Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[CH:47]=[CH:48][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[N:50][CH:51]=1>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.O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:43])([CH3:44])[CH3:42])=[CH:37][CH:36]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[CH:47]=[CH:48][C:49]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=5)=[N:50][CH:51]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:30][CH:29]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: Brc1ccc(-c2ccccn2)nc1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccccn5)nc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55.6 %

Procedure:
Under a stream of argon, 0.35 ml of a hexane solution containing 0.55 mmol of butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C. in which 0.25 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained by Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.15 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 5 ml portion of tetrahydrofuran prepared by dissolving 0.14 g of 5-bromo-2,2′-bipyridyl and 0.03 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 15 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:chloroform=1:1 to 0:1) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 5-{4-[4,6-bis(4-tert-butylphenyl)-1,3,5-triazin-2-yl]phenyl}-2,2′-bipyridyl (0.16 g, yield 56%). Its melting point and glass transition temperature are shown in Table 4.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][C:2]2=[O:11])=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 3,4-dihydro-1H-quinolin-2-one (27 mmol) in 250 mL of anhydrous DMF is added NaH (60% in mineral oil) (30 mmol) and the mixture is stirred at room temperature for 30 minutes. 4-Methoxybenzyl chloride (30 mmol) is then added and the reaction mixture is stirred at room temperature for 2 hours. The solvent is evaporated. The residue is dissolved in 100 mL of water and extracted with CH2Cl2 three times. The combined organic layers are dried over MgSO4, filtered, and evaporated to give the crude 1-(4-methoxy-benzyl)-3,4-dihydro-1H-quinolin-2-one, which is used in the next step without further purification. Yield: 95%.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:27][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: COc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)CCc1cc(Nc3ccccc3N)ccc1C2=O
Yield: 35 %

Procedure:
In accordance with general method O, 0.48 g (1.8 mmol) of 2-chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 1.05 g (9.7 mmol) of phenylenediamine, 0.04 g of Pd(OAc)2, 0.20 g of phosphine ligand and 1.65 g (17 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Purification is carried out by column chromatography (flash; SiO2; hexane 80%/ethyl acetate 20%). Yield: 35%; m.p.: 200° C.
Reaction SMILES: [Li+].[CH3:2][O-:3].[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][CH2:17][O:18][C:19]1[C:27]2[CH:26]=[CH:25][S:24][C:23]=2[C:22](C=O)=[CH:21][CH:20]=1.CN([CH:33]=[O:34])C>>[CH3:2][O:3][C:33](=[O:34])/[C:8](/[O:9][CH3:5])=[CH:10]/[C:22]1[C:23]2[S:24][CH:25]=[CH:26][C:27]=2[C:19]([O:18][CH2:17][CH2:16][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:9][C:5]=2[CH3:4])=[CH:20][CH:21]=1
Reactant: CN(C)C=O
Reactant: C[O-]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2sccc12
Agent: [Li+]
Product: COC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)OC
Temperature: 75 °C
Yield: 73 %

Procedure:
A suspension of 6.39 g (15.9 mmol) of methyl 2-methoxy-2-(triphenylphosphonium)-acetate chloride (Prepared from methyl 2-chloro-2-methoxyacetate and triphenylphosphine, in analogy to: P. Seneci, I. Leger, M. Souchet, G. Nadler, Tetrahedron 1997, 53, 17097-17114), 0.68 g of lithium methylat (17.0 mmol) and 3.89 g of 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-carbaldehyde (10.6 mmol) in 40 ml of DMF was heated for 23 h at 75° C. The light brown reaction solution was cooled to 0° C., the formed white crystals were filtered off, washed with 40 ml of methanol and dried to constant weight (20° C./1 mbar/16 h) to afford 3.54 g (73%) of the title compound with a purity of 97.5% (GC area; Method: column: DB-1 (15 m*0.32 mm); injector: 270° C.; detector: 320° C.; oven 150-310° C. (4° C./min); carrier gas: H2 (60 KPa). Retention times: starting material (aldehyde 1), 23.8 min; E-ester 5, 28.8 min; Z-ester 5, 30.8 min). m.p.: 165° C. MS: 450.3 (M+H)+. 1H-NMR (CDCl3): 2.40 (s, 3H); 3.08 (t, J=6.5, 2H); 3.78 (s, 3H); 3.88 (s, 3H); 4.45 (t, J=6.5, 2H); 6.86 (d, J=8.4, 1H); 7.21 (s, 1H); 7.34 (d, J=5.5, 1H); 7.38-7.45 (m, 3H); 7.49 (d, J=5.5, 1H); 7.95-8.00 (m, 2H); 8.10 (d, J=8.4, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][C:14]([CH2:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(O)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)[Cl:29]>ClCCl>[ClH:29].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][C:14]([CH2:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([Cl:29])[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(CC1(O)CCN(Cc2ccc3c(c2)OCO3)CC1)c1ccccc1
Solvent: ClCCl
Product: Cl
Product: O=C(CC1(Cl)CCN(Cc2ccc3c(c2)OCO3)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-benzoylmethyl-4-piperidinol (III-13) is firstly prepared according to the method of synthesis and post-treatment in Example 13. 1.41 g (4.0 mmol) of N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-benzoylmethyl-4-piperidinol is dissolved into 20 ml of anhydrous dichloromethane and cooled in an ice-water bath with temperature controlled at below 0° C. The reaction solution is added dropwise a dichloromethane solution (8 mol, 25 ml) of SOCl2. After completion of addition, the temperature is raised to room temperature slowly and reacting for 1 hour. Then operating according to the post-treatment method in General Method seven obtains 0.65 g of a white crystal, with yield of 38.1%.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH:32]2C[CH:29]1[CH2:30][N:31]2[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc(N)nc1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Yield: 95.8 %

