Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:14][C:15]1[O:19][C:18]([C:20](OC)=[O:21])=[CH:17][CH:16]=1.Cl>C1COCC1>[CH3:14][C:15]1[O:19][C:18]([C:20](=[O:21])[CH2:2][C:1]#[N:3])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C)o1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)CC#N)o1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Following the method of Turner and Jacks (J. Org. Chem. 1989, 54, 4229), to a stirred solution of 5.6 ml (107 mmol) acetonitrile in 20 ml dry THF under argon at −78° C. was added dropwise 47.0 ml (47.09 mmol) lithium bis(trimethylsilyl)amide solution (1M in THF) and stirring continued for 30 minutes, after which a solution of 3.0 g (21.4 mmol) methyl 5-methyl-2-furoate in 20 ml THF was added dropwise and stirring continued while the reaction mixture was allowed to warm slowly to −20° C. The reaction mixture was then cannulated into a rapidly stirred solution of 1M hydrochloric acid at 0° C. The mixtured was extracted twice with ether and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetatephexane 1/1) afforded 1.77 g (55%) 3-(5-methyl-furan-2-yl)-3-oxo-propionitrile as a yellow crystalline solid. EI-MS m/e (%): 149 (M+, 24), 109 ([M—CH2CN]+, 100), 53 (30).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:44]([CH2:48][CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[C:45](O)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:44]([CH2:48][CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[C:45]([NH:55][C:56]2[S:57][CH:58]=[CH:59][N:60]=2)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1
Reactant: O=C(O)C(CC1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
A solution of triphenylphosphine (409 mg, 1.56 mmol) in methylene chloride (8 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (277 mg, 1.56 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid (370 mg, 0.92 mmol) in methylene chloride (5 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (276 mg, 2.76 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/2 hexanes/ethyl acetate) afforded 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide (83 mg, 18%) as an amorphous solid: EI-HRMS m/e calcd for C20H20ClF3N6OS (M+) 484.1060, found 484.1068.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C[O-].[Na+].[C:14]1([C:20]2[O:21][C:22]([CH3:29])=[C:23]([C:25](=[O:28])[CH2:26]Br)[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([C:20]2[O:21][C:22]([CH3:29])=[C:23]([C:25]([C:26]3[O:10][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=4[CH:7]=3)=[O:28])[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1C(=O)c1cc2cc(Br)ccc2o1
Temperature: 78 °C
Reaction time: 0.33 h

Procedure:
To a slurry of 294 g of 5-bromosalicylaldehyde in 3 liters of dry ethanol was added 79.06 g of sodium methoxide and the mixture allowed to stir for 20 minutes. To the resulting yellow slurry was added 410 g of 2-phenyl-4-bromoacetyl-5-methyloxazole and the slurry heated to 78° C. for 2 hours. An additional 250 mg of sodium methoxide was added and heating continued overnight under a nitrogen atmosphere. The reaction was cooled and the solids filtered and washed with ethanol, 393 g, mp 212°-213° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:35])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)[C@@H:17]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C@@H:12]3[O:13]C(=O)C)[C:6]=2[N:7]=1>N>[NH2:1][C:2]1[N:3]=[C:4]([Cl:35])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)[C@@H:17]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C@@H:12]3[OH:13])[C:6]=2[N:7]=1
Reactant: CC(=O)O[C@H]1[C@H](OC2CCCCO2)[C@@H](COC2CCCCO2)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Agent: N
Product: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COC4CCCCO4)[C@@H](OC4CCCCO4)[C@@H]3O)c2n1
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A mixture of the compound from Step F (0.27 g, 0.53 mmol) and methanolic ammonia (saturated at 0° C.; 10 mL) was kept overnight at 0° C. Evaporation of the solvent yielded the desired compound (0.25 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH2:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(C)(C)c1cc(N)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Yield: 92.9 %

Procedure:
Using the procedure described in Example 161C, 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-amine (0.429 g, 1.75 mmol) and phenyl chloroformate (0.329 g, 2.1 mmol) were reacted in the presence of K2CO3 (0.415 g, 3 mmol) in THF (15 mL), and purified by silica gel chromatography with 15-35% EtOAc/hexane as eluants to afford phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate as solid (0.594 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.53 (m, 5H), 7.41-7.48 (m, 4H), 7.14-7.38 (m, 2H), 6.6 (s, 1H), 3.37 (q, 2H), 1.59 (s, 6H), 1.14 (t, 3H); LC-MS (ESI) m/z 320 (M−OEt)+.
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)([CH2:5][OH:6])[CH2:3][OH:4].C(N(CC)CC)C.C(=O)=O.CO.[C:35](Cl)(=[O:37])[CH3:36]>C(O)C.C(Cl)(Cl)Cl.ClCCl>[C:35]([NH:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:12]=1)([CH2:5][OH:6])[CH2:3][OH:4])(=[O:37])[CH3:36]
Reactant: CCCCCCCCCCc1ccc(C(N)(CO)CO)cc1
Reactant: CC(=O)Cl
Agent: O=C=O
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCc1ccc(C(CO)(CO)NC(C)=O)cc1
Temperature: 25 °C

