Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.Cl>O.CN(C)C=O>[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][N:5]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1
Reactant: CC(C)CCNc1nc(-c2ccccc2)cs1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of N-(3-methylbutyl)-4-phenyl-1,3-thiazol-2-amine (370 mg), sodium hydride (60% oil, 50 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by preparative HPLC (gradient cycle A) to give the title compound (250 mg, yield 47%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12](C#C)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].O=C(C1C=CC([Br:30])=CC=1)CCC(C)C.C[Al](C)C>CCCCCC>[CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([Br:30])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)CCC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc(C(C)(C)CCC(C)C)cc1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)CCC(C)(C)c1ccc(Br)cc1

Procedure:
Reaction Scheme 6 discloses specific synthetic steps leading to 4-(1,1,4-trimethylpentyl)phenylethyne (Compound 32). In this synthetic route 4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 29, obtained as shown in Reaction Scheme 5) is reacted under a nitrogen atmosphere with trimethylaluminum in hexane to yield 4-(1,1,4-trimethylpentyl)bromobenzene (Compound 33). The bromobenzene derivative 33 is converted through the corresponding trimethylsilylethyne derivative 34 into the target intermediate 32 by treatment with trimethylsilyl ethyne and subsequently with KOH in isopropanol, as described above. ##STR10##
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH:22]([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[F:21][CH:22]([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-(difluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 391.78 g/mol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH:7]=1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1ccccc1
Reactant: COc1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C=Cc1ccccc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
Palladium acetate (21 mg, 7 mol %) was added to a solution of 2-bromo-4-chloroanisole (300 mg, 1.4 mmol), styrene (211 mg, 2 mmol), triethylamine (13 μL, 0.1 mmol) and triphenylphosphine (50 mg, 1.9 mmol) in acetonitrile (6 mL), and the mixture was refluxed for 8 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate (15 mL). After the solution was washed successively with 2N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (118 mg, 35.6%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=1[N+:23]([O-:25])=[O:24].Cl.[CH:27]1([CH:30]([NH2:34])[CH2:31][CH2:32][CH3:33])[CH2:29][CH2:28]1>>[CH:27]1([CH:30]([NH:34][C:11]2[C:10]([N+:23]([O-:25])=[O:24])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:14]=[CH:13][N:12]=2)[CH2:31][CH2:32][CH3:33])[CH2:29][CH2:28]1
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1OS(=O)(=O)C(F)(F)F
Reactant: CCCC(N)C1CC1
Agent: Cl
Product: CCCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 72.3 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl-ester (1.0 g, 2.40 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-butylamine HCl (1.0 g, 4.79 mmol) were treated substantially as described in Part C of Example 19a to produce 0.66 g (72%) of crude (1-cyclopropyl-butyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine: MS (AP) m/z 380.3 [(M+H)+, 100].
Reaction SMILES: [C:1]12([CH2:12][C:11](=[O:13])[O:10][C:8](=[O:9])[CH2:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[NH2:14][OH:15].Cl.NO.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:15][N:14]=[C:8]([OH:9])[CH2:7][C:1]1([CH2:12][C:11]([OH:10])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CC1(CC(O)=NO)CCCCC1
Temperature: 70 °C

Procedure:
50 g. 1,1-Cyclohexane-diacetic anhydride was introduced portionwise, while stirring, into an aqueous solution of hydroxylamine, prepared from 23.4 g. hydroxylamine hydrochloride and 21.12 g. sodium carbonate. After completion of the addition, the reaction mixture as heated for 2 hours at 70° C.; an oil separated out. After cooling, the pH was adjusted to 2 with 2N hydrochloric acid and the crystalline precipitate was filtered off with suction. The precipitate was washed with water, taken up in methanol, any undissolved material was removed and, after the addition of water, it was evaporated in a vacuum. There was obtained 45.5 g of 1,1-cyclohexane-diacetic acid N-hydroxyimide; m.p. 104° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4].[Si]([O:46][CH:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C@H:50]3[CH2:51][CH2:52][C@H:47]([OH:46])[CH2:48][CH2:49]3)=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(-c2ccc(O[C@H]3CC[C@H](O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h

