Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[S:31][C:32](B2OC(C)(C)C(C)(C)O2)=[C:33]([CH3:35])[N:34]=1>C(O)C.C1(C)C=CC=CC=1.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>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:32]3[S:31][C:30]([CH3:29])=[N:34][C:33]=3[CH3:35])[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3sc(C)nc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
1-Methylethyl((cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol) were dissolved in ethanol (1 mL) and Toluene (1 mL), mixed with potassium carbonate (74.9 mg, 0.542 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroian-2-yl)-1,3-thiazole (78 mg, 0.325 mmol, available from Maybridge), followed by tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) and refluxed under nitrogen at 90° C. for 18.5 hours reaction time. The reaction mixture was partitioned between distilled water (40 mL) and EtOAc (40 mL). The organic and aqueous layers were run off and the latter extracted twice more using EtOAc (2×40 mL). Organic fractions were combined, dried (brine (80 mL) and sodium sulfate), filtered and evaporated to dryness to give a pale white solid (0.123 g). This was purified on a 25+M Biotage silica column, eluting with cyclohexane:EtOAc (1:0 to 1:3). Product-containing fractions were evaporated to dryness to give a clear, colourless solid which was repurified on a 12+M column using the same solvent system. Analysis of the product still showed contamination and it was further purified using MDAP. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (41 mg). LCMS (Method C): Rt=0.76, MH+=402
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nnc(C(F)(F)F)s1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nnc(C(F)(F)F)s3)(CC1)CC2
Yield: 16.4 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (57.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (12.0 mg).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH:27]([NH:29][CH2:30][C:31]1[S:35][C:34]2=[CH:36][N:37]=[CH:38][N:33]2[CH:32]=1)=[O:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:37]3[CH:36]=[C:34]4[S:35][C:31]([CH2:30][NH:29][CH:27]=[O:28])=[CH:32][N+:33]4=[CH:38]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: O=CNCc1cn2cncc2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4sc(CNC=O)c[n+]4c3)[C@H](C)[C@H]12
Yield: 5 %

Procedure:
The same procedure as in Example 1 was repeated except that 97.2 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 73.0 mg of 2-(formylamino)methylimidazo[5,1-b]thiazole were used, thereby obtaining 5.4 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]([CH3:12])[CH3:11])[N:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:11][N:10]([C:4]1[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[N:3]=1)[CH3:12]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)c1cc(C#N)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CN(C)c1cc(C#N)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 68 %

Procedure:
The nitrile 25C (2.0 g, 11.1 mmol), 4-trifluoromethylphenylboronic acid (2.32 g, 1.1 mol eq), palladium acetate (50 mg, 0.02 mol eq), cesium carbonate (7.23 g, 2 mol eq), and XPhos (210 mg, 0.04 mol eq) were mixed, placed under a nitrogen atmosphere and dioxane (10 mL) was added. The mixture was heated at 100° C. for 3 h. After cooling, the mixture was filtered through a celite pad, washed with dioxane (2×20 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (9.5/0.5 petroleum ether/EtOAc) to afford 26E as a pale yellow solid (2.2 g, 68% Yield). 1HNMR (DMSO, 200 MHz) δ 3.13 (s, 6H), 7.12 (s, 1H), 7.58 (s, 1H), 7.82 (d, 2H, J=7.7), 8.30 (d, 2H, J=7.8).
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([O:3]CC1C=CC=CC=1)=[O:2].[Li]CCCC.CCCCCC.[Cl-].[NH4+].[O:32]1[CH2:36][CH2:35][CH2:34]C1>>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[CH2:34][C@H:35]([CH2:36][OH:32])[O:3][C:1]2=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
132 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in the Preparation example 1 was dissolved in 1.3 L of tetrahydrofuran and the solution was cooled to −78° C. 370 ml of n-buthyllitium (n-BuLi, 1.6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84 ml of (R)-(−)-glycidylbuthylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (NH4Cl) solution and extracted with 0.5 L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80 g. Yield 70%.
Reaction SMILES: C([CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18]2[S:19][CH:20]=[C:21]([S:23]([CH3:25])=[O:24])[N:22]=2)[C:10]1=[O:26])[C:6]([O-:8])=[O:7])(C)(C)C.C(Cl)Cl>C(C(O)=O)(F)(F)F>[CH3:25][S:23]([C:21]1[N:22]=[C:18]([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH2:5][C:6]([OH:8])=[O:7])[C:10]2=[O:26])[S:19][CH:20]=1)=[O:24]
Reactant: CS(=O)c1csc(-n2c(=O)n(C(C(=O)[O-])C(C)(C)C)c3ccccc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)c1csc(-n2c(=O)n(CC(=O)O)c3ccccc32)n1

