Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].[CH3:27][O:28][C:29](=[O:62])[NH:30][CH:31]([C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]1[NH:43][C:44]([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][CH:48]=2)=[CH:45][N:46]=1)=[O:36])[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].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.O>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:50]5[CH:51]=[CH:52][C:47]([C:44]6[NH:43][C:42]([CH:38]7[CH2:39][CH2:40][CH2:41][N:37]7[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:62])[CH:32]([CH3:34])[CH3:33])=[N:46][CH:45]=6)=[CH:48][CH:49]=5)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC(=O)N2C(CCC2c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCC6CN(C(=O)OC)CC(=O)N65)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 16 %

Procedure:
A mixture of 6-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (65 mg, 0.15 mmol), [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (77 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol), potassium carbonate (42.8 mg, 0.31 mmol), 1,2-dimethoxyethane (4 mL) and water (1 mL) was heated in a microwave reactor at 120° C. for 20 minutes. The mixture was cooled and all volatiles were removed under reduced pressure. The resulting residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 6-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (16.8 mg, 0.024 mmol, 15%). C38H44BrN8O6 calculated 708.3 observed [M+1]+ 709.4; rt=1.39 min. 1H (DMSO-d6): δ=8.10 (s, 2H), 7.89 (m, 7H), 7.33 (d, J=9 Hz, 1H), 5.03 (t, J=7.8 Hz, 1H), 5.12 (m, 1H), 4.30 (m, 1H), 4.23 (m, 1H), 4.11 (t, J=8.1 Hz, 1H), 3.99 (m, 2H), 3.83 (m, 1H), 3.67 (s, 3H), 3.54 (m, 3H), 2.90 (m, 1H), 2.41 (m, 1H), 2.18 (m, 2H), 2.01 (m, 4H), 1.67 (m, 1H), 0.82 (m, 6H).
Reaction SMILES: [C:1]([CH2:4][S:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=4)[N:24]=3)=[CH:20][C:7]1=2)([OH:3])=O.[C:34]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[C:34]1([S:40]([NH:43][C:1]([CH2:4][S:5][CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]3[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=5)[N:24]=4)=[CH:20][C:7]2=3)=[O:3])(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)CSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(CSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 28.7 %

Procedure:
0.27 g of 11-carboxymethylthio-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Example 21, 0.9 g of benzenesulfonamide and 0.14 g of 4-dimethylaminopyridine and 0.11 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride dissolved in 10 ml of methylene chloride were stirred at room temperature for 7 days. After 10 ml of water and 1.13 ml of 1N-hydrochloric acid were added to the reaction mixture, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 0.1 g of the title compound as light brown powder.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([OH:7])=[O:6].[CH2:8]([O:24][CH2:25][CH:26]([OH:50])[CH2:27][O:28]C(C1C=CC(OC)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>C1(C)C=CC=CC=1>[CH2:8]([O:24][CH2:25][CH:26]([CH2:27][OH:28])[O:50][CH2:4][C:5]([OH:7])=[O:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)CCl
Reactant: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(CO)OCC(=O)O
Yield: 53.5 %

Procedure:
To a suspension of 13.1 g of 50% sodium hydride in 200 ml of toluene was add a solution of 12.6 g of chloroacetic acid in 50 ml of toluene over a 45 minute period. A solution of 65.5 g of 1-(hexadecyloxy)-3-[(4-methoxyphenyl)diphenylmethoxy]-2-propanol in 100 ml of toluene was added over 30 minutes. The mixture was refluxed for 65 hours, poured into water and acidified to pH 4. The mixture was extracted with ether. The ether solution was dried and evaporated. The residue was purified by chromatography giving 22.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:11][C:12]([F:13])([F:14])[F:15])[CH:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1Cl
Product: CCC(C(=O)OC(C)(C)C)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 1B using 2-chloro-4-[(2,2,2-trifluoroethyl)amino]benzonitrile and tert-butyl 2-bromobutanoate: MS (ES) m/z 377 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]=[CH:14][N:15]([CH3:17])[CH3:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
0.325 g of 4-bromobenzenesulfonamide was admixed with 0.82 g of dimethylformamide dimethyl acetal in 1.6 ml of dry dimethylformamide and stirred at room temperature for 90 min. For workup, the reaction mixture was admixed with 10 ml of water, and the precipitate was filtered off with suction, filtered and dried under reduced pressure. 4-Bromo-N-[1-dimethylaminomethylidene]benzenesulfonamide was obtained in a yield of 85%. Molecular weight 289.97 (C9H11BrN2O2S); retention time Rt=1.3 min. [B]; MS (ESI): 290.96 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([Cl:34])[CH:36]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: NCc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (200 mg, 0.42 mmol) and 3-chlorobenzylamine (238 mg, 1.7 mmol) was heated at 130° C., with stirring for 2 hours. The oil obtained was purified by chromatography (silica gel, 6 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) and then further purified by prep-HPLC to afford (4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 38 mg, 16.4%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[C:16]([Cl:18])[CH:17]=1>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:14]2[CH:13]=[C:12]([Cl:11])[CH:17]=[C:16]([Cl:18])[CH:15]=2)(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g) and 3,5-dichlorobenzenesulphonyl chloride (0.24 g). Yield 0.012 g.
Reaction SMILES: [F:1][C:2]([F:19])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C@H:4]([N:9]=[C:10]=[O:11])[C:5]([O:7][CH3:8])=[O:6].FC(F)(F)C(O)=O.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28]1>>[CH2:28]1[C:29]2([CH2:34][CH2:33][N:32]([C:10]([NH:9][C@@H:4]([CH2:3][C:2]([F:19])([F:1])[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]([O:7][CH3:8])=[O:6])=[O:11])[CH2:31][CH2:30]2)[CH2:27]1
Reactant: C1CC2(CCN1)CC2
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)N=C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CC1)CC2

