Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:26]=[CH:25][C:17]2[C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:19][O:20][C:16]=2[CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:31]O>>[CH3:31][O:23][C:22](=[O:24])[CH2:21][C:18]1[C:17]2[CH:25]=[CH:26][C:14]([NH:13][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])=[CH:15][C:16]=2[O:20][CH:19]=1
Reactant: O=C(O)Cc1coc2cc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1coc2cc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
(6-{[(2-Nitrophenyl)sulfonyl]amino}-1-benzofuran-3-yl)acetic acid (2.84 g, 7.55 mmol) was suspended in methanol (8 mL), and thionyl chloride (2 mL, 27.4 mmol) was added dropwise under ice-cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (1.82 g, yield 62%) as yellow prism crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][C:12]([CH2:19][CH2:20][CH3:21])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:17][CH2:16][CH2:15][C:14]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:11]=[C:12]([CH2:19][CH2:20][CH3:21])[CH:13]=2)[CH2:31][CH2:30]1
Reactant: CCCc1cc(CCC=O)n(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
70 mg (82.5%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propanal 54 mg, 0.188 mmol), 1-(2-fluorophenyl)piperazine (39 mL, 0.244 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=2[Cl:28])[CH:14]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=3[F:9])=[CH:23][C:22]=2[Cl:28])[CH:14]=1
Reactant: COC(=O)c1ccc(C)c(C(=O)c2ccc(N)cc2Cl)c1
Reactant: Fc1cc(Cl)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(C(=O)c2ccc(Nc3ccc(Cl)cc3F)cc2Cl)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
1-Bromo-4-chloro-2-fluorobenzene (820 μL, 6.58 mmol) was dissolved in 20 mL dry 1,4-dioxane under an argon atmosphere. Compound 402 (2.00 g, 6.58 mmol) was added and dissolved in the solvent. Dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (125 mg, 0.26 mmol), Pd(OAc)2 (30 mg, 0.13 mmol) and Cs2CO3 (2.68 g, 8.22 mmol) were added, and the reaction mixture was stirred under an argon atmosphere at 120° C. for 48 h. The reaction mixture was filtered and then purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:9 as the eluent to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[C:12]([NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=1)(=[O:14])[CH3:13]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[O:9][CH2:21][C:19]1[N:20]=[C:16]([NH:15][C:12](=[O:14])[CH3:13])[S:17][CH:18]=1
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: Cc1cc(Br)c(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(COc2cnc(C)cc2Br)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 270 mg (1.44 mmol) 4-bromo-6-methyl-pyridin-3-ol (Stage 40.4) in DMF (5 mL), 44.8 mg NaH (1.87 mmol) was added and this mixture was stirred for 1 h at rt. 301 mg (1.58 mmol) 2-acetamido-4-(chloromethyl)-1,3-thiazole (Apollo OR15549) was added and stirring was continued at rt for another 17 h. The reaction mixture was poured on water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to leave 350 mg of the title compound (white solid) considered sufficiently pure without further purification. LCMS: tR=1.36 min, M+H=342 (79Br), 344 (81Br) (method J).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31]([O:38][C:39](=[O:49])[C@H:40]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:49])[CH:40]([NH:41][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:8])=[O:9])=[O:18])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)NC(Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.3 %

Procedure:
0.602 g (2 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.939 g (2.2 mmol) of L-phenylalanine benzyl ester p-toluenesulfonic acid salt, 0.454 g (2.2 mmol) of DCC and 0.224 g (2 mmol) of DMAP were dissolved in 30 mL of CH2Cl2, 0.4 ml (2.7 mmol) of TEA was added. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: CH2Cl2:CH3Cl=1:1) to obtain the product as a glassy solid (0.80 g).
Reaction SMILES: Cl.[F:2][C:3]1[C:12]2[O:11][CH2:10][C@H:9]([N:13]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:8][C:7]=2[C:6]([O:22]C)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[F:2][C:3]1[C:12]2[O:11][CH2:10][C@H:9]([N:13]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH:18]3[CH2:19][CH2:20][CH2:21]3)[CH2:8][C:7]=2[C:6]([OH:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(F)c2c1C[C@@H](N(C1CCC1)C1CCC1)CO2
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc(F)c2c1C[C@@H](N(C1CCC1)C1CCC1)CO2
Temperature: -40 °C
Yield: 88.1 %

