Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])/[C:3](/O)=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=O.[CH2:21]([O:23][C:24](=[O:29])/[CH:25]=[C:26](\[NH2:28])/[CH3:27])[CH3:22]>C(#N)C>[CH2:21]([O:23][C:24](=[O:29])[C:25]1[C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)=[N:28][C:26]=1[CH3:27])[CH3:22]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C
Yield: 48 %

Procedure:
To an acetonitrile (35 ml) solution of (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethoxy-phenyl)-but-2-en-1-one (2.9 g, 10 mmol) was added ethyl-3-aminocrotonate (2.5 g, 19 mmol) under an argon atmosphere. The mixture was heated at reflux for 12 h. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/ethyl acetate) to yield 1.9 g (4.8 mmol, 50%) of the title compound as yellow oil.
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([Si](C)(C)[O:26][C@H:27]1[CH2:31]C[N:29](/[CH:32]=[CH:33]/[NH:34][C:35](=[NH:38])[CH:36]=[CH2:37])[CH2:28]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[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]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([N:29]4[CH2:28][CH:27]([OH:26])[CH2:31]4)=[CH:33][N:34]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: C=CC(=N)N/C=C/N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC(O)C4)cn3)nc2n1C1CCCC1
Yield: 10.6 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (120 mg, 0.411 mmol) and N-{(E)-2-[(S)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-vinyl}-acrylamidine (112 mg, 0.401 mmol), followed by deprotection with 2 mL of TBAF to give 7-cyclopentyl-2-[5-(3-hydroxy-azetidin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (18 mg, 46%). MS (ESI) m/z 422.5 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:28][C:29]1[CH:46]=[CH:45][C:32]([CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:46][CH:45]=3)=[CH:41][CH:40]=2)[C:3]=1[N:22]1[CH2:25][C:24]([F:27])([F:26])[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(F)(F)C2)c1Br
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(F)(F)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
The Pd(Ph3P)4 (43.2 mg, 0.037 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (84 mg, 0.187 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (53.5 mg, 0.206 mmol), and sodium carbonate (139 mg, 1.31 mmol) in dioxane (2 mL) and water (0.15 mL) and stirred in a screw-capped pressure vessel for 4 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(3,3-difluoroazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 60 mg (55%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.29 (d, J=8.1 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.04-6.95 (m, 3H), 5.22 (s, 1H), 5.01-4.95 (m, 1H), 4.23 (t, J=7.0 Hz, 2H), 4.07-4.00 (m, 2H), 3.87-3.80 (m, 2H), 3.06 (t, J=7.0 Hz, 2H), 2.35 (s, 3H), 2.05 (s, 3H), 1.21 (d, J=6.2 Hz, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.12 (s, 9H). UPLC (M+H)=586.4.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:21][CH2:20][C:17]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:18]#[N:19])[CH2:16][CH2:15]1.[BH4-].[Na+]>CO.O>[OH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:21][CH2:20][C:17]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:18]#[N:19])[CH2:16][CH2:15]1
Reactant: N#CC1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Finely-ground 1-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)-methyl]-4-anilino isonipecotonitrile, hydrochloride (1:1) (5.0 g) is slurried in methanol (100 ml) and cooled in ice. To this mixture is added an aqueous solution of sodium borohydride (3.0 g) in water (25 ml). The resulting mixture is stirred for 15 hours at room temperature under nitrogen. Dilution of the reaction mixture mixture with water (200 ml), extraction with methylene chloride, and concentration of the dried organic solution give the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][C:63]=1[O:64][CH3:65]>>[F:57][C:58]1[CH:59]=[C:60]([C:2]2[C:3](=[O:30])[C:4]3[C:9]([C:10]=2[C:11]2[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=2)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][S:25](=[O:28])(=[O:29])[CH2:24][CH2:23]2)[CH:5]=3)[CH:61]=[CH:62][C:63]=1[O:64][CH3:65]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCN4CCS(=O)(=O)CC4)cc3C2=O)cc1F
Yield: 94 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 92 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (94%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:24][CH:25]([O:31][CH:32]([CH3:34])C)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[O:41][CH:42]=[CH:43][CH:44]=1)CCC.[Cl-].[Li+].O1CCOC[CH2:56]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:24][CH:25]([O:31][CH2:32][CH:34]([C:40]2[O:41][CH:42]=[CH:43][CH:44]=2)[CH3:56])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [Cl-]
Agent: [Li+]
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(CNC(=O)OC(C)(C)C)c1)OCC(C)c1ccco1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
334 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-2-isopropoxypropionate was dissolved in 4 ml dioxane. 280 mg of 2-tributylstannylfuran, 75 mg of tetrakistriphenylphosphine palladium and 83 mg of lithium chloride were added thereto, followed by stirring overnight at 80° C. in a nitrogen atmosphere. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography, to give 180 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-2-(2-furyl)propoxypropionate from fractions eluted with hexane-ethyl acetate (7:1).
