated sodium chloride solution (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution and dried over magensium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g) with ethyl acetate/heptane (2:1) to give 1.23 g of N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl)-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)[CH:3]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][C:2]([S:14][C:11]3[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=3)=[CH:3][C:4]=2[C:16]2[CH:21]=[CH:20][C:19]([S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: CSc1ccc(-c2nnc(Cl)cc2-c2ccc(F)cc2)cc1
Reactant: Sc1ccccc1
Product: CSc1ccc(-c2nnc(Sc3ccccc3)cc2-c2ccc(Sc3ccccc3)cc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]pyridazine (198 mg, 0.599 mmol) and thiophenol (165 mg, 1.5 mmol) were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as a yellow oil (217 mg, 73.1%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H](C#N)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[OH-:14].[K+].Cl.C(O)CO[CH2:20][CH2:21][OH:22]>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:20]([C:21]([OH:22])=[O:14])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: [OH-]
Reactant: C=CCCC[C@H]1CC[C@H](C#N)CC1
Reactant: OCCOCCO
Agent: Cl
Agent: [K+]
Product: C=CCCC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 180 °C
Reaction time: 3.5 h

Procedure:
A solution of 2.9 g of trans-4-(4-pentenyl)cyclohexanecarbonitrile in 80 ml of diethylene glycol was treated with 8.0 g of potassium hydroxide and the mixture was stirred for 3.5 hours at a bath temperature of 180° C. Subsequently, the reaction mixture was treated with ice, made acid with 25 ml of 25 percent hydrochloric acid and partitioned in methylene chloride/water. The aqueous phase was extracted three times with methylene chloride. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and concentrated. Chromatographic separation of the brown, oily residue (3.5 g) on silica gel with ethyl acetate/petroleum ether (vol. 10:90) gave 2.9 g (90%) of trans-4-(4-pentenyl)cyclohexanecarboxylic acid as a yellowish oil.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.Cl[O-].[Na+].[CH3:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:37])[CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH2:34][CH:35]=[CH2:36])[CH2:30][CH2:29]3)=[CH:20][C:18]=2[N:19]=1.C(N(CC)CC)C>ClCCl.CO>[CH3:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@H:26]([OH:37])[CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH2:34][CH:35]4[O:1][N:2]=[C:3]([C:4]5[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=5)[CH2:36]4)[CH2:30][CH2:29]3)=[CH:20][C:18]=2[N:19]=1
Reactant: Cc1ccc(C=NO)cc1
Reactant: C=CCN1CCN(CC(O)COc2ccc3sc(C)nc3c2)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C2=NOC(CN3CCN(C[C@@H](O)COc4ccc5sc(C)nc5c4)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.2 %

Procedure:
To a solution of (hydroxyimino)(4-methylphenyl)methane (97 mg, 0.72 mmol) in 1 ml of dichloromethane was added aqueous sodium hypochlorite solution (>4%, 1.33 ml, 0.72 mmol). The reaction mixture was stirred at room temperature for 30 minutes, after which time TLC (20:1 dichloromethane:methanol) showed conversion of oxime to chlorinated oxime (17). 1-(2-Methylbenzothiazol-5-yloxy)-3-(4-prop-2-enylpiperazinyl)propan-2-ol (50 mg, 0.144 mmol) in 0.5 ml of dichloromethane and triethylamine (0.022 ml, 0.145 mmol) were added. The reaction was stirred at room temperature overnight. Thin layer chromatography (10:1 dichloromethane:methanol) showed consumption of starting material and product formation. The solution was evaporated under reduced pressure, and the residue purified by preperative HPLC, to yield (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-{[3-(4-methylphenyl)(4,5-dihydroisoxazol-5-yl)]methyl}piperazinyl)propan-2-ol (3.6 mg, M+1=481.35)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[Cl:1][CH2:2][CH2:3][CH:4]([O:5][S:20]([CH3:19])(=[O:22])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC(CCCl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCCl)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (R) 3-chloro-1-phenyl-propan-1-ol (Aldrich) (0.250 g) in 40 ml dichloromethane was added triethylamine (0.272 g) at 0° C. followed by the dropwise addition of methanesulfonyl chloride (0.185 g). The reaction mixture was stirred at this temperature for 2 hours and then quenched by the addition of sodium bicarbonate solution. The phases were separated and the organic phase was evaporated to dryness to afford methanesulfonic acid 3-chloro-1-phenyl-propyl ester as an oil which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[S:9]1[C:13](B(O)O)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2.[NH2:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[N:25]([OH:30])[C:24]([CH3:32])([CH3:31])[CH2:23]1>>[S:9]1[C:13]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH:22]3[CH2:27][C:26]([CH3:28])([CH3:29])[N:25]([OH:30])[C:24]([CH3:32])([CH3:31])[CH2:23]3)[N:7]=2)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2
Reactant: CC1(C)CC(N)CC(C)(C)N1O
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Clc1ccnc(Cl)n1
Product: CC1(C)CC(Nc2nccc(-c3cc4ccccc4s3)n2)CC(C)(C)N1O

