Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([C:47]([F:49])([F:50])[F:48])=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1c(F)cccc1C(F)(F)F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-(trifluoromethyl)phenyl)boronic acid gave 331. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.81-7.68 (m, 3H), 7.42 (s, 2H), 4.78-4.68 (m, 1H), 4.45-4.26 (m, 1H), 4.14-3.86 (m, 2H), 3.76 (s, 3H), 2.07-1.97 (m, 1H), 1.88-1.76 (m, 1H), 1.76-1.65 (m, 2H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]=[C:6]1[C:10]([CH2:14][C:15](O)=[O:16])([CH2:11][CH2:12][CH3:13])[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[O:7]1>C1C=CC=CC=1>[O:5]=[C:6]1[C:10]([CH2:14][C:15]([Cl:3])=[O:16])([CH2:11][CH2:12][CH3:13])[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[O:7]1
Reactant: O=S(Cl)Cl
Reactant: CCCC1(CC(=O)O)C(=O)Oc2ccccc21
Solvent: c1ccccc1
Product: CCCC1(CC(=O)Cl)C(=O)Oc2ccccc21

Procedure:
23.7 g of double-distilled thionyl chloride are added dropwise to a solution, stirred and heated to 70° C., of 23.4 g of (2,3-dihydro-2-oxo-3-propyl-3-benzofuranyl)acetic acid in 250 ml of anhydrous benzene. When the addition is complete, the mixture is heated until the evolution of gas has completely ceased. The medium is concentrated under vacuum, the residue washed with 200 ml of anhydrous benzene and the solvent evaporated off. This operation is repeated twice, and a very thick oil which does not crystallize is obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([NH2:9])=[CH:7][CH:6]=[N:5]2)[CH2:3][CH2:2]1.[I:10]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([N:4]2[C:8]([NH2:9])=[C:7]([I:10])[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccnn1C1CC1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c(I)cnn1C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
A 100-mL round-bottom flask was charged with 1-cyclopropyl-1H-pyrazol-5-amine (0.410 g, 3.33 mmol) and N,N-dimethylformamide (10 mL). N-Iodosuccinimide (0.820 g, 3.64 mmol) was added, and the resulting solution stirred for 18 h at room temperature. The reaction mixture was poured into saturated aqueous sodium bisulfite solution (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether) to afford 1-cyclopropyl-4-iodo-1H-pyrazol-5-amine (0.440 g, 48%) as light yellow oil. MS (ESI, pos. ion) m/z 250 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[C:5]([C:7]#[N:8])[N:6]=1.O.[Sn](Cl)[Cl:21]>C(O)(C)C.Cl>[ClH:21].[CH3:1][C:2]1[S:3][C:4]2[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:7]([NH2:8])[C:5]=2[N:6]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
Combine a suspension of 2-methyl-5-(2-nitroanilino)thiazole-4-nitrile (36 g, 138.5 mmol) in isopropanol (400 ml) in a 2.0 liter 3-necked RB flask equipped with a reflux condenser, thermometer, magnetic stirrer bar and heat with stirring to 65° C. (orange solution). Add tin (II) chloride hydrate (78.7 g, 415.4 mmol) in hydrochloric acid (400 ml; 5M) and heat the resulting solution at reflux. After 2.5 h., cool the reaction to 15° C., filter the suspension, wash with isopropanol/water (2:1) and dry at 50° C. under reduced pressure to leave a yellow solid (36.7 g). Evaporate the filtrate to around 200 mL to form a yellow slurry. Filter the slurry again and dry at 50° C. under reduced pressure to leave a yellow solid (10 g). Combine the solid and suspend in 1 N HCl (700 mL) and heat to reflux for 20 min, cool to 15° C. Filter the resulting yellow slurry and dry at 50° C. under reduced pressure to leave a yellow solid (32.4 g, 88%): mass spectrum (m/e): 231 (M+1); 1HNMR(300 MHz, DMSO-d6, ppm): δ 2.5(s, 3H), 6.78(dd, 1H), 6.85(dd, 1H), 6.98(t, 1H), 7.02(t, 1H), 8.80(s, 1H), 9.10(s, 1H), 9.98(s, 1H), 10.78(s, 1H). 13CNMR(75 MHz, DMSO, ppm): δ 19.6, 120.1, 120.8, 123.6, 125.8, 127.8, 129.2, 137.6, 154.4, 159.3, 160.4. Formula C11H11N4S.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[SH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1>C1C=CC=CC=1>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[S:47][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: Sc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(CSc2ccccn2)C1
Reaction time: 0.08 h