Procedure:
Using General Buchwald method 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.683 mmol, 1.0 eq) was combined with 5-(6-Amino-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (218 mg, 0.751 mmol, 1.1 eq) to give 4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (350 mg, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 6H) 1.39 (s, 6H) 1.62 (br. s., 3H) 1.94 (br. s., 8H) 2.41 (br. s., 3H) 2.92-3.02 (m, 2H) 3.05 (br. s., 7H) 3.26 (d, J=11.12 Hz, 3H) 3.34 (br. s., 3H) 3.51-3.64 (m, 1H) 4.39 (s, 1H) 4.45 (br. s., 1H) 4.55 (br. s., 1H) 4.72 (t, J=8.59 Hz, 1H) 6.58 (s, 1H) 7.12 (dd, J=9.09, 3.03 Hz, 1H) 7.74 (d, J=2.53 Hz, 1H) 8.02 (t, J=8.08 Hz, 1H) 8.72 (s, 1H) 9.15 (s, 1H); MS m/z 547.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13].Cl>O>[Cl:10][CH2:11][C:12]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:13]
Reactant: CC(C)(N)C(=O)O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(NC(=O)CCl)C(=O)O
Temperature: 5 °C
Yield: 62.4 %

Procedure:
To a stirring mixture of 2-aminoisobutyric acid (165.8 g; 1.61 mol), sodium hydroxide (64.4 g; 1.61 mol) and 800 ml water cooled to 5° C., was added chloroacetyl chloride (200 g; 1.77 mol) and then a solution of sodium hydroxide (70.8 g; 1.77 mol) in 143 ml water. The temperature was maintained between 5 to 10° C. during the additions. The reaction mixture was then allowed to warm to room temperature and the solution was acidified with 165 ml of concentrated aqueous HCl. The precipitated solid was filtered and dried under vacuum to afford 180.4 g (62%) of product.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].Cl.Cl.NC1C=[CH:30][C:31]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41](N3CCCC3)=O)[CH2:36]2)=[N:32]C=1N.NC1N=C(N2CCC[C@@H](C(N3CCOCC3)=O)C2)C=CC=1[N+]([O-])=O.C1(C2C=CN=C(C(=N)OCC)N=2)CC1>>[CH:37]1([C:38]2[CH:39]=[CH:40][N:35]=[C:31]([C:30]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:20][CH2:21][O:22][CH2:23][CH2:24]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[N:32]=2)[CH2:36][CH2:41]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)nc1N
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CCOC(=N)c1nccc(C2CC2)n1
Agent: Cl
Agent: Nc1nc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)ccc1[N+](=O)[O-]
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4nccc(C5CC5)n4)[nH]c3n2)C1)N1CCOCC1