Procedure:
The title compound was prepared analogous to Method A, starting from 2,4-dichloro-pyrimidine, benzo[b]thiophen-2-boronic acid and 4-amino-2,2,6,6-tetramethylpiperidine-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19](SC)[N:20]([CH2:23][CH3:24])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>COCCOC.C(O)C.[Ni]>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[CH:19][N:20]([CH2:23][CH3:24])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCn1c(SC)nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Agent: [Ni]
Solvent: CCO
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCn1cnc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 40 °C
Yield: 71.3 %

Procedure:
In a mixture of DME (15 ml) and ethanol (1.5 ml) was dissolved 7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (221 mg) followed by addition of acetic acid (185 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound could be verified by TLC. The catalyst was then filtered off and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in the order mentioned, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (141 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]([CH2:18][CH2:19][F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH:25](=O)[CH3:26]>C(O)=O>[CH2:25]([N:15]1[CH2:16][CH2:17][N:12]([C:11]2[N:10]=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[CH2:18][CH2:19][F:20])=[CH:3][C:2]=2[F:1])[CH2:13][CH2:14]1)[CH3:26]
Reactant: CC=O
Reactant: O=C(O)c1cn(CCF)c2nc(N3CCNCC3)c(F)cc2c1=O
Solvent: O=CO
Product: CCN1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)CC1