Procedure:
To a stirred solution of tert-butyl 3-(hydroxymethyl)-1-piperidinecarboxylate (Preparation 52, 1.0 g, 5 mmol) in benzene (40 ml) under nitrogen was added triphenyl phosphine (1.44 g, 5.5 mmol). Diethyl azodicarboxylate (0.86 ml, 5.5, mmol) in benzene (4 ml) was added dropwise and the reaction mixture was stirred for 5 min. 2-mercapto pyridine (0.61 g, 5.5 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture washed with sodium hydroxide (1M), water, and saturated brine. The organic extracts were dried (Na2SO4) and concentrated to an oil which was purified by flash chromatography on silica gel eluting with dichloromethane:ethyl acetate (9:1). The title compound was obtained as an oil (1.0 g, 65%).
Reaction SMILES: [CH3:1][C:2]([OH:16])([C@H:4]([CH3:15])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:3].[CH3:17][Si:18]([CH3:25])([CH3:24])N1C=CN=C1>CN(C)C=O>[CH3:17][Si:18]([CH3:25])([CH3:24])[O:16][C:2]([CH3:1])([CH3:3])[C@H:4]([CH3:15])[CH2:5][S:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: C[Si](C)(C)n1ccnc1
Reactant: C[C@H](CS(=O)(=O)c1ccccc1)C(C)(C)O
Solvent: CN(C)C=O
Product: C[C@H](CS(=O)(=O)c1ccccc1)C(C)(C)O[Si](C)(C)C
Temperature: 80 °C
Yield: 96 %

Procedure:
The compound of Example 10B (0.95 g, 3.9 mmol) was dissolved in 3 mL of dimethylformamide; 1 mL of 1-(trimethylsilyl)imidazole was added, and the resultant solution was stirred overnight at ambient temperature, then heated at 80° C. for 8 hours. The crude mixture was partitioned between ethyl acetate and water; the organic phase was washed with brine and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 0% to 20% ethyl acetate in hexanes to provide the titled compound (1.18 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:22][CH2:23][CH:24]=[CH2:25]>O1CCCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:22][CH2:23][CH:24]=[CH2:25])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reactant: C=CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1CC(Oc2ccc(F)cc2)C1
Temperature: 25 °C
Yield: 162.6 %

Procedure:
A stirred and cooled (32° C.) mixture of 5.52 g (0.022 mole) of crude 3-(4-fluorophenoxy)-1-azetidine carbonyl chloride and 3 g (0.02 mole) of potassium carbonate in 30 ml of tetrahydrofuran was treated with 1.5 g (0.02 mole) of 3-aminopropylene. The reaction mixture was still exothermic and was stirred for 5 hr as it cooled to ambient temperature. The reaction mixture was diluted with 200 ml of water to produce an oil phase separation. The oil portion was dissolved by extracting with 2×50 ml of benzene. The extracts were combined, dried over magnesium sulfate and concentrated in vacuo to yield 8.14 g of orange-red oil. The oil partially crystallized from benzene-ligroin with charcoal treatment, yielding first a reddish oil followed by a crystalline product, The total material was concentrated in vacuo to yield 7.45 g of amber-red oil. This oil solidified and was repeatedly triturated with isopropyl ether until only a red oil residue remained. The isopropyl ether portions were repeatedly cooled to the crystallization of residue, decanted from residue and heated to reduce volume until only a straw colored isopropyl ether solution remained. Upon cooling of this solution the title product crystallized and yielded 2.3 g (42.3%) of white crystalline product, m.p. 92°-94° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 88.2 %