Procedure:
2-Amino-2-(4-decylphenyl)-1,3-propanediol (313 mg) was dissolved in a mixed solvent of ethanol (20 ml) and chloroform (5 ml). Thereto was added triethylamine (0.4 ml) and the mixture was cooled to -60° C. with dry ice-methanol. Thereto was dropwise added a solution of acetyl chloride (0.12 ml) in dichloromethane (5 ml) under ice-cooling and the mixture was heated to room temperature. The solvent was distilled away and the residue was dissolved in ethyl acetate. The mixture was washed with brine, an aqueous dilute hydrochloric acid solution and an aqueous sodium hydrogencarbonate solution. The resultant mixture was dried over anhydrous sodium sulfate and the solvent was distilled away. The residue was purified by preparative thin layer chromatography (silica gel) and recrystallized from hexane to give 130 mg of the colorless, crystalline subject compound.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[C:19]([OH:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>>[F:17][C:18]1[C:19]([OH:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16]
Reactant: O=Cc1cccc(F)c1O
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1cccc(F)c1O
Yield: 52.3 %

Procedure:
6-phenyl-2-oxindole (50 mg, 0.3 mmol) was condensed with 3-fluoro-2-hydroxybenzaldehyde (50 mg, 0.36 mmol) using method B to give 52 mg (53%) of 3-(3-fluoro-2-hydroxybenzylidene)-6-phenyl-1,3-dihydroindol-2-one as a yellow/orange solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:27])[CH2:4][CH2:3]2.[CH3:28]I>>[CH3:28][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:27]
Reactant: CI
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Sc3ccc4ccccc4c3)ccc12
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5ccccc5c4)cc3CC[C@@H]12

Procedure:
A 282 mg portion of (4aR)-(10bR)-10b-methyl-8-(2-naphthylthio)-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f]quinolin-3-one was methylated with methyl iodide following the process of Example 95 to obtain 137 mg of the desired product. mp 138°-139.5° FDMS: m/e=387. α[D]589 =+69.6, α[D]365 =+261.4 (chloroform).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH2:11][OH:12].C(N(CC)CC)C>O1CCCC1>[CH3:4][S:1]([O:12][CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][O:6]1)(=[O:3])=[O:2]
Reactant: OCC1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1CCCO1
Reaction time: 2 h

Procedure:
Mesyl chloride (6.17 g) was dropwise added to a solution of 5.0 g of (tetrahydro-2furanyl)methanol, 2.18 g of triethylamine and 30 ml of tetrahydrofuran under ice-cooling over 30 minutes, followed by stirring at the same temperature for 2 hours. After the completion of reaction, the insolubles were filtered, and the filtrate was then concentrated under a reduced pressure to obtain (tetrahydro-2-furanyl)methyl methanesulfonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1cc2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-chloro-1-methyl-1H-indol-2-yl)heptyl]amino}phenyl)carbonyl]amino}propanoate (349 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (302 mg, 92%) as a pale-brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:26]([C:32]1[CH:38]=[CH:37][C:35]([OH:36])=[CH:34][C:33]=1[OH:39])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>C1(C)C(C)=CC=CC=1>[OH:36][C:35]1[CH:34]=[C:33]([OH:39])[C:32]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:38][C:37]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1
Reactant: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3)n2)cc1
Reactant: CCCCCCc1ccc(O)cc1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: CCCCCCc1cc(-c2nc(-c3ccc(C)cc3)nc(-c3ccc(C)cc3)n2)c(O)cc1O
Temperature: 90 °C