Procedure:
The title compound was prepared by a method analogous to the one used for Example 95, but using (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(morpholino)methanone dihydrochloride (synthesized by hydrogenation analogous to the one used for Intermediate 1, starting from Intermediate 40) and Intermediate 42. MS (ES+APCI) (M+H) 434.2; LCMS retention time 1.996 min (Method G).
Reaction SMILES: [CH2:1]([N:3]1[CH2:20][C@H:19]([CH3:21])[N:18]2[C:5](=[C:6]([O:22][CH3:23])[C:7]3[C:12](=[O:13])[NH:11][N:10]=[C:9]([C:14]([NH:16]N)=[O:15])[C:8]=32)[C:4]1=[O:24])[CH3:2].[CH3:25]N.II.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([N:3]1[CH2:20][C@H:19]([CH3:21])[N:18]2[C:5](=[C:6]([O:22][CH3:23])[C:7]3[C:12](=[O:13])[NH:11][N:10]=[C:9]([C:14]([NH:16][CH3:25])=[O:15])[C:8]=32)[C:4]1=[O:24])[CH3:2]
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(C(=O)NN)c32)C1=O
Reactant: CN
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(C(=O)NC)c32)C1=O
Reaction time: 0.17 h

Procedure:
To a solution of (6S)-8-ethyl-10-methoxy-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-carbohydrazide (0.39 g, 1.2 mmol) and methylamine (5.9 mL, 11.8 mmol; 2 M in THF) in anhydrous dichloromethane (25 mL) in a water bath at room temperature, a solution of iodine (0.60 g, 2.4 mmol) in dichloromethane was added dropwise. After the addition was completed, an aqueous solution of sodium sulfite was added and the mixture was stirred vigorously for 10 minutes. The organic phase was separated, diluted with chloroform, and washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with a mixture of ethanol (7 mL) and diethyl ether (25 mL). The white solid precipitated was obtained by filtration and dried from its solution in toluene under vacuum.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:10](F)(F)[C:11](OC(=O)C(F)(F)F)=[O:12].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:11](=[O:12])[CH3:10])=[CH:3][CH:2]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(C)=O)cc1
Yield: 78 %

Procedure:
Reference is made to the work of H. Burton and P. F. G. Praill (Journal of Chemical Society, April-1950, pp-1203-1206) wherein it is reported that Acetyl perchlorate formed in-situ from silver perchlorates and acetyl chloride, is an effective acylating agent and will convert anisole into p-methoxyacetophenone in about 70% yield. However, this process has disadvantages of using perchlorates which is hazardous chemical. Reference is made to the work of E. J, Bourne, et al. (Journal of Chemical Society, March-1951, pp-718-720) wherein trifluoroacetic anhydride catalyst is shown to promote, the condensation between suitably activated aromatic compound and carboxylic acid or sulphonic acid to give ketones or sulphones, respectively. In this process, reaction was done at room temperature. Anisole was added to a mixture of trifluroacetic anhydride and acetic acid. After three hours the solution was poured into the excess of sodium hydrogen carbonate solution and then extracted by chloroform The extract were dried, filtered and evaporated to dry syrup. After crystallization it gave 78% of p-methoxyacetophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>C(Cl)Cl>[F:15][C:16]([F:30])([F:31])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=1)[C:20]([N:13]1[CH2:12][CH2:11][NH:10][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14]1)=[O:21]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccc(C2CNCCN2)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
To a cooled solution of CH2Cl2 (103 mL) containing 2-(3,4-dichlorophenyl)piperazine (1.15 g 5.0 mmol), 3,5-bis-(trifluoromethyl)benzoic acid (1.34 g, 5.09 mmol), and N-hydroxybenzotriazole monohydrate (0.688 g, 5.09 mmol) at -20° C. were added Et3N (0.711 mL 5.09 mmol) and N,N-dimethylaminopropyl-ethylcarbodimide (DEC) (0.967 g, 5.09 mmol) under nitrogen. The reaction was kept at -20° C. for an hour and gradually warmed to RT overnight. After stirring 20 h, the reaction was complete and CH2Cl2 (200 mL) was added. The organic solution was washed with 5% NaHCO3 (80 mL) and brine (80 mL, 2×), dried over MgSO4, filtered and concentrated under vacuum to give 2.1 g of crude product. The product was purified by flash chromatography on flash grade silica gel (120 g), eluting with 2% NH3 -MeOH/CH2Cl2 to give a foam solid (1.25 g, 2.65 mmol, 53%). m.p. 50°-53° C.; FAB MS [M+1]+ 470.9;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:10]=1.Cl.[CH3:26][O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH2:30]>>[CH3:26][O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH:30][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:9]([CH2:8][O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: Cc1ccccc1-c1cc(COCc2cccs2)ccc1C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COCc2cccs2)cc1-c1ccccc1C