Procedure:
Using 6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid as a starting material, by reaction with acetoaldehyde in the presence of formic acid in accordance with the method of Example 1 is obtained 7-(4-ethyl-1-piperazinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (compound 2) m.p. 223°-224° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C@@H:9]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].Br[CH:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([F:41])[CH:35]=2)[C:30]1=[O:42].CCOC(C)=O>CN(C=O)C>[F:8][C@@H:9]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:29]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([F:41])[CH:35]=3)[C:30]2=[O:42])[CH2:10]1
Reactant: Oc1ccc([C@H]2CCNC[C@@H]2F)cc1
Reactant: Cc1ccc(N2CCC(Br)C2=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCC(N3CC[C@H](c4ccc(O)cc4)[C@@H](F)C3)C2=O)cc1F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-((3R,4R)-3-fluoropiperidin-4-yl)phenol trifluoroacetate, from step B (120 mg, 0.39 mmol) in DMF (2.0 mL) was added K2CO3 (134 mg, 0.97 mmol) and racemic 3-bromo-1-(3-fluoro-4-methyl-phenyl)pyrrolidin-2-one (106 mg, 0.39 mmol, from step C). The mixture was heated to 60° C. and stirred for 30 min. It was then allowed to cool to rt and stirred overnight, followed by the addition of 50 mL of EtOAc, which induced precipitation of a solid. The solid was removed by filtration and discarded, and the filtrate was concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0-100% ethyl acetate/hexanes to give 110 mg of (R and S) 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one) as a mixture of two diastereomers. A portion (35 mg) of the diastereomer mixture was separated (chiral HPLC method H) into homochiral example 49 P-1 (14 mg) and P-2 (14 mg). Data for P-1 (S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 6.97 min, 98% AP; 1H NMR (500 MHz, methanol-d4) δ 7.60-7.52 (m, 1H), 7.32-7.22 (m, 2H), 7.12 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 4.72-4.65 (m, 1H), 4.63-4.55 (m, 1H), 3.84 (d, J=9.2 Hz, 4H), 3.51-3.44 (m, 1H), 2.87-2.80 (m, 1H), 2.76-2.68 (m, 1H), 2.64-2.54 (m, 1H), 2.53-2.46 (m, 1H), 2.37-2.30 (m, 1H), 2.26 (d, J=1.4 Hz, 3H), 2.24-2.18 (m, 1H), 1.84 (br s, 3H). Data for P-2 (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one: Chiral HPLC (method H-2) RT 8.84 min, 99.3% AP; 1H NMR (500 MHz, methanol-d4) δ 7.56 (dd, J=12.0, 1.9 Hz, 1H), 7.32-7.23 (m, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.80-6.73 (m, 2H), 4.70-4.63 (m, 1H), 4.60-4.54 (m, 1H), 3.88-3.77 (m, 5H), 3.23-3.17 (m, 2H), 3.07 (d, J=10.7 Hz, 2H), 2.75-2.68 (m, 2H), 2.64-2.48 (m, 4H), 2.33 (dd, J=6.6, 2.4 Hz, 2H), 2.26 (d, J=1.5 Hz, 5H), 2.21 (dd, J=12.7, 9.6 Hz, 2H), 1.90-1.83 (m, 4H).
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[OH-].[Na+].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O.C(OCC)C>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:17]=[CH:18][C:7]([N:2]3[CH:6]=[CH:5][N:4]=[CH:3]3)=[CH:8][CH:9]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(NCCCCOc1ccc(-n2ccnc2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.8 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butylamine hydrochloride (Example 2) in 50 ml of water is treated successively with 4 ml of 10N NaOH and 2.0 g of 4-chlorobenzoyl chloride in 100 ml of diethyl ether. Stirring at room temperature for 3 hours gives a precipitate which is collected, washed with diethylether and water, and air dried. Recrystallization from 33% aqueous ethanol gives the desired product, m.p. 138°-139° C.; yield, 1.3 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].C(O)(=O)C.BrBr.[CH2:15]([O:17][P:18]([O:22]CC)[O:19][CH2:20][CH3:21])[CH3:16]>C(OCC)C>[CH2:15]([O:17][P:18]([CH:8]1[C:6](=[O:7])[NH:5][C:3](=[O:4])[N:2]1[CH3:1])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: CN1CC(=O)NC1=O
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methylhydantoin (20.25 g, 180 mmole) and acetic acid (100 ml) is heated to 90° C. Bromine (10 ml, 195 mmole) is introduced dropwise at such a rate that instant decolorization occurred. After the addition is completed, the reaction mixture is stirred at 90° C. for 60 minute and at room temperature overnight. The acetic acid is decanted from white precipitate and removed in vacuo. The residue is combined with the precipitate and suspended in diethylether (200 ml). Triethylphosphite (32 ml, 180 mmole) is added portionwise with stirring and cooling. A solution resulted which on continued stirring, yield trace of white precipitate. The mixture is diluted with diethyl ether and allowed to stand overnight. Decanted the solvent, and pumped in vacuum oven to give white crystal ylide, (3-Methyl-2,5-dioxo-imidazolidin-4-yl)-phosphonic acid diethyl ester: 16.57 g (36.8%) MS (ES+): (M+H)=251.0
Reaction SMILES: [C:1]([C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([O:7]C)=[O:6])#[N:2].[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>CCOCC>[CH3:1][N+:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH3:14].[C:1]([C:3]([F:11])([F:12])[C:4]([F:9])([F:10])[C:5]([O-:7])=[O:6])#[N:2]
Reactant: COC(=O)C(F)(F)C(F)(F)C#N
Reactant: CCN(CC)CC
Solvent: CCOCC
Product: CC[N+](C)(CC)CC
Product: N#CC(F)(F)C(F)(F)C(=O)[O-]
Reaction time: 96 h

