Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:48]([O:55][C:56]1[CH:83]=[C:82](I)[CH:81]=[CH:80][C:57]=1[C:58]([NH:60][C:61]1[CH:73]=[C:72]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[CH:71]=[CH:70][C:62]=1[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[O:59])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl.O.C1(C)C=CC=CC=1>[CH2:48]([O:55][C:56]1[CH:83]=[C:82]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])[CH:81]=[CH:80][C:57]=1[C:58]([NH:60][C:61]1[CH:73]=[C:72]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[CH:71]=[CH:70][C:62]=1[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[O:59])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(I)cc1OCc1ccccc1
Reactant: CNCCN(C)C
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CCN(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
N,N,N′-Trimethylethylenediamine (0.12 mL), cesium carbonate (0.35 g), tris(dibenzylideneacetone)dipalladium(0) (3.3 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (8.6 mg), and palladium(II) acetate (1.6 mg) were added to a toluene (3.0 mL) suspension of tert-butyl 2-(2-(benzyloxy)-4-iodobenzamido)-4-phenylbenzoate (0.22 g), followed by heating to reflux under a nitrogen atmosphere for 4 hours and 10 minutes. The reaction mixture was cooled to room temperature, and then N,N,N′-trimethylethylenediamine (0.12 mL), cesium carbonate (0.35 g), tris(dibenzylideneacetone)dipalladium(0) (3.3 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (8.6 mg), and palladium(II) acetate (1.6 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 8 hours. The reaction mixture was cooled to room temperature, and then water and chloroform were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-93% chloroform/methanol] to obtain 0.072 g of tert-butyl 2-(2-(benzyloxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)benzamido)-4-phenylbenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:17])([CH3:16])[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12].C(NC(C)C)(C)C.[Li].[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:17])([CH3:16])[CH2:9][CH:10]([C:11]([F:13])([F:14])[F:12])[O:15][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CC(O)C(F)(F)F)c1ccccc1Br
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a round bottom flask was added 4-(2-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-ol (1.76 g, 5.66 mmol) in 30 mL of dry THF at 0° C. under nitrogen, followed by the dropwise addition of a solution of 2 M lithium diisopropylamine in THF (5.7 mL, 11.4 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, followed by the addition of tert-butyldimethylsilyl chloride (4.26 g, 28.3 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then concentrated, diluted with 500 mL of ethyl acetate, and washed with 100 mL of saturated sodium bicarbonate solution. The organic phase was separated, washed with 100 mL of water, 100 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography. The column was eluted with hexane to afford 875 mg (36%) of [3-(2-bromophenyl)-3-methyl-1-trifluoromethylbutoxy]-tert-butyldimethylsilane.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[Cl:30][C:31]1[CH:37]=[C:36]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:35]=[CH:34][C:32]=1[NH2:33]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]3[CH:3]=[C:2]([NH:33][C:32]4[CH:34]=[CH:35][C:36]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:37][C:31]=4[Cl:30])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(S(C)(=O)=O)cc4Cl)cc3n2C(=O)OC(C)(C)C)cn1