Procedure:
To a 350 mL sulfonation flask equipped with a mechanical stirrer, condenser and a nitrogen atmosphere are charged 29.6 g (100 mmol) of 2-chloro-4,6-bis(4-methylphenyl)-s-triazine, and 100 mL of xylene (mixture of isomers). To the beige suspension are added 11.3 g (85 mmol) of aluminum chloride in one portion. The mixture is warmed to ca. 90° C. for 75 minutes. 21.4 g (110 mmol) of 4-hexylresorcinol are then added in five portions over 45 minutes to the now homogeneous solution. The reaction mixture is heated at 90° C. for 18 hours. After cooling to room temperature, the contents of the flask are poured into 120 mL of 6% aqueous hydrochloric acid. The precipitate formed is removed by filtration, washed to pH 7 with water, rinsed with methanol and dried at 70° C. under vacuum. The title compound is obtained as a crude orange product (43.1 g) and melts at 228°-231° C. It can be used without further purification.
Reaction SMILES: [Br-].[PH4+].C1([C:9](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])C=CC=CC=1.[H-].[Na+].[CH3:32][C:33]1[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:34]=1[CH2:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O>CS(C)=O>[CH2:10]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH:16]=[CH:40][C:39]1[CH:42]=[CH:43][CH:44]=[C:37]([O:36][CH2:35][C:34]2[C:33]([CH3:32])=[CH:48][CH:47]=[CH:46][C:45]=2[CH3:49])[CH:38]=1)[CH3:9]
Reactant: CCCCC(=O)OCC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C)c1COc1cccc(C=O)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCC=Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 23.200000762939453 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
A mixture of 13.29 g of triphenylethylvalerate phosphonium bromide and 0.745 g of sodium hydride in 40 ml of DMSO was stirred for 30 min, under nitrogen in a 3-necked, 100 ml round bottom flask equipped with a stir bar, reflux condenser with a nitrogen inlet and a thermocouple. The mixture changed from light yellow to brown and heated to 40.2° C. from 23.2° C. 5.00 g of 3-(2,6-dimethylbenzyloxy)benzaldehyde was dissolved in 20 ml of DMSO and added, dropwise over a 4 min. period to the reaction mixture. The mixture heated to 26.8° C. from 21.8° C. The reaction mixture was stirred and allowed to cool to room temperature. The reaction was analyzed after 1 hr. and LC-MS showed almost all the starting aldehyde left and ˜3% desired product. The reaction mixture was heated to 50° C. and stirred for 3 hrs. The reaction was analyzed after 2 and 3 hrs. LC-MS showed ˜20% starting aldehyde left and 17% desired product. The reaction was cooled to room temperature and placed in a refrigerator overnight.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)([F:4])[F:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([O:34][C:35](=[O:38])[CH2:36]Br)(C)(C)C.FC(F)(F)C(O)=O>O1CCCC1.C(OCC)C.ClCCl>[F:1][C:2]([S:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:36][C:35]([OH:38])=[O:34])[CH2:15][CH2:14]2)=[CH:10][CH:11]=1)([F:4])[F:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O[C@H]1CC[C@H](Nc2ccc(SC(F)(F)F)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)CO[C@H]1CC[C@H](Nc2ccc(SC(F)(F)F)cc2)CC1
Reaction time: 0.25 h

Procedure:
Trans-4-(4-trifluoromethylsulfanyl-phenylamino)-cyclohexanol (160 mg, 0.55 mmol, prepared in accordance with Example 29) was placed under an inert atmosphere and dissolved in dry tetrahydrofuran (2 mL). A molar solution of lithium bis(trimethylsilyl)-amide (1 mL, 1.0 mmol) was added. After 15 min, tert-butyl-bromoacetate (75 μL, 0.55 mmol) was added. After two additional hours, more lithium bis-(trimethylsilyl)-amide solution (500 μL, 0.50 mmol) and tert-butyl-bromoacetate (37 μL, 0.28 mmol) was added. After 4 hr, the mixture was diluted with diethylether (20 mL), washed with water (10 mL), and washed with saturated aqueous hydrogencarbonate (10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford an oil. This crude product was diluted in dichloromethane (4 mL) and treated with trifluoroacetic acid (3 mL) at room temperature. After 3 hr, the mixture was diluted with diethylether (20 mL) and washed with water (3×10 mL), and washed with aqueous saturated hydrogencarbonate (2×10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The oily residue obtained was purified by column chromatography on silica gel (dichloromethane followed by dichloromethane/methanol, 95:5). The desired product was isolated as a yellow solid (68 mg, 35% yield).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:42])[CH2:20][CH2:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)[N:26]([CH2:34][C:35]2[CH:36]=[N:37][C:38](Cl)=[CH:39][CH:40]=2)[CH:25]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>CO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][O:18][C:19](=[O:42])[CH2:20][CH2:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)[N:26]([CH2:34][C:35]2[CH:36]=[N:37][C:38]([C:4]3[C:5]4[O:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)=[CH:39][CH:40]=2)[CH:25]=1)=[O:23]
Reactant: COC(=O)CCC(=O)c1cn(Cc2ccc(Cl)nc2)c2ccc(Cl)cc12
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1cn(Cc2ccc(-c3cccc4c3oc3ccccc34)nc2)c2ccc(Cl)cc12
Temperature: 90 °C
Yield: 82.1 %