Procedure:
Methyl (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpentanoate was prepared analogously to example 61, starting from 904 mg of methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate (3.36 mmol) and 907 mg of 6-azaspiro[2.5]octane trifluoroacetate (1.2 eq.). Chromatographic separation by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA) gave methyl (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpentanoate as a yellow oil. Yield: 234 mg (18% of theory)
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:20]([O:22]C)=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1>CO.O>[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:20]([OH:22])=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
6N Sodium hydroxide (260 mL) is added slowly at room temperature to a solution of 183 g of methyl 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylate in 1200 mL of methanol. The reaction mixture is heated under gentle reflux for 2.5 hours, cooled to room temperature and diluted with 300 mL of water. The reaction mixture is evaporated under reduced pressure (110-120 mbar/40° C.) to a suspension of about 750 mL which is filtered through the filter agent Celite® 521, and the filter cake is washed sequentially with 250 mL of water and 250 mL of heptane. The organic layer is separated and the aqueous layer is washed with 250 mL of heptane. The aqueous layer is acidified with 500 mL of 4N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water and filtered through the filter agent Celite® 521. The ethyl acetate solution (ca. 1000 mL) is evaporated under reduced pressure. (110-120 mbar/40° C.) to a volume of 600 mL to which is added heptane (3125 mL). The suspension is then heated to reflux until a clear solution is obtained, the solution is cooled to 0° C. and the resulting solid is filtered off to yield 6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxylic acid.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[Cl:41][C:42]1[CH:47]=[C:46]([NH:48][CH2:49][C:50]2[O:51][CH:52]=[CH:53][CH:54]=2)[C:45]([C:55]([O:57][CH2:58][C:59]([Cl:62])([Cl:61])[Cl:60])=[O:56])=[CH:44][C:43]=1[S:63]([NH:66][CH2:67][O:68][C:69](=[O:79])[CH2:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][CH2:77]Cl)=[O:75])(=[O:65])=[O:64]>C(#N)C>[Cl:41][C:42]1[CH:47]=[C:46]([NH:48][CH2:49][C:50]2[O:51][CH:52]=[CH:53][CH:54]=2)[C:45]([C:55]([O:57][CH2:58][C:59]([Cl:60])([Cl:62])[Cl:61])=[O:56])=[CH:44][C:43]=1[S:63]([NH:66][CH2:67][O:68][C:69](=[O:79])[CH2:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][CH2:77][N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:75])(=[O:65])=[O:64]
Reactant: O=C(CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)OCCl
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride, (700) (U.S. Pat. No. 3,819,706; U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) are stirred with cooling on an ice bath. A solution of chloromethyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles are removed by spin evaporation, and the residue is partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that is recrystallized to give 2-[(6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone. See U.S. Pat. No. 5,104,870; Sandler et al., Organic Functional Group Preparations, (1968) p. 324.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.[CH3:24]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([CH3:24])=[N:3][N:4]=[C:5]2[CH2:10]1)=[O:12]
Reactant: CB1OB(C)OB(C)O1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1CCN(C(=O)c1cccc(C(F)(F)F)c1Cl)C2
Temperature: 110 °C

Procedure:
3-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.366 mmol, e.g. see Example 1 for methods of preparation) was dissolved in 1,4-dioxane (3 mL) and treated with trimethylboroxine (55.2 mg, 0.439 mmol, commercially available e.g. from Sigma-Aldrich or Thermo Fischer Scientific), potassium carbonate (76 mg, 0.549 mmol) and tetrakis(triphenylphosphine)palladium(0) (42.3 mg, 0.037 mmol). The reaction mixture, under argon, was heated at 110° C. for 20 hours. The mixture was then cooled, diluted with water and extracted with ethyl acetate (three times). The organic phase was dried and evaporated. The residue was purified on the mass-directed automated (preparative) HPLC (MDAP) and the residue was triturated with isohexane to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.028 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(NC(C)C)(C)C>C1COCC1.[Pd](Cl)Cl.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>[CH3:16][Si:15]([C:13]#[C:14][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cccc(C#C[Si](C)(C)C)c1
Yield: 90 %