Reaction SMILES: [CH3:1][OH:2].[C:3]([CH:7]=[C:8]([F:10])[F:9])([F:6])([F:5])[F:4]>C(OOC(C)(C)C)(C)(C)C>[C:3]([CH2:7][C:8]([CH2:1][OH:2])([F:10])[F:9])([F:6])([F:5])[F:4]
Reactant: CO
Reactant: FC(F)=CC(F)(F)F
Agent: CC(C)(C)OOC(C)(C)C
Product: OCC(F)(F)CC(F)(F)F
Yield: 76.5 %

Procedure:
Under nitrogen, into a quartz reactor equipped with a dry-ice condenser was added anhydrous methanol (100 g, 3.10 mol) and di-tertiarybutylperoxide (3.95 g, 0.015 mol). The quartz reactor tube was placed in a Rayonet UV photochemical reactor and HFC 1225, CF3CH═CF2 (57.9 g, 0.438 mol) was added drop-wise via a dry-ice condenser (−78° C.) over a period of ˜5 hours while being irradiated at 254 nm. After complete addition, the reaction mixture was irradiated for additional hour. Then the reaction mixture was concentrated under reduced pressure, the residue (˜65 g) was mixed well with 120 mL aq. Na2SO3 (20%), separated the lower layer, and washed with brine (40 mL). The crude product was then distilled under reduced pressure (24-28 mm Hg) to afford 55 g CF3CH2CF2CH2OH (yield 77% based on HFC 1225).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[N:22]1([C:2]2[CH:19]=[CH:18][C:5]([C:6]([C:8]3[C:9]([C:14]([O:16][CH3:17])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=3)=[O:7])=[CH:4][CH:3]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COC(=O)c1ncccc1C(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1C(=O)c1ccc(-n2ccnc2)cc1
Temperature: 120 °C

Procedure:
A solution of 3-(4-fluorobenzoyl)-2-carbomethoxypyridine (2.37 g, 9.14 mmol) in 30 mL of DMF is added dropwise to a solution of NaH (0.43 g, 10.75 mmol) and imidazole (0.62 g, 9.14 mmol) in 26 mL of DMF. The mixture is heated at 120° C. for 1 day, then allowed to cool, quenched with ice H2O, and extracted with EtOAc (3×50 mL). The combined organic layers are dried (Na2SO4), evaporated, and the residue chromatographed on silica gel (eluting with EtOAc-CH3OH, 9:1) to generate 3-[4-(1H-imidazol-1-yl)benzoyl]-2-carbomethoxypyridine. M.P. 150°-157° C.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[CH3:9][N:8]([CH3:10])[C:5]1[N:4]=[C:3]([O:11][CH3:12])[C:2]([B:13]([OH:18])[OH:14])=[CH:7][N:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1nc(N(C)C)ncc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc(N(C)C)ncc1B(O)O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of 5-bromo-4-methoxy-N,N-dimethylpyrimidin-2-amine (0.300 g, 1.29 mmol) and triisopropyl borate (0.416 mL, 1.81 mmol) in 7 mL of THF at −70° C. was added butyllithium (1.6 m in hexanes, 1.13 mL, 1.81 mmol) dropwise. The reaction stirred for 30 min at −70° C. and was allowed to warm up. At −20° C. ammonium chloride (sat.) was added. The mixture was extracted with ethyl acetate (3X). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 250 mg of crude material, which was purified by column chromatography (5% MeOH in dichloromethane) to give 157 mg of 2-(dimethylamino)-4-methoxypyrimidin-5-ylboronic acid as a white solid. ES+=198.1 (M+H).
