Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]1=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:24]([O:26]C=O)C>C(COC)OC>[CH:24]([CH:17]([CH2:16][C:13]1[CH:14]=[CH:15][N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:11](=[O:23])[CH:12]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:26]
Reactant: CCOC(=O)CCc1ccn(Cc2ccccc2)c(=O)c1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccn(Cc2ccccc2)c(=O)c1
Temperature: 0 °C
Yield: 67.7 %

Procedure:
To a cooled (0° C.), stirred suspension of 50% sodium hydride in oil (6.37 g) in dimethoxyethane (80 ml) was added dropwise over 25 minutes a mixture of ethyl β-(N-benzyl-2-oxo-4-pyridyl)propionate (30.29 g) and ethylformate (11.80 g), whilst maintaining the reaction temperature between 5°-8° C. The reaction mixture was allowed to warm slowly to room temperature overnight and then was poured on to ice. A brown solution formed which was extracted successively with petroleum ether (40°-60° C.) (60 ml) and diethyl ether (70 ml). The combined organic extracts were washed with water. The combined aqueous layer and aqueous washings were taken to pH 5 with glacial acetic acid. The solution was cooled whereupon a solid appeared which was collected by filtration, washed with water, washed with ethyl acetate and dried in vacuo to yield ethyl α-formyl-β-(N-benzyl-2-oxo-4-pyridyl)propionate (22.52 g), m.p. 140°-143° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:42][OH:43]>>[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:42][O:43][C:5]1[N:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CS(=O)(=O)c1nc(OC2CCCCC2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: Fc1ccc(COc2nc(OC3CCCCC3)c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(cyclohexyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (LRf product) (Example 52, Step A), (24 mg, 0.045 mmol) was reacted with 1 equivalent each of n-butyl lithium and 3,4-difluorobenzyl alcohol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 93/7 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=577 (M++1); Rt=5.34 min; 1H-NMR 500 MHz (CDCl3): 1.28-1.40 (m, 3H), 1.40-1.55 (m, 2M), 1.50-1.60 (m, 2H), 1.60-1.70 (m, 2H), 1.8-1.90 (m, 2H), 5.26 (m, J=4 Hz, 1H), 5.40 (s, 2H), 7.03 (d, J=8 Hz, 2H), 7.05 (d, J=1 Hz), 7.15-7.27 (m, 5H), 7.34 (d over multiplet, J=2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:31][C:30]=1[Cl:29]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1Cl

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=585.9 [M+H+].
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26](B(O)O)[CH:25]=1>>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:26]5[CH:25]=[N:24][C:33]6[C:28]([CH:27]=5)=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: OB(O)c1cnc2ccccc2c1
Product: c1ccc2ncc(-c3ccc4cnc(Nc5ccc(N6CCOCC6)cc5)nn34)cc2c1

Procedure:
(4-Morpholin-4-yl-phenyl)-(7-quinolin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 3-quinolineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (21 mg, 17%). m.p.=decomposed at 268° C.; LCMS (m/e) 423 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.40 (s, 1H), 9.30 (s, 1H), 8.77 (s, 1H), 8.14 (d, 1H, J=8.7 Hz), 7.85 (d, 1H, J=7.7 Hz), 7.77-7.68 (m, 2H), 7.63-7.55 (m, 2H), 7.24-7.19 (m, 1H), 6.96 (d, 2H, J=7.6 Hz), 6.93-6.86 (m, 1H), 6.70 (s, 1H), 3.95-3.87 (m, 4H), 3.22-3.14 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:10]2[N:11]=[N:12][C:8]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=3)=[N:9]2)=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Brc1cncc(-c2nn[nH]n2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2nnc(-c3cncc(Br)c3)n2)cc1

