Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[C:27]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccccc2-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a 20 mL pressure resistant vial which contained a suspension of (R)-2-[4-(4-iodo-benzyl)phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol), thiophene-2-boronic acid (52 mg, 0.4 mmol), palladium(II) acetate (10 mg, 0.05 mmol) and triphenyl phosphine (30 mg, 0.1 mmol) in DME (5 mL) was added potassium carbonate (100 mg, 0.7 mmol), ethanol (0.05 mL) and water (0.05 mL) at rt. The tube was sealed and the mixture was allowed to warm to rt and stir at rt for 30 min and then was heated to 98° C. and stirred at 98° C. for 16 h. After cooling to rt, the mixture was poured onto 200 mL ice-water solution and then extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL) and brine (20 mL) and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product, which was purified by silica gel flash chromatography to afford desired product (68 mg, 75% yield); LCMS; 100%, APCI+, Calcd: 449.6; Found m/z: 449.6, M); 1H NMR (400 MHz, CDCl3); δ 1.46 (s, 9H), 1.79-2.08 (m, 4H), 3.27-3.44 (m, 2H), 3.70-3.95 (m, 1H), 3.92 (s, 2H), 4.03-4.18 (m, 2H), 6.91 (d, J=8.0 Hz, 2H), 7.09-7.11 (m, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.39-7.42 (m, 2H), 7.58 (d, J=8.4 Hz, 2H):
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[C:4]([C:5](O)=[O:6])[CH:3]=1.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[C:4]([C:5]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:6])[CH:3]=1
Reactant: COc1ccc2nc(C(=O)O)cc(Cl)c2c1
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: COc1ccc2nc(C(=O)Nc3nnn[nH]3)cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N'-Carbonyldiimidazole (13.3 g) and 4-chloro-6-methoxyquinaldic acid (19.5 g) in dimethylformamide (100 ml) was stirred at room temperature for 2 hours. 5 -Aminotetrazole was added and the mixture was stirred for 16 hours at room temperature. The solution was concentrated to 50 ml. and cooled. The solid was collected and dissolved in a warm mixture of dimethylformamide (50 ml) and dimethylaminoethanol (10 ml). The solid which crystallised was dissolved in water and the solution was acidified to pH 1 with dilute hydrochloric acid. The solid which separated was collected, washed with water and dried, m.p. 300° (d).
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[CH3:4].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([CH:3]([N:2]([CH3:1])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:4])=[CH:6][CH:7]=1)#[N:10]
Reactant: CNC(C)c1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(c1ccc(C#N)cc1)N(C)CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared following the general procedure 11 starting from 4-[1-(methylamino)ethyl]benzonitrile and tert-butyl bromoacetate. It was isolated as a colorless oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.79 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 3.89 (q, J=6.7 Hz, 1H), 3.27 (d, J=16.7 Hz, 1H), 3.07 (d, J=16.7 Hz, 1H), 2.21 (s, 3H), 1.41 (s, 9H), 1.26 (d, J=6.8 Hz, 3H). HPLC (Method A) Rt 2.83 min (Purity: 96.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH2:38][C:39]1([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:38][C:39]3([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NC1(CO)CCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3(CO)CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (1-amino-cyclopentyl)-methanol according to conditions described in general procedure C. Mp: 115-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.50 (m, 8H), 3.00-3.34 (m, 2H), 3.27 (m, 4H), 3.77 (m, 4H), 6.30 (d, J=5.5 Hz, 1 H), 6.65 (s, 1 H), 7.05 (d, J=12.1 Hz, 1 H), 7.27 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.56-7.61 (m, 3H), 7.82 (d, J=6.6 Hz, 1 H), 8.00 (d, J=8.4 Hz, 1 H), 8.20 (d, J=5.5 Hz, 1 H), 10.46 (s, 1 H).
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([OH:23])=O)[N:19]=1)=[O:13].Cl.[NH2:28][CH:29]1[C:49](=[O:50])[N:31]2[C:32]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])=[CH:33][CH2:34][S:35][C@H:30]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([NH:28][CH:29]2[C:49](=[O:50])[N:31]3[C:32]([C:36]([O:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)=[O:37])=[CH:33][CH2:34][S:35][C@H:30]23)=[O:23])[N:19]=1)=[O:13]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 49.4 %