Procedure:
To a solution of 6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) and triphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwise diisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). After stirring for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and a mixture of the residue, hydroxylammonium chloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (9 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 30 min. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.45 g, 33%) as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12]3[N:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:16]([CH3:17])[C:11]=3[C:10](=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=O)(C)(C)C.Cl>>[CH3:17][C:16]1[C:11]2[C:10]([OH:24])=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:38][CH:35]4[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]4)=[CH:3][CH:4]=3)=[N:13][C:12]=2[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=1
Reactant: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(Br)cc3)cc(=O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Product: Cc1nn(-c2ccccc2)c2nc(-c3ccc(NC4CCNCC4)cc3)cc(O)c12

Procedure:
The title compound was prepared according to the procedure as described in Example 97 reacting via Suzuki coupling of 6-(4-bromo-phenyl)-3-methyl-1-phenyl-1,7-dihydro-pyrazolo[3,4-b]pyridin-4-one and 4-amino-piperidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])OC(C)(C)C)#[N:2].Cl.N1C=CC=CC=1.[C:34]([O:37][C:38](C)([CH3:42])[C:39](Cl)=O)(=[O:36])[CH3:35]>>[C:34]([O:37][C:38]([CH3:42])([CH3:39])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:3]=1[C:1]#[N:2])=[O:19])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(C)(C)C(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
To a solution of tert-butyl 6-(2-cyano-3-nitrophenoxy)hexylcarbamate (333 mmol, 121 mg) (Example 277c) in dixoane (2 mL) was added con. HCl (1 mL). After 15 minutes, the solution was concentrated in vacuo and dried on high vacuum. The crude HCl salt was suspended in DCM (dry, 10 mL) and treated with pyridine (2.664 mmol, 215 μL) and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (1.332 mmol, 193 μL). The reaction mixture was refluxed under a nitrogen atmosphere until clear (6 h), then cooled to room temperature and the volatiles removed in vacuo. The residue was purified on silica gel (40% to 100% EtOAc in hexanes) to give the product (117 mg, 90%) as a light yellow heavy oil. MS 392 (MH+).
Reaction SMILES: [F:1][C:2](F)([CH2:12][CH:13](I)[Si](C)(C)C)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=O.[NH3:20]>O1CCCC1>[F:1][C:2]1[CH:12]=[CH:13][NH:20][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11]
Reactant: Cc1ccccc1C(=O)C(F)(F)CC(I)[Si](C)(C)C
Reactant: N
Solvent: C1CCOC1
Product: Cc1ccccc1-c1[nH]ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
To a solution (20 mL) of 2,2-difluoro-4-iodo-1-(2-methylphenyl)-4-trimethylsilylbutan-1-one (2.5 g) in tetrahydrofuran was added 28% aqueous ammonia solution (6 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (15 mL) and water (8 mL), and potassium fluoride (0.75 g) was added. The reaction mixture was stirred at 60° C. for 3 hr, and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=20:1) to give the title compound as a pale-yellow oil (yield 0.87 g, 78%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][C:23]1([CH2:28][NH2:29])[CH2:27][CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>C(#N)C>[NH2:29][CH2:28][C:23]1([CH3:22])[CH2:27][CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:17])[C:10]=2[F:16])[CH2:24]1
Reactant: CC1(CN)CCNC1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(C)(CN)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 0.60 g (2.02 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.28 g (2.45 mmol) of 3-methyl-3-pyrrolidinemethanamine, 0.61 g (6.06 mmol) of triethylamine, and 20 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight. The precipitate was filtered, washed with ether, and dried to give 0.61 g of the title compound, mp 182°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:29]3[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=3[NH:27][C:26](=[O:35])[C:10]3([CH2:15][CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12][CH2:11]3)[N:9]=2)=[CH:4][CH:3]=1.Br>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]2[NH:27][C:26](=[O:35])[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:29]=2[CH:30]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)N=C(c1ccc(Cl)cc1)c1cc(Cl)ccc1NC2=O
Agent: Br
Product: O=C1Nc2ccc(Cl)cc2C(c2ccc(Cl)cc2)=NC12CCNCC2