Procedure:
A mixture of 2 g (11.59 mmol) of 2-chloro-4-methyl-5-nitropyridine, 1.41 g (11.59 mmol) of phenylboronic acid, 1.33 g (1.16 mmol) of tetrakis(triphenylphosphine)palladium and 4 g (28.97 mmol) of potassium carbonate suspended in 50 ml of degassed dioxane is refluxed for 12 hours. The mixture is then cooled, diluted with 50 ml of ethyl acetate, successively washed twice with 20 ml of water and then with 20 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluents: heptane/ethyl acetate) and then recrystallized from an isopropanol/isopropyl ether mixture. 2.19 g of a yellow solid are thus isolated, and are used without further purification in the following synthesis.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]([CH2:14][CH2:15][CH3:16])[C:12]#[N:13].Cl>CC(C)=O.[Cl-].[Na+].O>[CH:2]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]([CH2:14][CH2:15][CH3:16])[C:12]#[N:13])=[O:1]
Reactant: CCCC(C#N)c1sccc1C1OCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCC(C#N)c1sccc1C=O
Temperature: 70 °C
Yield: 94.3 %

Procedure:
2.16 g (9.10 mmol) of 2-[3-(1,3-dioxolan-2-yl)-2-thienyl]-4-methylbutyronitrile was dissolved in 40 ml of acetone, 115 ml of 5N HCl was added, and the mixture was heated at 70° C. for 3 minutes. After completion of the reaction, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated, to give a crude product. The crude product was subjected to 75 g of silica gel (ethyl acetate:hexane=1:2), to give 1.66 g (8.58 mmol, 94.3%) of the title compound as a brown oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:32])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][C:19]([CH3:31])=[CH:18][C:17]=12)=[O:12])(C)(C)C.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[NH2:7][C:8]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:32])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][C:19]([CH3:31])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ncccc3F)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3ncccc3F)cc(C)cc12
Temperature: 50 °C
Yield: 9.9 %

Procedure:
20 mg (0.039 mmol) of rac-{1-[({7-[(3-fluoropyridin-2-yl)methoxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 144A) were dissolved in 1 ml of trifluoroacetic acid. The reaction mixture was heated to 50° C. for 1 hour. Water was added, and the pH was adjusted to −9 with 2 N sodium hydroxide solution. The aqueous phase was extracted with dichloromethane, separated off and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography (Method 21), which gave 1.59 mg (10% yield) of the target compound.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH3:22])[CH:20]=[O:21])=[CH:17][CH:18]=1
Reactant: CC(CO)c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C=O)c1ccc(Cl)cc1