Procedure:
The tetrazole (27.3 g, 104 mmol) from Step (a) was treated with 4-bromomethyl-benzoic acid tert-butyl ester (31.0 g, 114 mmol) and cesium carbonate (74.3 g, 228 mmol) in dimethylformamide (400 mL) at room temperature for 5.5 hours. The solvent was evaporated in vacuo and the residue passed through a pad of silica gel eluting with CH2Cl2:THF 19:1, to give a 9:1 mixture of regioisomers (40.07 g, 93%). 1H NMR (DMSO-d6) δ 9.16 (s, 1H), 8.87 (s, 1H), 8.54 (s, 1H), 7.91 (d, J=8 Hz, 2H), 7.51 (d, J=9 Hz, 2H), 6.13 (s, 2H), 1.57 (s, 9H).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:49])=[C:11]([CH:17]([C:19]2[N:23]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]3[CH:43]=[C:44]([CH3:48])[C:45]([CH3:47])=[CH:46][C:21]=3[N:20]=2)[OH:18])[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:47][C:45]1[C:44]([CH3:48])=[CH:43][C:22]2[N:23]([C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]([CH:17]([OH:18])[C:11]3[C:10]([F:49])=[C:9]([OH:8])[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=3)=[N:20][C:21]=2[CH:46]=1
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(O)c(F)c(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.7 %

Procedure:
To a solution of Intermediate 415.2 (115 mg, 0.171 mmol) in 2 mL THF at rt, was added TBAF (1 M in THF, 171 μL, 0.171 mmol). The mixture was stirred at rt for 20 min, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 80% EtOAc/hexanes gradient) to afford 34 mg of 3-((5,6-dimethyl-1-trityl-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-ethyl-2-fluorophenol as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1>>[CH3:19][CH:20]1[NH:21][CH2:22][CH2:23][N:24]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:25]1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Reactant: CC1CNCCN1
Product: CC1CN(c2nccnc2OCCOc2ccc(Cl)cc2)CCN1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) and 2-methylpiperazine (256 mg, 2.56 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 143 mg (77%) of the title product. HRMS m/z calcd for C17H21ClN4O2 (M)+ 348.1353, found 348.1370. Anal. (C17H21ClN4O2) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:19])=[N-]>>[CH3:19][O:15][C:14](=[O:16])[CH2:13][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH3:12]
Reactant: C=[N+]=[N-]
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
2 Parts of N-p-chlorobenzenesulfonyl-sarcosine is added to a diazomethane-ethereal solution. After the generation of nitrogen has ceased, the precipitated reaction product is collected by filtration to obtain 1.2 parts of N-p-chlorobenzenesulfonyl-sarcosine methyl ester, m.p. 80°-80.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1

Procedure:
A mixture of 7-benzyloxy-6-cyano-1,4-dihydroquinolin-4-one (3.5 g), thionyl chloride (50 ml) and DMF (10 drops) was heated at reflux for 3 hours. The volatiles were removed by evaporation and the residue was partitioned between water and methylene chloride. A saturated solution of sodium hydrogen carbonate was added until the aqueous phase became alkaline. The aqueous phase was extracted with methylene chloride, the organic phases were combined, washed with water and dried by passing through phase separating paper. Removal of the solvent by evaporation gave a solid which was triturated with ether (50 ml) and collected by filtration. The orange solid obtained was dried in a vacuum oven to give 7-benzyloxy-4-chloro-6-cyanoquinoline (2.28 g, 36% over the last two steps).
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13]CC)=[O:12])[NH:8][C:9]=1[CH3:10])#[N:4]>CO>[C:3]([C:5]1[CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8][C:9]=1[CH3:10])#[N:4]
Reactant: CCOC(=O)c1cc(C#N)c(C)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(C(=O)O)cc1C#N
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide (2 N, 2 ml) was warmed to 40° C. and a solution of ethyl 4-cyano-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 14, 0.16 g) in 2 ml of MeOH was added. The reaction temperature was gradually increased to 90° C. and the reaction was stirred at that temperature for 2 hours. Then MeOH was removed and the remaining aqueous solution was cooled to 0° C. and acidified with 3 M HCl (pH ˜2). The acidic solution was extracted with EtOAc, the combined organic extracts were dried over magnesium sulfate and concentrated to give brown solid (0.07 g, crude).
Reaction SMILES: [Si:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:36])=[C:23]([S:25]([NH:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])(=[O:27])=[O:26])[CH:24]=3)=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:37]N1C(=O)CCC1=O>O1CCCC1.C(OCC)C>[Br:37][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:36])=[C:23]([S:25]([NH:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])(=[O:27])=[O:26])[CH:24]=3)=[O:18])=[CH:13][CH:12]=2)[N:8]([Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3ccn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Reaction time: 6 h