Procedure:
Vilsmeier reagent prepared from dimethylformamide (0.43 g.) and phosphorus oxychloride (0.92 g.) was suspended in dry ethyl acetate (10 ml.). To the suspension was added 2-(2-formamido-4-thiazolyl)-2-methoxyimino acetic acid (syn isomer, 1.15 g.) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 30 minutes to prepare the activated acid solution. On the other hand, p-nitrobenzyl 7-amino-3-cephem-4-carboxylate hydrochloride (1.79 g.) and trimethylsilylacetamide (5.0 g.) were dissolved in ethyl acetate (40 ml.). To the solution was added the activated acid solution at -20° C. all at once, and the mixture was stirred at the same temperature for 2.5 hours. Water (60 ml.) and ethyl acetate (200 ml.) were added to the resultant solution, and the ethyl acetate layer was separated, washed with 10% hydrochloric acid (60 ml.), a saturated aqueous solution of sodium bicarbonate (60 ml.) and an aqueous solution of sodium chloride (50 ml.) in turn, dried over magnesium sulfate, treated with activated charcoal, and then evaporated under reduced pressure. Diethyl ether was added to the residue, and the precipitates were collected by filtration to give p-nitrobenzyl 7-{2-(2-formamido-4-thiazolyl)-2-methoxyimino-acetamido}-3-cephem-4-carboxylate (syn isomer, 1.30 g.), m.p. 210° to 212° C. (dec.).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[O:26])[CH:19]=1>>[F:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]([NH:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:19]=3)=[O:26])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Nc1ccc(Oc2cc(F)ncn2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1ccc(Oc2cc(F)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(6-fluoro-pyrimidin-4-yloxy)-phenylamine (Example 111) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a white solid: ESMS: 392.9 [M+H]+; single peak at tR=8.90 min (System 2); Rf=0.14 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.[C:23](Cl)(=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[C:14]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:22]
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-(3-chlorobenzoyl)-5-nitroindole (step 2) and isovaleryl chloride. m.p.: 197-199° C. 1H-NMR (CDCl3) δ: 9.91 (1H, br s), 9.37 (1H, d, J=2.2 Hz), 8.73 (1H, br.s), 8.24 (1H, dd, J=2.2, 9.2 Hz), 7.51-7.80 (4H, m), 7.38 (1H, d, J=9.2 Hz),2.37 (2H, br.s), 2.24-2.29 (1H, m), 1.07 (3H, s), 1.05 (3H, s)
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:26][CH2:25][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[CH:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(Nc2ccccc2)nc1
Product: O=C(NCCCc1ccccc1)c1ccc(Nc2ccccc2)nc1

Procedure:
The title compound was prepared in analogy to example 1, but starting from 6-phenylamino-nicotinic acid and using 3-phenyl-propylamine in the third step.
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[CH2:2][C:3]#[C:4][CH2:5][CH3:6].N1C2C(=CC=CC=2)C=CC=1>[Pd]>[CH2:1]([C@@H:7]1[CH2:11][O:10][C:9]([CH3:12])([CH3:13])[O:8]1)[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]
Reactant: CCC#CCC[C@@H]1COC(C)(C)O1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Product: CC/C=C\CC[C@@H]1COC(C)(C)O1
Reaction time: 2 h

