Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:13]2[C:14](=[O:23])[C:15]([CH3:22])=[C:16]([CH3:21])[C:17](=[O:20])[C:18]=2[CH3:19])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:28](O)[CH3:29]>>[C:1]1([CH:7]([C:13]2[C:14](=[O:23])[C:15]([CH3:22])=[C:16]([CH3:21])[C:17](=[O:20])[C:18]=2[CH3:19])[CH2:8][CH2:9][C:10]([O:12][CH2:28][CH3:29])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C)C(=O)C(C(CCC(=O)O)c2ccccc2)=C(C)C1=O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
4-Phenyl-4-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)butanoic acid (1.2 g) was dissolved in ethanol (50 ml), and thionyl chloride (0.4 ml) was added to the solution, followed by stirring at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in isopropyl ether, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and the object compound was eluted with isopropyl ether to give ethyl 4-phenyl-4-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)butanoate (1.1 g, 84%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this example, the Compound No. 42 was prepared.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C:1]2=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1C=CCCC1
Product: O=C1CCCCC1c1ccccc1

Procedure:
Lastly, to examine the utility of the catalyst on a somewhat larger scale, the reaction of cyclohexenone with phenylboronic acid was performed on a 20 mmol scale and the product 2-phenyl cyclohexanone was isolated in identical yield (83%) to the small-scale reaction (Table 1, entry 5). Thus, the ligands described herein may have practical application in larger scale reactions.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[CH2:56]([C:63]1[S:67][C:66]([NH2:68])=[N:65][N:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>ClCCl>[CH2:56]([C:63]1[S:67][C:66]([NH:68][C:20]([C:19]2[CH:23]=[CH:24][C:16]([C@H:13]3[CH2:12][CH2:11][C@H:10]([O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)=[O:21])=[N:65][N:64]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: Nc1nnc(Cc2ccccc2)s1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Reaction time: 16 h

Procedure:
0.6 g of trans-4-(4-tert-butoxycarbonylmethoxycyclohexyl)benzoic acid (1.79 mmol, 1 eq.) is placed in 8 mL of dichloromethane with stirring. 0.7 mL of diisopropylethylamine (4.49 mmol, 2.5 eq.), 0.275 g of hydroxybenzotriazole (1.79 mmol, 1 eq.) and 0.413 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.15 mmol, 1.2 eq.) are successively added, followed, after 10 minutes, by addition of 0.377 g of 5-benzyl-1,3,4-thiadiazol-2-amine (1.97 mmol, 1.1 eq.). After 16 hours, 0.137 g of hydroxybenzotriazole (0.895 mmol, 0.5 eq.) and 0.172 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 mmol, 0.5 eq.) are added. After 18 hours, the medium is evaporated, diluted with ethyl acetate and washed three times with brine. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel with a gradient of methanol in dichloromethane ranging from 0% to 2%. 0.09 g of tert-butyl trans-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyloxy}acetate is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25]2[CH2:27][O:26]2)[CH:22]=[CH:23][CH:24]=1>C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25]([OH:26])[CH2:27][NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([S:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[CH:8][CH:9]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: NCCc1ccc(Sc2ccc(O)cc2)cc1
Solvent: CCO
Product: Oc1ccc(Sc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)cc1
Yield: 32.2 %

Procedure:
4-[[4-(2-Aminoethyl)phenyl]thio]phenol (295 mg) and (2R)-2-(3-chlorophenyl)oxirane (186 mg) in ethanol (3.5 ml) was refluxed for 6 hours. The mixture was evaporated. The residue was purified by column chromatography on silica gel (chloroform/methanol=100/3) to give 4-[[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]thio]phenol (155 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C@@H:9]1[C@H:13]([CH2:14]I)[CH2:12][CH2:11][N:10]1[C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C@@H:9]1[C@H:13]([CH2:14][N:1]=[N+:2]=[N-:3])[CH2:12][CH2:11][N:10]1[C@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])=[O:8]
Reactant: COC(=O)[C@@H]1[C@H](CI)CCN1[C@@H](C)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@H](CN=[N+]=[N-])CCN1[C@@H](C)c1ccccc1
Reaction time: 18 h