Procedure:
A solution of dibenzofuran-4-boronic acid (422 mg, 1.98 mmol) in methanol (10 mL) was added to a stirred solution methyl-4-[5-chloro-1-(6-chloropyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyrate (650 mg, 1.66 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (72 mg, 5 mol %) in toluene (40 mL). 2N sodium carbonate (1.66 mL, 3.32 mmol) was added and the reaction was heated to 90° C. (oil bath temp.) for 2-3 hrs until complete (TLC control). The reaction mixture was cooled to room temperature and partitioned between water and diethyl ether. The phases were separated, the aqueous phase being further extracted with diethyl ether (2×30 mL). The combined extract was washed with water and brine. The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield methyl-4-[5-chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyrate as a white solid (713 mg, 82%); Rf: 0.5 (50% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.71 (1H, s, ArH), 8.41 (2H, m, ArH), 8.27 (1H, d, J=8 Hz, ArH), 8.00 (2H, m, ArH), 7.89 (2H, s, ArH), 7.44-7.58 (4H, m, ArH), 7.39 (2H, m, ArH), 5.43 (2H, s, CH2N), 3.71 (3H, s OMe), 3.21 (2H, t, J=7 Hz, CH2CO), 2.80 (2H, t, J=7 Hz, CH2CO); ESI-LCMS e/z calculated for C31H23ClN2O4 522.980, found 523 [M+H (35Cl)]+, 525 [M+H (37Cl)]+, 545 [M+Na (35Cl)]+, 547 [M+Na (37Cl)]+.
Reaction SMILES: Cl.Cl[C:3]1C=CC(NN)=CC=1.BrCCCC1C=CC(C(F)(F)F)=NC=1.ClC1C=CC(N(CCCC2C=NC(C(F)(F)F)=CC=2)N)=CC=1.C(OC(OCC)CCCNC)C.[Cl:59][C:60]1[CH:61]=[C:62]2[C:66](=[CH:67][CH:68]=1)[N:65]([CH2:69][CH2:70][CH2:71][C:72]1[CH:73]=[N:74][C:75]([C:78]([F:81])([F:80])[F:79])=[CH:76][CH:77]=1)[CH:64]=[C:63]2[CH2:82][CH2:83][NH:84][CH3:85].C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Cl:59][C:60]1[CH:61]=[C:62]2[C:66](=[CH:67][CH:68]=1)[N:65]([CH2:69][CH2:70][CH2:71][C:72]1[CH:73]=[N:74][C:75]([C:78]([F:81])([F:80])[F:79])=[CH:76][CH:77]=1)[C:64]1[CH2:85][N:84]([CH3:3])[CH2:83][CH2:82][C:63]2=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CNCCc1cn(CCCc2ccc(C(F)(F)F)nc2)c2ccc(Cl)cc12
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2c(n(CCCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)C1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 5-(3-bromopropyl)-2-(trifluoromethyl)pyridine, and triethylamine (General Method 1), 1-(4-chlorophenyl)-1-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)hydrazine and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[CH3:48][Si:49]([CH3:76])([CH3:75])[CH2:50][CH2:51][O:52][CH2:53][N:54]1[C:58]2=[N:59][CH:60]=[CH:61][C:62]([C:63]3[CH:64]=[N:65][N:66]([C:68]4([CH2:72][C:73]#[N:74])[CH2:71][NH:70][CH2:69]4)[CH:67]=3)=[C:57]2[CH:56]=[CH:55]1.Br[C:78]1[CH:79]=[CH:80][C:81]([C:84]([NH:86][C@H:87]([CH:89]2[CH2:91][CH2:90]2)[CH3:88])=[O:85])=[N:82][CH:83]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:73]([CH2:72][C:68]1([N:66]2[CH:67]=[C:63]([C:62]3[CH:61]=[CH:60][N:59]=[C:58]4[N:54]([CH2:53][O:52][CH2:51][CH2:50][Si:49]([CH3:75])([CH3:48])[CH3:76])[CH:55]=[CH:56][C:57]=34)[CH:64]=[N:65]2)[CH2:69][N:70]([C:78]2[CH:79]=[CH:80][C:81]([C:84]([NH:86][C@H:87]([CH:89]3[CH2:91][CH2:90]3)[CH3:88])=[O:85])=[N:82][CH:83]=2)[CH2:71]1)#[N:74]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Reactant: C[C@H](NC(=O)c1ccc(Br)cn1)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C1CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (91.1 mg, 0.146 mmol, Aldrich: Cat. #481084) was added to a mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrochloride (0.445 g, 1.00 mmol), 5-bromo-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamide (0.273 g, 1.01 mmol), and cesium carbonate (0.971 g, 2.98 mmol) in toluene (10 mL) under N2, followed by palladium acetate (32.2 mg, 0.143 mmol). The reaction mixture was stirred at 120° C. overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-70%) to afford the desired product (0.350 g, 58.6%). LCMS (M+H)+: m/z=597.3.