Procedure:
To a solution of 19.8 g (0.092 mole) of pyridinium chlorochromate in 80 mL of methylene chloride is added a solution of 7.8 g (0.046 mole) of 2-(4-chlorophenyl)propanol in 20 mL of methylene chloride. After one hour this mixture is diluted with 100 mL of diethyl ether, and the remaining solution is decanted from the insoluble material. Additional diethyl ether is added to the solids, and, after being mixed thoroughly, the solution is decanted from the solids and combined with the original solution. The combination is washed sequentially with 10 mL of a 10% aqueous solution of sodium hydroxide, 10 mL of 10% hydrochloric acid, and finally with 10 mL of water. After being dried over an hydrous magnesium sulfate, this solution is evaporated under reduced pressure, leaving a residue. This residue is passed through a column of silica gel, eluting with ethyl acetate/hexane (5:95). Product-containing fractions are combined, and the solvent is evaporated from the combined fractions under reduced pressure, leaving 2-(4-chlorophenyl)propionaldehyde as the residue.
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[S:13][C:14]([CH3:17])=[N:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[S:13][C:14]([CH3:17])=[N:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(-c3nnc(C)s3)cc12
Agent: BrB(Br)Br
Product: Cc1nnc(-c2cc3c(O)cccc3o2)s1
Yield: 96.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(4-methoxybenzo(b)furan-2-yl)-5-methyl-1,3,4-thiadiazole (0.98 g) and boron tribromide (2.3 ml), the title compound (0.89 g) was obtained as pale-yellow crystals.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:46]=[CH:45][C:33]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:46][CH:45]=3)=[CH:41][CH:40]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reactant: OB(O)c1ccc(OCc2ccc(F)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 1.5 h
Yield: 60.2 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.049 g, 0.108 mmol), (4-((4-fluorobenzyl)oxy)phenyl)boronic acid (0.040 g, 0.161 mmol) and 2M Na2CO3 (0.134 ml, 0.269 mmol) in DMF (2 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.012 g, 10.76 μmol) was added, degassed for 5 min and placed in a pre-heated oil bath at 100° C. After 1.5 h at 110° C., cooled and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0372 g, 0.065 mmol, 59.9% yield) as tan color solid. LCMS (M+H)=577.6.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:44]=[CH:43][C:34]([CH2:35][N:36]2[CH:40]=[C:39]([CH:41]=O)[CH:38]=[N:37]2)=[CH:33][CH:32]=1.O>O1CCCC1>[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][N:36]2[CH:40]=[C:39](/[CH:41]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:38]=[N:37]2)=[CH:43][CH:44]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)cn2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium hydride (60%, oily, 336 mg) was added at 0° C. to a solution of ethyl diethylphosphonoacetate (1.67 ml) in tetrahydrofuran (20 ml), which was stirred at 0° C. for 30 minutes. To this solution, a solution of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carbaldehyde (2.61 g) in tetrahydrofuran (20 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-yl]propenoate (2.78 g, yield: 90%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 112–113° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:11]O>Cl>[CH3:11][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccn1
Agent: Cl
Product: COC(=O)c1ccnc(C)c1

Procedure:
5 g 2-methyl-isonicotinic acid was stirred 24 h at 50° C. in 150 mL 1.3 mol/L HCl in methanol. The solvent was removed and water was added to the residue. The mixture was basified with saturated sodiumhydrogencarbonate solution and extracted with ethylacetate. The organic layer was dried with magnesiumsulfate and evaporated to give 4.5 g of the desired product.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][CH2:12][O:13][C:14]([CH3:16])=[O:15].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([CH2:16][C:14]([O:13][CH2:12][CH3:11])=[O:15])([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 106.8 %

Procedure:
A 1.0 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (40 mL, 40 mmol) was cooled to −70° C. under a nitrogen atmosphere. EtOAc (3.91 mL, 40 mmol) was slowly added dropwise thereto. The reaction mixture was stirred for 10 min at −70° C. stirred and a solution of 1-(tert-butyloxycarbonyl)-4-piperidone (7.34 g, 36.84 mmol, Lancaster, order number: 13361) in THF (16 mL) was slowly added dropwise thereto. After heating the reaction solution to 0° C., water (50 mL) was added and the reaction mixture repeatedly extracted with ether. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. 11.31 g of the desired product 4-ethoxycarbonylmethyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (A1) were obtained and further reacted without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:28]3[CH:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[O:30][N:29]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1cc(C(F)(F)F)on1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Agent: Cl
Product: O=C(NCc1cc(C(F)(F)F)on1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 5-trifluoromethyl-isoxazol-3-methanamine hydrochloride (example BG) as starting materials; LC-MS (UV peak area/ESI) 100%, 480.0532 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1>CN(C=O)C.C(OC(C)C)(C)C>[CH3:25][C:19](=[CH:5][C:4]1[CH:3]=[C:2]([F:1])[C:9]([F:10])=[C:8]([F:11])[CH:7]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1cc(F)c(F)c(F)c1

Procedure:
1.0 eq. of 3,4,5-trifluorobenzaldehyde is dissolved in DMF and stirred at room temperature with 1.1 eq. of ethyl 2-(triphenylphosphanylidene)propionate until complete conversion can be determined by means of thin-layer chromatography. The mixture is freed from the solvent and the residue is stirred in diisopropyl ether. The insoluble residue is filtered off, the filtrate is concentrated in vacuo and the residue is chromatographed on silica gel (EA/heptane 1:1), the title compound being obtained in the form of a colorless solid. (M.p.: 66-68° C.).