Procedure:
Sodium azide (5.34 mmol) was added to a solution of (2S,3R)-3-iodomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (Step 5.5) (3.56 mmol) in DMF (30 mL) at rt. After 18 h, the reaction mixture was poured onto water and extracted with MTBE (2×). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to to afford the title compound as a brown oil. HPLC: tR=3.26 min (method A); ESI-MS: [M+H]+ 289.
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:45][CH2:46][C:47]([NH:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([O:57]CC1C=CC=CC=1)=[O:56])=[O:52])=[O:48])=[O:44])=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[H][H]>C(O)C.[Pd]>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:45][CH2:46][C:47]([NH:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([OH:57])=[O:56])=[O:52])=[O:48])=[O:44])=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)NCC(=O)NCC(=O)O
Yield: 96.6 %

Procedure:
(C18H37)2NCOCH2OCH2CO-Gly-Gly-Gly-OCH2Ph (1.0 g, 1.1 mmol) was dissolved in absolute ethanol (100 mL), 10% Pd/C (0.2 g) was added, and this mixture was shaken under 70 psi hydrogen pressure for 3 h in a Parr apparatus. The reaction mixture was heated to reflux and filtered through a celite layer and the solvent was evaporated under reduced pressure to leave (C18H37)2NCOCH2OCH2CO-Gly-Gly-Gly-OH as a white solid (0.86 g, 96%), mp 163–164° C. 1H-NMR (300 MHz, δ, CD3OD): 0.90 (6H, t, J=6.9 Hz), 1.29 (64H, m), 1.57 (4H, bs), 3.21 (2H, t, J=7.8 Hz), 3.35 (2H, t, J=7.8 Hz), 3.93 (2H, s), 3.94 (2H, s), 3.97 (2H, s), 4.12 (2H, s), 4.40 (2H, s). IR (KBr, cm−1): 1740 (CO), 1650 (CO).
Reaction SMILES: O1CCOC1C[CH2:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1.[C:34](=[O:37])([O-])O.[Na+]>CC(C)=O.Cl>[C:28]1([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]2[CH:14]=[C:10]([CH2:9][CH2:8][CH2:7][CH:34]=[O:37])[N:11]=[CH:12]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C([O-])O
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(CCCCC3OCCO3)c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=CCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
A suspension of the product from step b (19.8 g, 46.6 mmol) in a mixture of acetone (300 ml) and 2M hydrochloric acid (50 ml) was stirred at room temperature for 20 h. The mixture was neutralised with sodium hydrogen carbonate, filtered and the filtrate extracted with dichloromethane (3×100 ml). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give the product as a colourless oil (16.1 g, 91%).
Reaction SMILES: C(OC(=O)C)C.Cl.[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:48])[C:12]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)=[CH:13][N:14]2[CH2:23][C:24]([NH:26][CH:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)=[O:25]>C(O)C>[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:48])[C:12]([C:40]1[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1)=[CH:13][N:14]2[CH2:23][C:24]([NH:26][CH:27]1[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]1)=[O:25]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)NC3CCNCC3)c12
Temperature: 25 °C
Reaction time: 28 h
Yield: 27.5 %

Procedure:
A 4N hydrochloric acid ethyl acetate solution (25 ml) was added to an ethanol solution (12 ml) of tert-butyl 4-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetylamino}piperidine-1-carboxylate (820 mg, 1.44 mmol), followed by stirring at room temperature for 28 hours. The resulting mixture was concentrated under reduced pressure. After adding an aqueous sodium bicarbonate solution to the residue to adjust the pH to 8, the residue was washed with ethyl acetate. A 2N aqueous sodium hydroxide solution was added to the water layer to adjust its pH to 11, followed by extraction using dichloromethane. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethanol-ethyl acetate, giving a white powder of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-piperidin-4-ylacetamide (185 mg, yield: 27%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:21]=[CH:20][CH:19]=[C:17]([NH2:18])[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cc1OC
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: COCCOC
Product: COc1ccc(-c2cccc(N)c2)cc1OC
Temperature: 25 °C
Yield: 63 %