Procedure:
A mixture of ethyl 3-bromobenzoate (1.0 g, 4.37 mmol), ethynyl trimethylsilane (644 mg, 6.56 mmol), diisopropylamine (929 mg, 9.20 mmol), cuprous iodide(I) (16.6 mg, 0.0872 mmol), and bis(triphenylphosphine) palladium(II) chloride (123 mg, 0.175 mmol) was heated at 45° C. for 5 h in dried THF (8 ml) under argon atmosphere. After cooling, the reaction was quenched by the addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=50/1) to give ethyl 3-[(trimethylsilyl)-ethynyl]benzoate (90%)
Reaction SMILES: [NH2:1][CH:2]([C:6]([CH3:9])([SH:8])[CH3:7])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:20]=1[CH2:21]O>C(Cl)Cl>[NH2:1][CH:2]([C:6]([CH3:9])([S:8][CH2:21][C:20]1[C:23]([O:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=1[O:18][CH3:17])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: COc1cc(OC)c(CO)c(OC)c1
Reactant: CC(C)(S)C(N)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(CSC(C)(C)C(N)C(=O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A suspension of 2-amino-3-methyl-3-sulfanylbutanoic acid (D-penicillamine) (5.0 g, 34 mmol) in CH2Cl2 (150 mL) was cooled to 0° C. Trifluoroacetic acid (54 mL, 703 mmol) was added dropwise over a period of 5 minutes. Then 2,4,6-trimethoxybenzyl alcohol (6.64 g, 34 mmol) in CH2Cl2 (137 mL) was added dropwise at 0° C. with stirring. Stirring was continued for 1 hour at 0° C. and 2 hours at room temperature. The solvent was removed in vacuo and the residue was dried under high vacuum for 3 hours. The crude red solid was recrystallized from 1:1:1 CH2Cl2/MeOH/EtOAc to give the title compound as a white solid (10.5 g, 95%). 1H NMR (300 MHz, CDCl3) δ6.10 (s, 2H), 3.84 (s, 6H), 3.76 (s, 3H), 3.40-4.10 (m, 3H), 1.69 (s, 3H), 1.23 (s, 3H). LRMS (EI) m/z 330 (MH+).
Reaction SMILES: O.Cl.[CH2:3]([N:10]1[CH2:15][C:14]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21](O)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[O:13][CH2:12][C:11]1=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N1CC(CCN2CCC(C3C=CC=CC=3)(O)CC2)(C2C=CC([Cl:59])=C(Cl)C=2)OCC1=O)C1C=CC=CC=1.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:89][N:90]([CH3:108])[C:91]1[S:92][CH:93]=[C:94](C2(C3C=CC=CC=3)CCNCC2)[N:95]=1>CN(C=O)C>[ClH:37].[ClH:59].[CH2:3]([N:10]1[CH2:15][C:14]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][C:21]([C:94]3[N:95]=[C:91]([N:90]([CH3:108])[CH3:89])[S:92][CH:93]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)[O:13][CH2:12][C:11]1=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1COC(CCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Reactant: CN(C)c1nc(C2(c3ccccc3)CCNCC2)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1nc(C2(c3ccccc3)CCN(CCC3(c4ccc(Cl)c(Cl)c4)CN(Cc4ccccc4)C(=O)CO3)CC2)cs1
Yield: 223.7 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 41 from 1.1 g of the compound obtained in step B of EXAMPLE 14, 1.3 g of 4-[2-(dimethylamino)thiazol-4-yl]-4-phenylpiperidine p-toluenesulfonate, 0.97 g of K2CO2 and 4 ml of DMF to give 0.76 g of the expected product. M.p.=155-160° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15](Br)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(NC(C)C)(C)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc2c(OCc3ccccc3)cccn12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of 8-(benzyloxy)-3-bromoimidazo[1,2-a]pyridine (10.0 g, 33.0 mmol), 9.39 mL (66.0 mmol) of ethynyltrimethylsilane, 0.580 g (0.825 mmol) of Pd(PPh3)2Cl2, 0.230 g (1.19 mmol) of Cul, and 5.09 mL (36.3 mmol) of diisopropylamine in 100 mL of acetonitrile was heated at reflux for 3 h under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 20-50% EtOAc/hexanes) to provide 6.74 g of product: 321 m/z (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[C:3]([C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.200 g (0.405 mmol) of the product from Example 26 in CH2Cl2 (4 mL) at 0° C. was treated with trimethylacetyl chloride (50 μL; 0.405 mmol) followed by triethylamine (113 μL; 0.810 mmol). After the addition, the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 30% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 578.0 (M+1), 580.0 (M+3); Rt=4.69 min.