Procedure:
To a solution of (R)-4-(hex-3-ynyl)-2,2-dimethyl-1,3-dioxolane (6.49 g, 35.6 mmol) in hexanes (100 mL) was added 5% palladium on BaSO4 (1.14 g), and quinoline (freshly distilled from Zn dust, 0.631 ml, 5.34 mmol). The flask was then purged with H2 and stirred under an H2 atmosphere for 2 h. The reaction mixture was filtered through celite and washed sequentially with 1N HCl (2×) and brine. The organics were dried over MgSO4, filtered, and concentrated to give (R,Z)-4-(hex-3-enyl)-2,2-dimethyl-1,3-dioxolane which was used without further purification. This material contained approximately 7% of the trans olefin isomer which was carried through the synthetic route as a mixture (data not shown for minor isomer) eventually producing the corresponding exo-ethyl pyrazole acid derivative after separation by reverse phase HPLC (vide infra). 1H NMR (400 MHz, CDCl3): δ 5.40 (1H, m), 5.31 (1H, m), 4.06 (2H, m), 3.52 (1H, t, J=4.8 Hz), 2.09 (4H, m), 1.71 (1H, m), 1.54 (1H, m), 1.41 (3H, s), 1.35 (3H, s), 0.96 (3H, t, J=Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([O:24][CH3:25])=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)O)c(N)c1
Product: COc1ccc2c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)[nH]c2c1
Yield: 57.3 %

Procedure:
313 mg (1.44 mmol) of 4-chlorobenzenesulfonylisocyanate and 200 mg (1.20 mmol) of 2-amino-4-methoxybenzoic acid were treated in the same way as in Example 1 to obtain 252 mg of the above-identified compound (yield 62.8%). Properties: colorless crystal, Melting point: 205°-206° C., PMR (δppm, DMSO-d6):3.79 (3H,s), 7.08 (1H,d), 7.28-7.30 (2H,m), 7.75 (2H,d), 8.16 (2H,d), 11.42 (1H,br).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][CH:31]([CH3:33])[CH3:32])[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCC(C)C
Temperature: 80 °C
Yield: 42.5 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (104 mg, 0.75 mmol) and isobutyl bromide (102 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (40 mg, 43%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH3:24])[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:24][N:12]([CH2:11][C:10]1[CH:25]=[CH:26][CH:27]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[N:7][CH:6]=2)[CH:9]=1)[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCC(N4CCOCC4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.9 %

Procedure:
tert-butyl (2-{[3-(2-Chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (250 mg) was dissolved in DMF (5 ml), and 4-piperidin-4-ylmorpholine (218 mg) and K2CO3 (265 mg) were added thereto, followed by stirring at room temperature for 3 days. To the reaction mixture was added water, followed by extraction with EtOAc, and then the organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl3) to obtain tert-butyl [2-(methyl{3-[2-(4-morpholin-4-ylpiperidin-1-yl)pyrimidin-5-yl]benzyl}amino)-2-oxoethyl]carbamate (285 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[N:28]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[N:54]1([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:61][CH2:60][CH2:59][C@H:55]1[C:56](O)=[O:57].C(=O)([O-])O.[Na+]>C(#N)C.O.C(N(CC)CC)C>[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:62]([N:54]1[CH2:61][CH2:60][CH2:59][C@H:55]1[C:56]([NH2:28])=[O:57])([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(N)=O

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile hydrochloride (998 mg, 2.65 mmols), 1,300 mg of a BOP reagent and 605 mg of Boc-L-Pro were dissolved in 50 ml of acetonitrile, and 0.8 ml of triethylamine were added thereto. The mixture was reacted at room temperature for 18 hours and at 50° C. for 20 hours. One-hundred milliliters of water and a small amount of sodium hydrogencarbonate were added thereto, and the resulting mixture was extracted with ethyl acetate. Subsequently, the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified using a silica-gel column (eluent, dichloromethane), and then concentrated to produce 1,310 mg (2.44 mmols) of the final product in a yield of 92%.
Reaction SMILES: Cl.C(C1(NC(C(N[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])CC(C)(C)C)=O)CCNCC1)#N.N1(C(Cl)=O)CC[O:31]CC1.CN1CCOCC1>C(Cl)Cl>[N:22]1([C:20]([OH:21])=[O:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(O)N1CCOCC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and 4-morpholine carbonyl chloride in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])=[CH:11][C:10]=1[O:23][CH2:24][C:25]1([CH3:32])[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[O:26]1)C1C=CC=CC=1>[Pd].C(O)C>[OH:31][CH2:30][CH:27]1[O:26][C:25]([CH2:24][O:23][C:10]2[CH:11]=[C:12]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH:13]=[CH:14][C:9]=2[OH:8])([CH3:32])[CH2:29][CH2:28]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCc2ccccc2)c(OCC2(C)CCC(CO)O2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(OCC2(C)CCC(CO)O2)c1
Reaction time: 3 h
Yield: 116 %