Procedure:
The title compound was prepared from tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (Preparation 10) and 2-chloro-4-(methylsulfonyl)aniline using the method described for Example 35. Purified using preparative TLC eluting with 20% ethyl acetate in CH2Cl2. 1H-NMR (500 MHz, DMSO-d6) 1.46, 1.60 (2×s, 9H each), 3.21 (s, 3H), 6.90 (s, 1H), 7.74 (dd, J=2.2, 8.9 Hz, 1H), 7.91 (d, J=2.30 Hz, 1H), 7.93 (s, 1H), 8.07 (s, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.52 (s, 1H), 8.57 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.O[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1ccn2c(-c3ccc4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
2-(7-(2-Methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (0.030 g, 0.0895 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.0198 g, 0.0984 mmol), triphenylphosphine (0.0352 g, 0.134 mmol) and diethyl azodicarboxylate (0.0211 ml, 0.134 mmol) were combined in anhydrous THF (1 mL). The reaction mixture was stirred overnight at ambient temperature, then diluted with EtOAc and washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography (dichloromethane followed by 40:1 dichloromethane/MeOH) which provided 29.0 mg of the desired product as a brown residue.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]=[S:21]1(=[O:40])[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:39])[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:23][CH2:22]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[O:40]=[S:21]1(=[O:20])[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[C:29]([NH:39][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:3]=3[CH3:19])[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:25][CH2:26]1
Reactant: Nc1cc(N2CCS(=O)(=O)CC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCS(=O)(=O)CC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (61 mg, 0.22 mmol), 5-(1,1-dioxidothiomorpholin-4-yl)-2-morpholin-4-ylpyridin-3-amine (70 mg, 0.22 mmol) and a 4.0M solution of HCl in dioxane (0.05 mL, 0.22 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(5-(1,1-dioxido-4-thiomorpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=3.5, 1.2 Hz), 7.87-7.99 (2H, m), 7.75-7.85 (2H, m), 7.61 (1H, d, J=2.7 Hz), 7.41 (1H, d, J=1.6 Hz), 7.32 (1H, s), 6.76 (1H, s), 6.22 (1H, d, J=2.7 Hz), 3.94 (4H, t, J=4.7 Hz), 3.53-3.67 (4H, m), 3.25 (4H, br. s.), 2.90-3.11 (4H, m), 2.37 (3H, s). Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.COC([CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:24][O:23][C:21]([CH:18]1[N:19]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:20][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17]1)=[O:22]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Chloro phenyl boronic acid (2.0 equiv, 3.68 mmol) and piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.0 equiv, 1.84 mmol) were dissolved in dichloromethane followed by the addition of copper acetate (1.0 equiv), 4 Å molecular sieves and pyridine (2.0 equiv). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (20%). ESI-MS m/z: 354 (M+1), UV retention time: 2.88 min. Reference: Tetrahedron Letters, 2001, 42, 3415–3418.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:11].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH2:10][Br:13])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Br)cccc1CBr
Temperature: 80 °C

Procedure:
2-Bromo-6-methyl-benzoic acid methyl ester (21.8 mmol), and N-bromosuccinimide (21.8 mmol), benzoyl peroxide (1.1 mmol) were combined in 50 mL carbontetrachloride and heated to 80° C. overnight. The resulting precipitate was filtered off, and filtrate concentrated to an oil.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[H-].[Na+].C(OC(=O)CBr)C.C([O:21][C:22](=[O:33])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)C.[OH-].[Na+].Cl>CN(C=O)C.CO.C1COCC1.ClCCl>[N:24]1([CH2:23][C:22]([OH:33])=[O:21])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: CCOC(=O)Cn1ccc2ccccc21
Agent: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)Cn1ccc2ccccc21
Temperature: 70 °C

Procedure:
1H-indole (5.0 g, 42.7 mmol) in anhydrous DMF (10 mL) was added to a suspension of sodium hydride (1.13 g, 46.9 mmol) in anhydrous DMF (20 mL) in a flame dried flask at 0° C. stirred under nitrogen atmosphere. Fifteen minutes after gas evolution had ceased, bromo-acetic acid ethyl ester (5.7 mL, 51.2 mmol) was added and the reaction was heated to 70° C. and stirred under nitrogen. Upon completion (TLC: 50% dichloromethane in heptane), the reaction mixture was quenched with water (50 mL) and extracted with diethyl ether (3×50 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. To a solution of crude indol-1-yl-acetic acid ethyl ester (9.37 g, 46.2 mmol) in methanol (20 mL) and THF (80 mL) was added 6N NaOH solution (25 mL). Upon completion (TLC: 10% methanol in dichloromethane), the mixture was acidified with 6N HCl solution to pH 2, and extracted with ethyl acetate (3×75 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the crude titled compound as a light brown solid. 1H NMR (DMSO-d6, 300 MHz) δ 7.51 (1H, dd, J=8, 1 Hz, Ar—H), 7.35 (1H, dd, J=8, 1 Hz, Ar—H), 7.30 (1H, d, J=3 Hz, Ar—H), 7.09 (1H, td, J=7.5, 1 Hz, Ar—H), 6.99 (1H, td, J=7.5, 1 Hz, Ar—H), 6.41 (1H, dd, J=3, 1 Hz, Ar—H), 4.99 (2H, s, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:12][C:11]3([N:16]([CH3:17])[CH2:15][CH2:14][CH2:13]3)[CH2:10]2)[C:6]([N+:18]([O-])=O)=[CH:5][C:4]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)[CH:25]=[CH:24][N:23]=1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][C:11]3([N:16]([CH3:17])[CH2:15][CH2:14][CH2:13]3)[CH2:12]2)[C:6]([NH2:18])=[CH:5][C:4]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 89.2 %