Procedure:
(R)-8-Fluoro-3-(N,N-dicyclobutylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran hydrochloride (0.77 g, 2.26 mmol) was dissolved in anhydrous CH2Cl2 (20 mL) and cooled to -40° C. To the solution was BBr3 (0.54 mL, 5.7 mmol), dissolved in anhydrous CH2Cl2 (3 mL), added dropwise. The cooling-bath was removed and after 2 h at room temperature the reaction was completed. The reaction was poured out onto an ice/2M NH3 solution and the mixture was extracted, twice, with (MgSO4), filtered, and the solvent removed in vacuo to diethyl ether. The combined ether portions were dried give the crude residue. Chromatography on silica (eluent: 50% ethyl acetate/hexane) gave 0.58 g (89% yield) of the title compound as a white solid. Mp: 170°-2° C. [α]21D =-114.4° (C=0.1; CHCl3) GC-MS (70 eV) M=291 (2%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc([N+](=O)[O-])cn2)cc1
Yield: 51 %

Procedure:
4-nitro-1H-pyrazole (500 mg, 4.4 mmol), 4-methylbenzene-1-sulfonyl chloride (840 mg, 4.4 mmol), and triethylamine (510 mg, 5 mmol) were stirred in DMF (25 mL) at 80° C. for 1 hour. The reaction was cooled, diluted with H2O (200 mL) and extracted with ethyl acetate (3×, 100 ml). The organic phase was washed with aqueous 1N HCl (200 mL) and H2O (200 mL), dried over sodium sulfate, filtered and concentrated on the rotovap. The solid was triturated with hexanes to afford 4-nitro-1-tosyl-1H-pyrazole (600 mg, 50%) as an off white solid. 1H NMR (DMSO-d6, 400 MHz) δ 2.40 (s, 3H), 7.52 (d, 2H, J=8.4 Hz), 7.98 (d, 2H, J=8.8 Hz), 8.57 (s, 1H), 9.58 (s, 1H).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[C@H:6]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:5]2[NH:4]1>O1CCOCC1>[ClH:1].[N:11]1([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9][CH:8]([N:7]2[C@H:6]3[CH2:27][CH2:28][CH2:29][CH2:30][C@H:5]3[NH:4][C:3]2=[O:2])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1N[C@@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 4N solution of hydrochloric acid in dioxane (1.0 mL, 4.0 mmol) was added to a solution of cis-(+/−)-tert-butyl 4-(2-oxooctahydro-1H-benzimidazol-1-yl)-1,4′-bipiperidine-1′-carboxylate (244 mg, 0.60 mmol) from Step A in dioxane (5 mL). The reaction was stirred at room temperature for 7 h and the mixture was concentrated in vacuo. The product (251 mg) was used directly for the next step without further purification. MS (M+1): 307.4
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[F:21][C:22]([F:39])([F:38])[C:23]1[N:28]=[CH:27][C:26]([NH:29][NH:30]C(OC(C)(C)C)=O)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:26]2[CH:27]=[N:28][C:23]([C:22]([F:21])([F:38])[F:39])=[CH:24][CH:25]=2)[N:30]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)nc1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 69.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-[6-(trifluoromethyl)pyridin-3-yl]hydrazinecarboxylate (Intermediate-61, 0.431 g, 1.55 mmol), DCM (50 mL) and trifluoro acetic acid (5.0 mL) to afford 0.500 g of the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C:19](=[O:21])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]([O:24][CH3:25])=[O:23])[NH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C:19](=[O:21])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]([O:24][CH3:25])=[O:23])[N:11]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(Cc1ccccc1)C3
Reactant: ICc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CN(Cc2ccccc2)CC1=O
Temperature: 25 °C
Yield: 49.1 %