Procedure:
A solution of 1.7 g of 5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide in tetrahydrofuran (110 mL) at −78° C. is treated with 0.564 g of N-bromosuccinimide. After 6 h at −78° C. the temperature is allowed to reach room temperature. The reaction mixture is taken up in diethyl ether, washed with water and dried (magnesium sulfate). The solvent is evaporated and the residue is triturated under sonication with diisopropylether to give 5-[3-bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamide as a tan powder. MS (m/z): 643 (M+1); Rf 0.90 (95:5 methylene chloride/methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[F:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[N:17]=[CH:16][C:15]([C:2]2[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: O=C(O)c1ncc(Br)cn1
Product: O=C(O)c1ncc(-c2ccc(F)nc2)cn1

Procedure:
Conducting the operations similar to those of Production Example 14 using 5-bromopyrimidine-2-carboxylic acid and 6-fluoro-3-pyridineboronic acid, the title compound was obtained as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][CH:3]=1.[C:9](=O)([O-])[O-].[Cs+].[Cs+].CI>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH3:9])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc(Br)c[nH]1
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4.38 g of the product from Step A in DMP was added 81 g of cesium carbonate and 30 mL of methyl iodide. The mixture was stirred at ambient temperature overnight, diluted with ethyl acetate, extracted sequentially with two portions of saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, and concentrated. Purification by HPLC (silica gel, 60% ethyl acetate/hexane) gave the title compound. 1H NMR (500 MHz, CDCl3) δ 7.46 (d, 1H, J=2.7 Hz), 7.38 (dd, 1H, J=2.7, 9.8 Hz), 6.52 (d, 1H, J=9.8 Hz), 3.55 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[N:22][OH:23])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([O:20][CH3:21])[CH:4]=1.[CH3:24][O:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33](O)=O)[CH:30]=[CH:29][C:28]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42]>>[CH3:21][O:20][C:5]1[CH:4]=[C:3]([C:2]2[N:1]=[C:33]([C:31]3[CH:30]=[CH:29][C:28]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[C:27]([CH2:26][O:25][CH3:24])[CH:32]=3)[O:23][N:22]=2)[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COc1cc(C(N)=NO)ccc1CN(C)CC(=O)OC(C)(C)C
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)c(OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following the procedure 7, starting from Intermediate 44 and Intermediate 3. It was isolated as a colorless gum. 1H NMR (CDCl3, 400 MHz) δ 8.43 (1H, s), 8.18 (1H, dd, J=7.9, 1.9 Hz), 7.80 (1H, dd, J=7.7, 1.5 Hz), 7.68 (1H, d, J=1.5 Hz), 7.55 (1H, d, J=7.8 Hz), 7.35-7.24 (4H, m), 7.13 (1H, d, J=7.4 Hz), 4.23 (2H, s), 3.95 (3H, s), 3.81 (2H, s), 3.33 (3H, s), 3.24 (2H, s), 2.44 (3H, s), 2.08 (3H, s), 1.49 (9H, s).
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3.[CH3:24]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:24][C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3
Reactant: CB1OB(C)OB(C)O1
Reactant: O=c1c2cc(-c3ccccc3)cnc2ccc2cccc(Br)c12
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+]
Product: Cc1cccc2ccc3ncc(-c4ccccc4)cc3c(=O)c12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10 mg, 0.027 mmol), trimethylboroxine (10 μL, 0.071 mmol), tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.004 mmol), and potassium carbonate (15 mg, 0.108 mmol) were combined in a dry flask. The flask was purged with argon and 0.5 mL of 10% aqueous dioxane were added. Argon was bubbled through the solution for 5 minutes and the solution was stirred and heated to 100° C. After 12 hours, the reaction mixture was filtered through a pad of Celite, eluted with EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 9.11 (d, 1H), 8.54 (d, 1H), 7.80 (d, 2H), 7.54 (m, 5H), 7.48 (m, 2H), 7.26 (d, 2H), 2.56 (s, 3H). LRMS (APCI) calculated for C21H16NO [M+H]+, 298.1; found 298.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccccc1
Product: O=C(Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-ylamine and benzoic acid as starting materials, MS (LC/MS): 379.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[N:9]([CH2:13]/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:4][CH:3]=1>[OH-].[Li+].C1COCC1.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:9]([CH2:13]/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(C(=O)O)c2)cc1
Yield: 92.5 %