Reaction SMILES: C([NH:4][C:5]1[CH:31]=[CH:30][C:8]2[C:9]([CH2:12][CH2:13][C:14]3[N:15]=[C:16]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[O:17][C:18]=3[CH:19]([CH3:21])[CH3:20])=[N:10][O:11][C:7]=2[CH:6]=1)(=O)C.C(=O)([O-])O.[Na+]>Cl>[NH2:4][C:5]1[CH:31]=[CH:30][C:8]2[C:9]([CH2:12][CH2:13][C:14]3[N:15]=[C:16]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[O:17][C:18]=3[CH:19]([CH3:21])[CH3:20])=[N:10][O:11][C:7]=2[CH:6]=1
Reactant: CC(=O)Nc1ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1oc(-c2ccc(Cl)cc2Cl)nc1CCc1noc2cc(N)ccc12
Yield: 94.4 %

Procedure:
The obtained 6-acetamido-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-1,2-benzisoxazole (900 mg, 1.96 mmol) was reacted in 3N hydrochloric acid (45 mL) at 100° C. for 4 hours. The reaction mixture was allowed to room temperature, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saline, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 6-amino-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-1,2-benzisoxazole (770 mg) as brown oil in the residue. The product (770 mg, 1.85 mmol) was'suspended in 25% sulfuric acid (9.3 mL), and cooled with ice. An aqueous sodium nitrite solution (166 mg, 2.41 mmol/1.3 ml) was dropwise added to the suspension for 5 minutes. The resulting solution was stirred for 45 minutes under the same conditions. The reaction mixture was dropwise added to a 75% sulfuric acid (7.4 mL) while refluxing for 5 minutes, and the mixture was refluxed for 4 hours. The reaction mixture was left to get cool, extracted with diethyl ether, washed with a saturated aqueous ammonium chloride solution and saline, and dried over anhydrous sodium sulfate. Diethyl ether was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound (138 mg) as pale yellow oil (yield of the two steps 17%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[Cl:12][C:13]([Cl:23])([Cl:22])[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCCC1.C(O)(=O)CCCCC>C1(C)C=CC=CC=1>[Cl:12][C:13]([Cl:22])([Cl:23])[C:14](=[O:21])[C:15](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(=O)C(Cl)(Cl)Cl
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC(=O)O
Product: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)C(Cl)(Cl)Cl
Yield: 28.9 %

Procedure:
3-Nitrobenzaldehyde (7.55 g, 50 mmoles), ethyl 4,4,4-trichloro-3-oxobutanoate (18.33 g, 59.5 mmoles), piperidine (0.66 ml) and hexanoic acid (0.33 ml) were heated at reflux in toluene (130 ml) for 48 hours using a Dean and Stark apparatus. The mixture was cooled, evaporated to dryness in vacuo and crystallised by trituration with ethyl acetate/petroleum ether (60°-80°). Recrystallisation from 2-propanol gave the sub-title compound (5.3 g) mp 105.5°-7°.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O)cc2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-((2,2-dimethylethyl)dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound I) 50.0 mg (0.095 mmol) in 1.0 ml of THF at room temperature was added 73.2 mg (0.29 ml, 0.29 mmol) of tetrabutylamonium fluoride (1M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4:1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.98 (2H, d, J=8.2 Hz), 7.52 (2H, d, J=8.3 Hz), 7.41-7.20 (5H, m), 6.88 (2H, d, J=8.4 Hz), 5.96 (1H, t, J=4.5 Hz), 4.37 (2H, q, J=7.1 Hz), 2.34 (2H, d, J=4.5 Hz), 1.39 (3H, t, J=7.1 Hz), (6H, s).