Procedure:
A mixture of N-[2-methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 163, 404 mg, 0.83 mmol), iron (278 mg, 4.98 mmol), NH4Cl (33.3 mg, 0.62 mmol), ethanol (15 mL) and water (5 mL) was heated at reflux for 1.5 h. After cooling, the mixture was filtered and the residues were washed with 1:10 CH3OH—CH2Cl2 (20 mL). The combined filtrates were concentrated in vacuo onto silica. Purification by FCC, eluting with 1-10% methanolic ammonia in CH2Cl2 gave the title compound (338 mg, 89%) as a yellow solid; 1H NMR: 1.72 (2H, dt), 2.11 (2H, dd), 2.42 (3H, s), 2.66 (2H, t), 3.63 (2H, d), 3.72 (3H, s), 3.87 (2H, d), 4.03 (2H, s), 6.29 (1H, s), 7.06 (1H, td), 7.10 (1H, s), 7.16 (1H, d), 7.35-7.42 (1H, m), 7.93 (1H, s), 8.27 (1H, d), 8.52 (1H, d), 8.74 (1H, s), 8.77 (1H, t); m/z: ES+ MH+ 457.36.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Cl:8])[C@H:3]1[C:9]([OH:11])=[O:10].[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Cl:8])[C@H:3]1[C:9]([O:11][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=1)=[O:10]
Reactant: CC1(C)[C@H](C=C=CCl)[C@H]1C(=O)O
Reactant: OCc1cccc(Oc2ccccc2)c1
Product: CC1(C)[C@H](C=C=CCl)[C@H]1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Example 1, 1.2 g of the acid of Example 27 and 1 g of 3-phenoxy-benzyl alcohol were reacted to obtain 3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3-(3-chloro-1,2-propadienyl)-cyclopropane-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)on1
Yield: 32.5 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (151 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H14) (190 mg, 0.63 mmol) according to the general procedure K. Obtained as an off-white solid (86 mg).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[NH:43][C:44]2[C:45]([N:63]=1)=[CH:46][C:47]1[C:48]([CH3:62])([CH3:61])[C:49](=[O:60])[N:50]([CH2:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C:51]=1[CH:52]=2>CN(C)C=O>[CH3:56][C:55]([CH3:58])([CH3:57])[C:54](=[O:59])[CH2:53][N:50]1[C:51]2[CH:52]=[C:44]3[NH:43][C:42]([NH:41][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:63][C:45]3=[CH:46][C:47]=2[C:48]([CH3:61])([CH3:62])[C:49]1=[O:60]
Reactant: CC(C)(C)C(=O)CN1C(=O)C(C)(C)c2cc3nc(N)[nH]c3cc21
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
A solution of benzoic acid (85.5 mg), TBTU (225 mg; 0.70 mmol) and DIPEA (240 μl) in N,N-dimethylformamide (8 ml) is stirred at RT for 5 min. Afterwards D7 (210 mg) is added and the mixture is stirred at RT for 18 h. After evaporation of the solvent the crude material is purified by RP-MPLC eluted with MeCN/water to give the desired compound (186 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]=[O:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:12]([C@H:26]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[OH:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: Fc1ccc([Mg]Br)cc1
Product: CC1(C)Cc2nc(C3CCCC3)c([C@@H](O)c3ccc(F)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-fluorophenylmagnesium bromide.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][O:4][C:5]1[CH:32]=[CH:31][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)=[CH:14][CH:13]=2)=[O:10])=[CH:7][N:6]=1.[ClH:35]>O1CCOCC1>[ClH:35].[NH:20]1[CH2:21][CH2:22][O:23][C@@H:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:31]=[CH:32][C:5]([O:4][CH2:3][C:2]([F:1])([F:33])[F:34])=[N:6][CH:7]=3)=[CH:17][CH:16]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccc(OCC(F)(F)F)nc3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1ccc(OCC(F)(F)F)nc1
Temperature: 60 °C
Yield: 94 %