Procedure:
A solution of ethyl 3-{(1E)-3-[2-(4-methylbenzoyl)-1H-pyrrol-1-yl]prop-1-enyl}benzoate (1.94 g) in 1N aqueous lithium hydroxide solution (10 ml), THF (10 ml) and methanol (10 ml) were stirred at 50° C. for 3 hours. Methanol and THF in the reaction solution were evaporated under reduced pressure, and the residue was diluted with water, and washed with diethyl ether. The aqueous layer was acidified with diluted hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.66 g, yield for 2 steps: 93%).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6](Cl)(=[O:10])/[CH:7]=[CH:8]/[CH3:9].[CH2:12]([C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]>ClCCl>[CH2:12]([C:16]1[CH:21]([C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9])[CH2:20][CH2:19][CH2:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)CC1=CCCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: C/C=C/C(=O)C1CCCC=C1CC(C)C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
At −70° C., a solution of tin tetrachloride (533 ml, 4.54 mol, 1.4 eq.) in dichloromethane (2.5 l) was treated with crotonyl chloride (350 ml, 90%, 3.24 mol, 1.0 eq.). The resulting solution was stirred for 30 min. and treated within 1.5 h with a solution of 1-isobutylcyclohex-1-ene (448 g, 3.24 mol) in dichloromethane (400 ml). The resulting mixture was stirred for 1 h at −70° C. and poured into ice/H2O. The org. phase was first washed with concentrated NaOH then with H2O, dried (MgSO4), and the solvent evaporated. Short-path Vigreux-distillation (0.15 mbar, bath temperature: 160° C.) of the crude product (592 g) gave a fraction (495 g, boiling range: 90-130° C.) that was redistilled using again a short-path Vigreux-column (0.11 mbar, bath temperature: 160° C.) to give (E)-1-(2-isobutylcyclohex-2-enyl)but-2-en-1-one (202 g, 30%). Boiling point: 120° C. (0.11 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@@:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.[H-].[Na+].[CH2:27]([O:34][C@H:35]1[C@H:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:39]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:38][C@@H:37]2[O:58][C@H:36]12)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:27]([O:34][C@@H:35]1[C@@H:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:39]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[O:38][C@@H:37]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[C@@:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:23][CH3:24])([F:22])[C:9]2=[O:21])[C@@H:36]1[OH:58])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(COC[C@H]2O[C@@H]3O[C@@H]3[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)Nc2cc(C(F)(F)F)ccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N([C@@H]2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-II) (0.200 g, 0.55 mmol) was added anhydrous tetrahydrofuran (3 mL) and 95% sodium hydride (0.018 g, 0.7 mmol). The yellow solution was allowed to stir at room temperature for 30 minutes. 1,2-Anhydro-3,4,6-tri-O-benzyl-α-D-glucopyranose (prepared by the method of Halcomb and Danishefsky J. Am. Chem. Soc. 1989, 111, 6661) (0.480 g, 1.1 mmol) was then dissolved in anhydrous tetrahydrofuran (2.5 mL) and added dropwise to the reaction mixture over 15 minutes. The reaction was allowed to stir at reflux overnight. Once complete, the reaction was cooled and then poured into saturated sodium bicarbonate. The solution was extracted with ethyl acetate (3×). The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The crude mixture was purified via flash chromatography (silica gel, 30% ethyl acetate in hexanes). The title product was obtained as a yellow oil (0.287 g, 65%). 1H NMR (CDCl3, 400 MHz): δ 7.79 (dd, 1H, J=1.8 Hz, 0.68 Hz), 7.45 (s, 1H), 7.39-7.20 (m, 18H), 6.69 (dd, 1H, J=7.6 Hz, 1.1 Hz), 5.43 (d, 1H, J=9.5 Hz), 4.93 (m, 3H), 4.67 (m, 1H), 4.55 (dd, 2H, J=12.3 Hz, 5.7 Hz), 4.3 (ddd, 1H, J=4.9 Hz, 4.2 Hz), 3.87 (d, 1H, J=9.3 Hz), 3.79-3.70 (m, 4H), 3.42 (s, 3H), 2.54 (d, 1H, J=4.3 Hz).