Procedure:
3,4-dimethoxyphenyl boronic acid (0.126 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.067 g in 63% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]2=[O:21])[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([NH2:35])=[CH:33][C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:26]1([C:29]2[C:34]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]4=[O:21])[C:3]=3[CH3:22])=[CH:33][C:32]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:31][N:30]=2)[CH2:25][CH2:24][O:23][CH2:28][CH2:27]1
Reactant: Cc1c(N2CCN(C)CC2=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C)CC2=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-methylpiperazin-2-one (25.0 mg, 0.077 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give 1-(4-((2,5-di-4-morpholinyl-3-pyridinyl)amino)-5,7-difluoro-3-methyl-2-quinolinyl)-4-methyl-2-piperazinone. 1H NMR (400 MHz, chloroform-d) δ ppm 8.12 (1H, br. s.), 7.68 (1H, d), 7.45 (1H, d, J=9.4 Hz), 7.04 (1H, ddd, J=13.6, 8.6, 2.4 Hz), 6.51 (1H, br. s.), 4.64 (1H, d, J=12.9 Hz), 3.84-4.00 (6H, m), 3.73-3.84 (4H, m), 3.36-3.54 (3H, m), 3.20-3.36 (2H, m), 3.15 (4H, br. s.), 2.93-3.09 (2H, m), 2.78 (3H, br. s.), 1.98 (3H, s). Mass Spectrum (ESI) m/e=554.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:25]([O-])=O)[N:9]=2)=[CH:4][CH:3]=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH2:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2nc(-c3ccc(Br)cc3)c(-c3ccc(Br)cc3)nc12
Solvent: C1COCCO1
Product: Nc1cccc2nc(-c3ccc(Br)cc3)c(-c3ccc(Br)cc3)nc12
Reaction time: 24 h

Procedure:
1.01 g (0.0021 mol) of 2,3-di(4-bromophenyl)-5-nitroquinoxaline was dissolved in 30 g of dioxane, and the reaction system was flushed sufficiently with argon. Thereafter, 0.3 g of PdC was added to the reaction mixture, the reaction system was again flushed sufficiently with argon, the system was then flushed with hydrogen gas, and reaction was allowed at room temperature for 24 hr. After the reaction was over, the reaction mixture was filtered, the filter cake was further washed with acetone and dioxane, and filtration was again conducted. The solvent was removed from the filtrate obtained, and the reaction product was extracted on a silica gel column.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=[C:8]2[NH:7][C:6]=1[CH3:24])=[O:4].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CCN(CC)CC>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=[C:8]2[N:7]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)[C:6]=1[CH3:24])=[O:4]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)C1=C(C)Nc2nn(C)c(=O)n2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(C)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 3.6 %