Procedure:
The desired compound was prepared by coupling 4-(2-thienylmethoxymethyl)-2-(2-methylphenyl)benzoic acid, prepared as in Example 272C, with methionine methyl ester hydrochloride using the procedure of Example 184A.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH2:18][OH:19])[CH2:8][C:9]=1[NH:10]2.[CH3:20][C:21]1[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=[CH:23][C:22]=1[N:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:45].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.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>[OH:19][CH2:18][CH:7]1[CH2:6][CH2:5][C:4]2[C:3]3[C:11](=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=[CH:14][C:2]=3[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N:36]4[CH2:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:37]4=[O:45])[C:21]=3[CH3:20])[NH:10][C:9]=2[CH2:8]1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2ccccc2C1=O
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(CO)CC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CCC(CO)C4)cccc1N1Cc2ccccc2C1=O
Temperature: 100 °C
Yield: 58.9 %

Procedure:
A mixture of 5-bromo-2-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (Intermediate 30-3(a), 80 mg, 0.248 mmol), 2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoindolin-1-one (Intermediate 50-4, 130 mg, 0.371 mmol), 2 M aqueous tripotassium phosphate (0.371 mL, 0.743 mmol), and tetrakis(triphenylphosphine)palladium (14.30 mg, 0.012 mmol) in toluene (3 mL) and ethanol (1 mL) was sealed in a vial and heated at 100° C. for 6 hrs. The mixture was cooled and diluted with EtOAc, and the solution was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 96:3.6:0.4 DCM-methanol-28% aqueous ammonium hydroxide) to provide 2-(hydroxymethyl)-5-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a light yellow solid (68 mg, 53%). 1H NMR (400 MHz, chloroform-d) δ 7.79 (1 H, d, J=7.91 Hz), 7.46-7.53 (1 H, m), 7.38-7.44 (2 H, m), 7.30 (1 H, dd, J=7.91, 3.08 Hz), 7.14-7.26 (3 H, m), 6.77 (1 H, dd, J=7.69, 2.86 Hz), 4.59-4.74 (2 H, m), 3.39-3.54 (3 H, m), 2.72-2.80 (2 H, m), 2.30-2.44 (2 H, m), 1.80-2.10 (3 H, m), 1.75 (3 H, d, J=8.35 Hz). Mass spectrum m/z 466.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]=2[CH2:21]Br)=[O:15])=[CH:6][CH:5]=1.[CH3:28][NH:29][CH3:30].O1CCCC1>ClC1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]=2[CH2:21][N:29]([CH3:30])[CH3:28])=[O:15])=[CH:6][CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2CBr)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2CN(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-{2-[(3-bromomethylbenzofuran-2-carbonyl)amino]ethoxy}-benzoic acid methyl ester (0.340 mol) in chlorobenzene (200 ml) and dichloromethane (800 ml) was added dropwise to a 0-5° C. solution of 2M dimethylamine in tetrahydrofuran (510 ml, 1.022 mol) over 30 minutes with the temperature below 20° C. The resulting mixture was stirred for one hour and allowed to warm to ambient temperature. After completion of reaction, the reaction mixture was washed with 5% potassium carbonate and water. Solvent was distilled at atmospheric pressure until the pot temperature reached 100° C. After cooling to ˜50° C., acetonitrile (400 ml) and ethyl Acetate (400 ml) were added to the pot. The reaction mixture was heated to reflux until all solids dissolved. The reaction mixture was allowed to cool to give 4-{2-[(3-dimethylaminomethyl-benzofuran-2-carbonyl)amino]ethoxy}benzoic acid methyl ester (76.6 g) as an off white powder.
Reaction SMILES: C[Si](C)(C)[C:3]1[C:4]2[C:9](C=C3[C:16]=1[C:15](C#C)=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>CO.[OH-].[K+].O>[C:22]([C:21]1[C:25]2[C:16]([CH:3]=[C:4]3[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)#[CH:23]
Reactant: C#Cc1cccc2cc3ccccc3c([Si](C)(C)C)c12
Reactant: C1CCOC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
27 g (0.098 mol) of 9-trimethylsilyl ethynyl anthracene was put into a 1 L round-bottomed flask equipped with a stirrer and dissolved in a mixture of 100 ml of THF and 200 ml of methanol. A solution in which 0.7 g of KOH was dissolved in 7 ml of water was dropped into the resulting solution. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, THF and methanol were removed under a reduced pressure. The reaction mixture was then extracted with methylene chloride. The organic layer was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed to obtain yellow viscous liquid, which was then purified by silica gel column chromatography using hexane as an eluent, to give 17 g (85.8% yield) of the desired product.