Procedure:
To a stirred suspension of (S)-tert-butyl 2-(4-(6-(2,2,2-trifluoroethoxy)nicotinamido)phenyl)morpholine-4-carboxylate (2.11 g) in dioxane (8 ml) was added dropwise a solution of hydrogen chloride in dioxane (16.7 ml, 4 M solution) and the mixture was heated at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with dioxane, and the crystalline product was collected by filtration, washing with Et2O. The product was dried in vacuo to afford (S)—N-(4-(morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamide hydrochloride (1.75 g, 94%) as a light yellow solid. MS (ISP): 382.2 ([M+H]+).
Reaction SMILES: [I:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.Br[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:4]2[C:5]([CH3:7])=[CH:6][C:2]([I:1])=[N:3]2)=[CH:12][CH:13]=1
Reactant: Cc1cc(I)n[nH]1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(I)nn1CCc1ccc(F)cc1
Temperature: 95 °C

Procedure:
A solution of 3-iodo-5-methyl-1H-pyrazole (1.45 g, 6.97 mmol) in dimethyl sulfoxide (10 mL) was treated with 1-(2-bromo-ethyl)-4-fluoro-benzene (1.41 g, 6.97 mmol) and potassium carbonate (2.89 g, 20.91 mmol), and the reaction mixture was heated to 95° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (hexanes:ethyl acetate, 1:1) to provide 1-[2-(4-fluoro-phenyl)-ethyl]-3-iodo-5-methyl-1H-pyrazole as a yellow oil. MS (M+H)+=331.
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=2)[CH2:15][C:14]2[CH:30]=[CH:31][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(CCC(=O)OC)cc2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(CCC(=O)OC)cc2)C(=O)CCC2CCCC2)cc1

Procedure:
The title compound was prepared following the procedure E using of methyl 3-(4-{[(4-dec-1-ynylbenzyl)amino]methyl}phenyl)propanoate and 3-cyclopentylpropanoyl chloride (purification by flash chromatography on SiO2. EtOAc/c-Hex 1/1) as a colorless oil (81%). 1H NMR (CDCl3) δ: 7.35-6.93 (m, 8H), 4.47 (s, 2H), 4.34 (s, 1H), 4.31 (s, 1H), 3.61 and 3.60 (2 s, 3H) 2.88 (q, J=7.9 Hz, 2H), 2.55 (q, J=7.2 Hz, 2H), 2.41-2.20 (m, 4H), 1.78-1.12 (m, 21H), 1.10-0.91 (m, 2H), 0.88-0.75 (m, 3H). M+ (ESI): 544.1. HPLC, Rt: 6.6 min (purity: 93.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].N1CCOCC1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[CH:23][C:24](Cl)=[O:25])[C:20](=[O:27])[O:19]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:24](=[O:25])[CH:23]=[C:21]1[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:22]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(Cl)c(Cl)c2)O1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred suspension of 3,4-dichlorobenzylamine (17.6 mg, 0.1 mmol) and resin bound morpholine (100 mg, 2.5–4.0 mmol/1 g) in CH2Cl2 (2 mL) was added (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (20 mg, 0.11 mmol) and the mixture stirred for 1 h. The mixture filtered and the filtrate concentrated to give the product as a white solid (33 mg, 100% yield). 1H NMR (500 MHz, CDCl3) δ: 7.39 (2H, m), 7.15 (1H, m), 6.60 (1H, s), 5.89 (1H, s), 4.50 (2H, d, J=6.0 Hz), 1.74 (6H, s). MS calcd for C14H14Cl2NO4 [M+H]+: 330.03. found: 330.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:23][C:22]([CH3:24])=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]=1[CH3:29])=O>>[CH3:24][C:22]1[NH:23][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:20]([CH3:29])[C:21]=1[CH2:25][C:26]([OH:28])=[O:27]
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(C)c1CC(=O)O

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid to give the title compound.