Procedure:
To a solution of 2-benzyl-4-oxo-5-carbomethoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (0.928 g, 2.78 mmol) in dry tetrahydrofuran (5 mL) was added 60% sodium hydride in oil (111 mg). The resulting mixture was stirred at room temperature until gas evolution ceased. A solution of benzyl iodide (0.606. g, 2.78 mmol) in dry tetrahydrofuran (5 mL) was added to the reaction mixture and the resulting solution stirred at room temperature for 60 h. The mixture was diluted with methylene chloride and washed twice with saturated sodium chloride solution. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate resulting in a yellow precipitate (163 mg). The filtrate was concentrated in vacuo and chromatographed (silica gel, 5% methanol/95% methylene chloride) to provide an additional 580 mg of the title compound (743 mg total, 63%) as a crystalline solid: mp 198-199° C. 1H NMR (CDCl3) d 7.43 (d, J=7 Hz, 1 H), 7.36 (d, J=8 Hz, 1 H), 7.25 (m, 9 H), 6.95 (m, 2 H), 5.24 (s, 2 H), 4.01 (s, 3 H), 3.78 (m, 4 H), 3.40 (bs, 2 H); MS EI+ m/e 425 (p+1); IR (KBr, cm−1) 1726, 1648, 1449, 1291, 1134, 1107.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:14]([OH:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[OH:16].CN(C=O)C.I[CH2:23][CH2:24][CH3:25]>O>[Br:3][C:4]1[C:5]([O:16][CH2:23][CH2:24][CH3:25])=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][C:14]=1[OH:15]
Reactant: CCCI
Reactant: CCOC(=O)c1cc(O)c(Br)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc(C(=O)OCC)cc(O)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% oil, 10.1 g) was added to a mixture of ethyl 4-bromo-3,5-dihydroxybenzoate (30.0 g) and DMF (200 mL), and the resultant mixture was stirred at 0° C. for 30 minutes in a nitrogen atmosphere. 1-Iodopropane (11.2 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (14.1 g).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15](Cl)(=[O:17])[CH3:16].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[C:9]([O:13][CH3:14])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc(C2CCCCC2)c1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(C2CCCCC2)ccc1C(C)=O

Procedure:
20 g of 3-cyclohexyl anisole are dissolved in 200 cc of benzene, 8.15 g of acetyl chloride are added, and 27.4 g of tin(IV) chloride are subsequently added dropwise at 5° - 10° while stirring. After stirring at 23° for 16 hours, the reaction mixture is poured on ice and extracted thrice with benzene. The organic phase is successively washed with 2 N hydrochloric acid, a 2 N caustic soda solution and water, is dried over anhydrous sodium sulphate and concentrated. The residue is recrystallized from acetone/petroleum ether. The resulting title compound has a M.P. of 99°-100°.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C([O-])([O-])=O.[K+].[K+].CCCCCCCCCCCC.I[C:31]1[CH:32]=[C:33]([CH3:38])[CH:34]=[C:35]([CH3:37])[CH:36]=1.Cl>[Cu]I.CN(C)C(=O)C>[CH3:38][C:33]1[CH:32]=[C:31]([O:10][C:1](=[O:11])[C@H:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[OH:3])[CH:36]=[C:35]([CH3:37])[CH:34]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(OC(=O)[C@@H](O)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 34.1 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (20 mg, 0.105 mmol, 10 mol %), (S)-mandelic acid (190 mg, 1.25 mmol), K2CO3 (430 mg, 3.11 mmol), evacuated and backfilled with argon. Dodecane (235 μL), 5-iodo-m-xylene (150 μL, 1.04 mmol), and N,N-dimethylacetamide (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting pale yellow suspension was poured into 20 mL of 10% aq HCl and extracted with 3×20 mL of dichloromethane. The combined organic phase was dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate-acetic acid 40:20:1; 15 mL fractions). Fractions 7-13 provided 91 mg (34% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.65(br s, 1H), 7.64-7.57 (m, 2H), 7.47-7.36 (m, 3H), 6.67 (s, 1H), 6.61 (s, 2H), 5.65 (s, 1H), 2.28 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:21]=O)=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]2)[CH:7]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:21]=[C:27]2/[C:26](=[O:28])[NH:25][C:24](=[O:29])[S:23]/2)=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:9]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc(Cl)ccc2C=O)C1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc(Cl)ccc2/C=C2\SC(=O)NC2=O)C1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A 100 mL round bottom flask was charged with a magnetic stir bar, (S)-tert-butyl 1-(5-chloro-2-formylphenyl)pyrrolidin-3-ylcarbamate (Method 78) (1.100 g, 3.39 mmol), thiazolidine-2,4-dione (0.397 g, 3.39 mmol), and ethanol (11.29 ml). Piperidine (0.034 mL, 0.34 mmol) was added and the reaction was heated to reflux for 2 h. Once the reaction was judged to be complete by LCMS, it was allowed to cool to ambient temperature and conc. in vacuo to afford the title compound (1.310 g, 91%) which was used in the next step without further purification; m/z 425.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:33]=[N:34][N:35]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=4)[C:36]=3[CH3:37])=[O:31])=[CH:25][N:24]=2)[CH2:22][CH2:21][C:16]2(OCC[O:17]2)[CH2:15][CH2:14]1)=[O:12])[CH3:9]>ClCCl>[CH2:8]([O:10][C:11]([C:13]1([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:33]=[N:34][N:35]([C:38]4[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=4)[C:36]=3[CH3:37])=[O:31])=[CH:25][N:24]=2)[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)C1(c2ccc(NC(=O)c3cnn(-c4ccc(C)cc4)c3C)cn2)CCC2(CC1)OCCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(c2ccc(NC(=O)c3cnn(-c4ccc(C)cc4)c3C)cn2)CCC(=O)CC1
Reaction time: 6 h
Yield: 94 %