Procedure:
A mixture of 4 g (9.1 mmole) of 1-benzyloxy-2-(5-hydroxymethyl-2-methyl-2-tetrahydrofuranylmethoxy)-4-t-octylbenzene, 1 g of 10% palladium-on-carbon and 75 ml of ethanol was shaken under an atmosphere of hydrogen at ca. 4 kg/cm2 for 3 hours. The resulting mixture was filtered, and the filtrate was evaporated in vacuo to give 3.7 g of the title compound as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12]Br.[CH3:14][Si:15]([CH3:31])([CH3:30])[CH2:16][CH2:17][O:18][CH2:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH2:22][C:21]1=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[N+:9]([C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][C:22]1([C:23]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:20]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:30])([CH3:14])[CH3:31])[C:21]1=[O:29])[CH2:12]2)([O-:11])=[O:10]
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene from Step E (40.9 g, 132 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one from Step C (31.5 g, 119 mmol) in DMF (2 L) was added cesium carbonate (129 g, 397 mmol) portion wise, over 5 min. After 18 h, acetic acid (7.6 mL) was added and the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and H2O (1 L). The organic layer was washed with H2O (1 L), then brine (500 mL), then dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=412 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH2:19]O)[C:3]=1[C:21]#[N:22].C(N(S(F)(F)[F:29])CC)C>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH2:19][F:29])[C:3]=1[C:21]#[N:22]
Reactant: N#Cc1c(CO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(CF)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-hydroxymethylpyrazole (1.25 g) in dichloromethane (10 ml) was added slowly to a stirred solution of diethylaminosulphur trifluoride (0.66 g) in dichloromethane (6 ml) cooled to -78° C. After 30 minutes at this temperature the solution was warmed to room temperature and stirred for 2 hours. The mixture was then poured onto water (20 ml) and the dichloromethane layer was separated, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The product was purified by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm-2) eluting with a mixture of dichloromethane and ethyl acetate (98:2), and subsequent recrystallization from dichloromethane-petroleum ether to give 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-fluoromethylpyrazole as a white solid m.p. 139°-141° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(O)(C(F)(F)F)=O>>[C:17]1([C:11]2([CH2:10][O:9][CH2:8][C:6]3[CH:7]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=4)[CH:3]=[N:4][CH:5]=3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1cncc(COCC2(c3ccccc3)CCNCC2)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cncc(COCC3(c4ccccc4)CCNCC3)c2)cc1
Yield: 62.8 %

Procedure:
This compound was prepared according to the experimental condition of Example 1 method A from 3-bromo-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)pyridine (75 mg, 0.16 mmoL), and 4-cyanobenzene boronic acid (90 mg, 0.64 mmol) to afford 50.0 mg (64%) of the desired compound as its TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 8.99 (s, 1H), 8.52 (s, 1H), 8.25 (s, 1H), 7.92 (d, 2H, J=7.2 Hz), 7.83 (d, 2H, J=7.2 Hz), 7.21-7.46 (m, 5H), 4.64 (s, 2H), 3.58 (s, 2H), 3.32-3.60 (m, 2H), 2.89-2.96 (m, 2H), 2.51-2.56 (m, 2H), 2.21-2.22 (m, 2H). Mass spec.: 384.14 (MH)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[N:16]1([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:19]2[CH2:18][CH2:17][N:16]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:21][CH2:20]2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(N1CCCC1)N1CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCN(C(=O)N3CCCC3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and piperazin-1-yl-pyrrolidin-1-yl-methanone (11.0 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.7 mg). Calcd for C20H24N4O3: 368.1848, found 368.1847.