Procedure:
Intermediate 8 (900 mg, 2.77 mmol), 3-trifluoromethylphenylboronic acid (1.05 g, 5.54 mmol), Et3N (925 μL, 6.6 mmol), and copper (II) acetate (1.0 g, 5.54 mmol) were dissolved in DCE (25 mL), and the reaction mixture was stirred at 80° C. for 18 hours. After cooling to RT the reaction mixture was partitioned between DCM and water. The organic layer was separated, washed with water, followed by brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 3-10% MeOH in DCM and then using HPLC system 1 to yield the title compound as an orange solid (47 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(C(C)(C)C)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccc(/C=C/C(=O)O)s2)cc1
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of methyl (E)-3-[5-(4-tert-butylphenyl)-thiophen-2-yl]acrylate (190 mg) of THF/ethanol (15/15 ml) was added at room temperature 2N sodium hydroxide solution (2.0 ml), and the mixture was stirred 18 hours. To the mixture was added 1N hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the precipitated crystals were collected by filtration, which were washed with hexane to give yellow crystals of (E)-3-[5-(4-tert-butylphenyl)thiophen-2-yl]acrylic acid (149.7 mg). This compound was used for the following reaction, without subjecting further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[I:13])[C:7]([OH:9])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:9])[CH:10]=[CH:11][C:12]=1[I:13])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOc1cc(C(=O)O)ccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCCCC2)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
3-Ethoxy-4-iodo-benzoic acid (2.73 grams, 9.36 mmol) was suspended in methylene chloride (25 mL), and oxalyl chloride (5.15 mL, 2.0 M in methylene chloride, 10.3 mmol) was added by pipette. Three drops of dimethylformamide was added and this mixture was stirred overnight at room temperature. The volatiles from the now homogeneous reaction were removed under vacuum and the residue reconstituted in methylene chloride. One half of this was treated with piperidine (2.0 mL, 20 mmol). The mixture was stirred at room temperature for 2 h. The reaction was diluted with methylene chloride, washed with 1.0 M hydrochloric acid, water, saturated sodium bicarbonate solution and brine. The organic layers was dried (magnesium sulfate), filtered and concentrated to give (3-ethoxy-4-iodo-phenyl)-piperidin-1-yl-methanone (1.69 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:22]2[CH3:25])=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ccc(Br)cc21
Product: CC1c2cc(Br)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=[O:9])[CH:3]=1.Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:29](=[CH:30][CH:31]=1)[CH2:28][C:18]1([C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]1=[O:27])[CH2:17]2>CC(O)C>[O:27]=[C:19]1[NH:20][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:26]2[C:18]21[CH2:17][C:16]1[C:29](=[CH:30][CH:31]=[C:14]([NH:13][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=3)[CH:15]=1)[CH2:28]2
Reactant: COC(=O)c1cc(Br)ccn1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: Cl
Solvent: CC(C)O
Product: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.17 g (0.79 mmol) methyl 4-bromo-pyridine-2-carboxylate and 17 μL (70 μmol) of a 4M aqueous hydrochloric acid solution were added to 0.20 g (0.78 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 5.0 mL of 2-propanol. The reaction mixture was refluxed for 2 h, then cooled to RT and evaporated down. The residue was taken up in THF and mixed with 0.50 mL (2.0 mmol) of a 4M aqueous NaOH solution and stirred overnight at RT. The reaction mixture was diluted with water, combined with 0.5 mL conc. HCl and the solvent was eliminated. The precipitated product was suction filtered and dried.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([OH:10])=O.S(Cl)([Cl:13])=O>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:13].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([Cl:1])=[O:10]
Reactant: Cc1[nH]cnc1C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1[nH]cnc1C(=O)Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a suspension of 880 g (5.4 moles) of 5-methyl-4-imidazolecarboxylic acid hydrochloride in 100 ml of dimethylformamide and 2 liters of toluene at 60° C., there was added slowly over 2 hours 790 ml (10.8 moles) of thionyl chloride. At the end of the addition, the mixture was held with good stirring for 1 hour at 80° C. It was allowed to cool, filtered, the solid was washed with 1 liter of toluene. 685 g of 5-methyl-4-imidazolecarbonyl chloride hydrochloride were obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=4)[NH:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:27]([Sn](CCCC)(CCCC)CCCC)=[N+:28]=[N-:29]>C1(C)C=CC=CC=1>[NH:27]1[C:25]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)=[N:26][N:29]=[N:28]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2[nH]nc(-c3ccc(OCCN4CCOCC4)cc3)c2c1
Solvent: Cc1ccccc1
Product: c1cc(-c2n[nH]c3ccc(-c4nnn[nH]4)cc23)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.9 %

Procedure:
A mixture of 3-[4-(2-morpholin-4-ylethoxy)phenyl]-1H-indazole-5-carbonitrile (290 mg, 0.832 mmol), azidotributyltin (Bu3SnN3, 1.56 g, 4.70 mmol, 5.65 equiv.), and 9.0 mL toluene was refluxed for 17.5 h and concentrated to an oil. To the oil was added 6.5 mL of dioxane and 6.5 mL of 6.0 N aq. HCl. The mixture was stirred at room temperature for 4 h and then added to 25 mL of 6.0 N aq. NaOH. The mixture was extracted with 3× hexanes, and 3×Et2O. The aqueous layer was filtered to remove particulates. The pH was adjusted with 6.0 N aq. HCl to give maximum visual turbidity (approximately pH 5.0–5.5) and then the mixture was extracted with 2×EtOAc. The combined organics were dried (Na2SO4), filtered, and concentrated. The product was triturated in 5% EtOAc in hexanes. Filtration and drying of the solid afforded the title compound (29.0 mg, 8.90% yield): 1H NMR (CDCl3/CD3OD) δ 8.75 (s, 1H), 8.08 (d, 1H), 7.95 (d, 2H), 7.70 (m, 1H), 7.13 (d, 2H), 4.30 (t, 2H), 3.85–3.79 (m, 4H), 3.07 (t, 2H), 2.89–2.80 (m, 4H); ES-MS (m/z) 392 [M+1]+.