Procedure:
8.8 g (0.017 mole) of 5-(4-chlorophenyl)-7-chloro-1'-benzyloxycarbonyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one are suspended in 150 ml of petroleum either (boiling range: 60°-80° C.), and 10 ml of 38 percent strength HBr/glacial acetic acid solution are added at 20° C., with stirring. The reaction mixture is stirred at room temperature for 6 hours and the crystalline product is filtered off with suction and rinsed with petroleum ether. The product is dissolved in water and the aqueous solution is shaken with diethyl ether and rendered alkaline with concentrated aqueous ammonia solution. The base which separates out is taken up in methylene chloride and the organic phase is dried over Na2SO4 and filtered. After evaporating off the solvent, the base is obtained in form of pale yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([S:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.Cl[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([S:22][CH2:23][CH2:24][NH:25][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NCCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NCCSc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1

Procedure:
6-[(2-{[7-(2,4-Dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]thio}ethyl)amino]nicotinonitrile (Example 88) is prepared in analogy to Example 82 from Example 47A (200 mg, 0.4 mmol), 2-chloro-5-cyanopyridine (75 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.8 ml, 4 mmol). 92 mg (47% of theory) of product are obtained as solid after purification by preparative RP-HPLC (gradient of eluent: water:acetonitrile 90:10 to 10:90).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:34](O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: Fc1cc(CO[C@H]2CCN(Cc3ccccc3)C[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1

Procedure:
The compound (28.8 mg) obtained in Example 26 and benzyl alcohol (12.4 μl) were reacted and treated in the same manner as in the method described in Example 54 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5](I)=[CH:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C.[Cu](I)I.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>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:6][CH:7]=1
Reactant: N#Cc1nc(I)ccc1N
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1ccc(N)c(C#N)n1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 9, using 3.8 grams (0.015 mole) of 3-amino-2-cyano-6-iodopyridine (prepared in Step A of Example 10), 2.1 grams (0.021 mole) of trimethylsilylacetylene, 10.6 mL of triethylamine, 0.13 gram of copper iodide, and 0.29 gram of bis(triphenylphosphine)palladium(II) chloride in 50 mL of acetonitrile, yielding 3-amino-2-cyano-6-(trimethylsilylethynyl)pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:26]([N:33]1[CH:41]=[C:40]2[C:35]([CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:39]2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]2=[C:8]([C:37]3[CH:38]=[CH:39][C:40]4[C:35]([CH:36]=3)=[N:34][N:33]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:41]=4)[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2cc(Br)c3c(N)ncnn23)C1
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: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 70.5 %

Procedure:
To a stirred, degassed mixture tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxypiperidine-1-carboxylate (292 mg, 0.71 mmol), Intermediate C (355 mg, 1.06 mmol), Na2CO3 (225 mg, 2.13 mmol) and H2O (1 mL) in DMF (6 mL) was added tetrakis(triphenylphosphine)palladium(0) (82 mg, 0.071 mmol). The reaction was heated (110° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (1×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified via ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 270 mg (71%) of the desired product, which contained trace impurities. ES-MS m/z 540.30 [M+H]+, HPLC RT (min) 2.91.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[F:25][CH2:26][CH:27]1[CH2:29][O:28]1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][N:23]([CH2:29][CH:27]([OH:28])[CH2:26][F:25])[CH:24]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: FCC1CO1
Reactant: O=C(NCC1(O)CCCCCC1)c1cc(-c2c[nH]cn2)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC1(O)CCCCCC1)c1cc(-c2cn(CC(O)CF)cn2)ccc1Cl
Yield: 87.6 %

Procedure:
A solution of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(1H-imidazol-4-yl)-benzamide (5 mg, 0.014 mmol) and 2-fluoromethyl-oxirane (0.06 mL, 0.086 mmol) in N,N-dimethylformamide (0.2 mL) was heated at 65° C. in a sealed tube for 20 h. The mixture was diluted with ethyl acetate and washed with water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (5.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:48])[CH2:39][C:40]1[CH:45]=[C:44](Br)[CH:43]=[CH:42][C:41]=1[F:47])[CH3:36]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:35]([O:37][C:38](=[O:48])[CH2:39][C:40]1[CH:45]=[C:44]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)[CH:43]=[CH:42][C:41]=1[F:47])[CH3:36]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1cc(Br)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)Cc1cc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)ccc1F

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, (5-bromo-2-fluoro-phenyl)-acetic acid ethyl ester, and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) were reacted to provide (4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-4-fluoro-biphenyl-3-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.