Procedure:
A homogeneous solution of 9.3 g (0.05 mole) of methyl 3-cyanotetrafluoropropionate prepared as in Example 3, and 5.1 g (0.05 mole) of triethylamine in 25 ml of ether was stirred at 25°. After 4 days, a second layer had slowly formed; no increase was observed during an additional 2 days. Removal of volatiles under full pump at 25° gave a deliquescent yellow solid, methyltriethylammonium-3-cyanotetrafluoropropionate, mp 52°-55°. IR (CDCl3): 2965 (sat'd CH), 2255 (CN), 1690 (CO2), and 1250-1100 cm-1 (CF). NMR (CDCl3): 1H 3.47 (q, JHH 7.1 Hz, 6H, CH2 --N, 3.08 (s, 3H, CH3 --N), and 1.37 ppm (t, JHH 7.1 Hz, of m, 9H, CH3); 19F -108.5 (t, JFF 8.4 Hz, 2 F, CF2CN) and -119.3 ppm (t, JFF 8.4 Hz, 2F, CF2C=O with only 3% of impurities present.
Reaction SMILES: N[C@H](C1[N:5](C2C=CC=CC=2)[C:6](=O)[C:7]2[C:12]([CH:13]=1)=CC=C[C:8]=2[Cl:14])C.COC1C=C(B(O)O)C=CN=1.[NH2:33][C:34]1[N:39]=[C:38]([Cl:40])[CH:37]=[C:36]([CH3:41])[N:35]=1.C1C(=O)N([I:49])C(=O)C1>C(#N)C.CO>[NH2:39][C:34]1[N:35]=[C:8]([Cl:14])[C:7]([C:6]#[N:5])=[C:12]([CH3:13])[N:33]=1.[Cl:40][C:38]1[C:37]([I:49])=[C:36]([CH3:41])[N:35]=[C:34]([NH2:33])[N:39]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: COc1cc(B(O)O)ccn1
Solvent: CO
Solvent: CC#N
Product: Cc1nc(N)nc(Cl)c1C#N
Product: Cc1nc(N)nc(Cl)c1I
Temperature: 60 °C

Procedure:
Compound 362 was prepared from compound 1 and 2-methoxypyridin-4-ylboronic acid in analogous fashion to Example 2. Compound 363 was prepared as follows: 2-amino-4-chloro-6-methylpyrimidine (5.00 g, 34.8 mmol) was suspended in ACN (50 mL) and MeOH (70 mL). The mixture was charged with NIS (11.75 g, 52.2 mmol) at room temperature and the mixture was heated to 60° C. for 5 h. The mixture was cooled to room temperature and 80% of the volatiles were removed. The suspension was diluted with Et2O (100 mL) and the solids were filtered to obtain 10 g of 4-chloro-5-iodo-6-methylpyrimidin-2-amine. A solution of iodide (500 mg, 1.855 mmol) in DMF (40 mL) was charged with CuCN (332 mg, 3.71 mmol), Pd(PPh3)4 (1072 mg, 0.928 mmol) and CuI (247 mg, 1.299 mmol). The mixture was degassed for 10 min, then heated to 80° C. for 90 min. The mixture was cooled to room temperature and the material was partitioned between water and EA, then filtered on celite. The organic layer of the filtrate was washed several times with brine, dried and concentrated. The filtrate was pre-adsorbed on SiO2 and purified on ISCO 40 g (EA/hex) to give 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile 363. Compound 363 was coupled to compound 362 according to Method G to afford compound 364. ESI-MS m/z: 504.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:15][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.CC1C(N)=CON=1.[CH:32]1C=C[C:35]2[N:40]([OH:41])N=[N:38][C:36]=2[CH:37]=1.C(Cl)CCl>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:15][C:11]=2[C:12]([NH:38][C:36]2[CH:35]=[N:40][O:41][C:37]=2[CH3:32])=[O:13])=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)O)c2)cn1
Agent: Cc1nocc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oncc1NC(=O)c1cc(-c2cnn(C)c2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)benzoic acid (may be prepared as described in Description 121; 80 mg, 0.25 mmol), 3-methylisoxazol-4-amine (49.5 mg, 0.37 mmol), HOBT (56.3 mg, 0.37 mmol) and EDC (70.5 mg, 0.37 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 16 hours. Water (50 ml) was added. A white precipitate was filtered, washed with ethyl acetate, and dried in vacuo to yield the title compound as a white solid. 54 mg,