Procedure:
Trifluoroacetic acid (0.96 ml) was added at room temperature to a solution of 8-[5-({[5-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]carbonyl}amino)pyridin-2-yl]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (1.27 g) described in Example D4 in dichloromethane (2.5 ml) and stirred at the same temperature for six hours. Trifluoroacetic acid (1.9 ml) was added at the same temperature and stirred at the same temperature for 18 hours. After the reaction, the solvent and trifluoroacetic acid were evaporated, a saturated aqueous solution of sodium bicarbonate was added and extracted with ethyl acetate twice. The organic solution was dried over anhydrous magnesium sulfate and concentrated to give 1-[5-({[5-methyl 1-(4-methylphenyl)-1H-pyrazol-4-yl]carbonyl}amino)pyridin-2-yl]-4-oxocyclohexanecarboxylic acid ethyl ester (1.09 g) as a white solid.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11](=[O:32])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][C:24]2[CH:29]=[C:28](Br)[CH:27]=[C:26](Br)[CH:25]=2)=[CH:16][CH:15]=1>C(N(CC)CC)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.[Cu]I>[CH3:9][O:10][C:11](=[O:32])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][C:24]2[CH:29]=[C:28]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:27]=[C:26]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:25]=2)=[CH:16][CH:15]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#Cc3ccccc3)cc(C#Cc3ccccc3)c2)cc1

Procedure:
A solution of phenylacetylene (0.20 g, 1.98 mmol), {4-[3-(3,5-dibromo-phenyl)-prop-2-ynyloxy]-phenoxy}-acetic acid methyl ester (0.3 g, 0.66 mmol), Pd(PPh3)4 (0.11 g, 0.1 mmol) and CuI (0.05 g, 0.26 mmol) in triethylamine (10 ml) was heated in a sealed tube in a microwave own at 65° C. for 1 hour. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified on HPLC using acetonitril/water as eluent to give {4-[3-(3,5-bis-phenylethynyl-phenyl)-prop-2-ynyloxy]-phenoxy}-acetic acid methyl ester in 150 mg (46%) yield.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].[NH2:12][CH2:13][C@H:14]([N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=2)=[N:17]1)[CH3:15]>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:12][CH2:13][C@H:14]([N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=3)=[N:17]2)[CH3:15])=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3cc(F)c(C#N)c(F)c3)n2)[nH]n1
Yield: 64.4 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-acetyl-1H-pyrazole-5-carboxylic acid (0.229 g, 1.486 mmol) and (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.380 g, 1.449 mmol). The product was purified by flash chromatography. Yield 64.4%. 1H-NMR (400 MHz; CDCl3): δ 1.62 (d, 3H), 2.55 (s, 3H), 3.74-3.83 (m, 1H), 3.90-3.98 (m, 1H), 4.60-4.69 (m, 1H), 6.59 (d, 1H), 7.31 (bs, 1H), 7.51 (d, 1H), 7.53 (s, 1H), 7.55 (s, 1H), 7.60 (bs, 1H), 10.97 (bs, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][C:15]12[CH2:22][CH2:21][CH2:20][N:19]1[CH2:18][CH2:17][CH2:16]2>>[N:19]12[CH2:20][CH2:21][CH2:22][C:15]1([CH2:14][CH2:13][NH:12][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH2:16][CH2:17][CH2:18]2
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: NCCC12CCCN1CCC2
Product: O=[N+]([O-])c1cc(F)ccc1NCCC12CCCN1CCC2

Procedure:
The procedures described in Example 1 were repeated except that 2,5-difluoronitrobenzene (1.00 g, 6.29 mmol) and 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (2.42 g, 15.7 mmol) were employed. In this case, the desired compound was obtained as a colorless liquid (2.00 g, quantitative).