Reaction SMILES: [CH:1]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:9]1[C:22]2[C:21]3([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([N:31]=[C:32]=[O:33])[CH2:27][CH2:26]4)[CH2:23][CH:14]([C:15]4[C:20]3=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13]=2[CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH:19]1[C:20]2[C:21]3([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH:7][CH2:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:33])[CH2:27][CH2:26]4)[CH2:23][CH:14]([C:13]4[C:22]3=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCCC1
Reactant: O=C=NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCC1CCCC1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a cold (ice bath) stirred solution of cyclopentylmethyamine (664 mg, 6.70 mmol) in methylene chloride (5 mL) was added [(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidyl]isocyanate hydrochloride (221 mg, 0.67 mmol). After stirring the resulting mixture for 0.5 h, at 0° C., the cooling bath was removed and the reaction was allowed to reach ambient temperature. After stirring for 18 h, the reaction mixture was treated with 1N sodium hydroxide and extracted with methylene chloride (2×50 mL). The combined extracts was washed with 1N sodium hydroxide (2×50 mL) and brine (50 mL), dried (sodium sulfate), and concentrated to give a tan syrup. Chromatography of this material over silica gel (eluant: 98:2 methylene chloride:methanol) affords a white foam. This was triturated with hot ether to provide the title compound as a white solid (101 mg, 35%), mp 197.0°-8.0° C.; MS(CI): 430 (M+H); NMR (300 MHz,DMSO-d6): 1.05-1.35 (m, 4H), 1.38-1.78(m, 8H), 1.89(quintet, 1H, J=7.3 Hz), 2.20-2.36(m, 2H), 2.45(s, 2H), 2.78-2.95(m, 4H), 3.26-3.42(m, submerged, 3H), 4.30(s, 1H), 5.66(d, 1H, J=7.5 Hz), 5.73(t, 1H, J=5.5 Hz), 6.84-6.99(m, 4H), 7.18(d, 2H, J=6.4 Hz), 7.26(d, 2H, J=6.9 Hz).
Reaction SMILES: COC1C=CC(C[N:8]2CCC(NC3C=C(C(F)(F)F)C(C(N)=O)=CN=3)CC2)=CC=1OCCC.Cl.Cl.CO[C:38]([C:40]1[CH:45]=[N:44][C:43]([NH:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[CH:42][N:41]=1)=[O:39].[Cl:53][C:54]1[CH:61]=[CH:60][C:57]([CH:58]=O)=[CH:56][C:55]=1[O:62][CH2:63][CH3:64]>>[Cl:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][N:50]2[CH2:49][CH2:48][CH:47]([NH:46][C:43]3[N:44]=[CH:45][C:40]([C:38]([NH2:8])=[O:39])=[N:41][CH:42]=3)[CH2:52][CH2:51]2)=[CH:56][C:55]=1[O:62][CH2:63][CH3:64]
Reactant: CCOc1cc(C=O)ccc1Cl
Reactant: CCCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)ccc1OC
Reactant: COC(=O)c1cnc(NC2CCNCC2)cn1
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cnc(C(N)=O)cn3)CC2)ccc1Cl

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide (example 197) from 5-(piperidin-4-ylamino)-pyrazine-2-carboxylic acid methyl ester dihydrochloride (intermediate B14) and 4-chloro-3-ethoxy-benzaldehyde (intermediate E2) in a yield of 12.1 mg (21%). MS (ISP): 390.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][N:33]=1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:34][N:33]=1)=[O:31]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cn1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 5-hydroxy-pyridine-2-carboxylic acid methyl ester (commercially available). White solid (82%). MS (Turbo Spray): m/z=526.1 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1)#[N:2].Cl[C:14](=[CH2:17])[C:15]#[N:16]>O>[C:15]([C:14]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Solvent: O
Product: N#Cc1ccc(Cn2cc(C#N)nn2)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 4-cyanobenzyl azide (0.8 g) and 2-chloroacrylonitrile (0.88 g) in water (5 ml) is stirred at about 80° C. for 20 hours. Excess 2-chloroacrylonitrile is distilled off in vacuo, the mixture is cooled to room temperature and the precipitated product is isolated by filtration and washed with water. The product (yield 0.92 g; 88% of theory) of m.p. 93.5-94° C. (recrystallization from ethyl acetate/toluene) is obtained after drying.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=3)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.28 (d, J 6.1, 2H), 4.50 (q, J 7.1, 1H), 7.41 (s, 1H), 7.49 (m, 2H), 7.56 (m, 1H), 7.80 (t, J 7.8, 1H), 7.95 (d, J 7.2, 1H), 8.21 (d, J 8.1, 1H), 8.32 (d, J 6.2, 1H), 8.60 (d, J 6.8, 1H), 8.72 (t, J 5.8, 1H), 9.56 (s, 1H).