Procedure:
(±)-tert-Butyl {3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step D (100 mg, 0.254 mmol) was dissolved in CF3CO2H (3 mL) and CH2Cl2 (3 mL) and the mixture was stirred at ambient temperature for 3 h, then concentrated in vacuo to give the title compound. MS: m/z=338 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]1=[O:22]
Reactant: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (12 mg, 0.034 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (12 mg, 0.10 mmol). Methyl iodide (0.006 mL, 0.10 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 9 mg (75%) of the title compound as a white solid, upon trituration from diethyl ether/hexanes. mp 175°-177°. FDMS: m/e=348.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[C:17]1[CH2:18][C:19]([CH3:26])([CH3:25])[O:20][C:21]([CH3:24])([CH3:23])[CH:22]=1>CO.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH:17]1[CH2:18][C:19]([CH3:26])([CH3:25])[O:20][C:21]([CH3:24])([CH3:23])[CH2:22]1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2C2=CC(C)(C)OC(C)(C)C2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(O)cc2C2CC(C)(C)OC(C)(C)C2)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)biphenyl-4-ol (124 mg) in methanol (3 mL) was added 20% palladium hydroxide (28 mg) and, under a hydrogen atmosphere, the mixture was stirred at 60° C. for 3 hr. The reaction mixture was filtered, and the solvent of the filtrate was evaporated under reduced pressure to give a crude product of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]([C:14]1[CH:27]=[CH:26][C:25]2[S:24](=[O:29])(=[O:28])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17](C(OC(C)(C)C)=O)[C:16]=2[CH:15]=1)[CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:5])C.[OH-].[Na+]>CO>[O:29]=[S:24]1(=[O:28])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]2[CH:15]=[C:14]([CH:6]([CH2:7][CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[C:4]([OH:5])=[O:3])[CH:27]=[CH:26][C:25]1=2
Reactant: CCOC(=O)C(CC1CCOCC1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)c1ccccc1S2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CC1CCOCC1)c1ccc2c(c1)Nc1ccccc1S2(=O)=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
700 mg of tert-butyl 2-[1-ethoxycarbonyl-2-(tetrahydropyran-4-yl)ethyl]-5,5-dioxo-5H-phenothiazine-10-carboxylate are suspended in 50 ml of methanol, and 10 ml of 2 M NaOH solution are added. The reaction mixture is stirred at 60° C. for one hour. The methanol is removed under reduced pressure and the reaction mixture is adjusted to pH 4 by addition of concentrated hydrochloric acid. The mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then concentrated under reduced pressure. This gives 600 mg of 2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionic acid. C20H21NO5S (387.46), LCMS (ESI): 388.1 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[C:23]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)[CH:22]=2)=[O:19])=[CH:37][C:38]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#Cc1ccc(NC2CC2)nn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CC5)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The intermediate compound 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide was made as for Example 24 (Step 1 to 2) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 10.78 (1H, s), 8.55 (1H, d, J=2.1 Hz), 8.26 (1H, s), 8.22 (1H, s), 8.11 (1H, s), 7.99-8.03 (1H, dd, J=2.1 and 8.1 Hz), 7.76-7.80 (2H, m), 7.49 (1H, s), 2.19 (3H, s). LCMS: m/z [M+H]+ 505.9663.
Reaction SMILES: C1(C([O:9][CH2:10][CH:11]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=O)C=CC=CC=1.[OH-].[Na+]>CO>[OH:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCOC(COC(=O)c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(CO)C1

Procedure:
A solution of 1,1-dimethylethyl 2-{[(phenylcarbonyl)oxy]methyl}-4-morpholinecarboxylate (enantiomer E2) (1.08 g, 3.36 mmol) in methanol (30 mL) with 6N NaOH (5.6 mL. 33.6 mmol) was stirred at room temperature for 2 h. The methanol was removed under reduced pressure and the resulting mixture was partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over sodium sulfate and solvent removed under reduced pressure to give the desired compound. 1H NMR (400 MHz, DMSO-d6) d ppm 1.41 (s, 50H) 3.25-3.37 (m, 22H) 3.39-3.46 (m, 7H) 3.70 (d, J=12.88 Hz, 6H) 3.76-3.88 (m, 10H) 4.78 (t, J=5.68 Hz, 5H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26]12([CH2:36][NH2:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:37][CH2:36][C:26]12[CH2:35][CH:30]3[CH2:29][CH:28]([CH2:34][CH:32]([CH2:31]3)[CH2:33]1)[CH2:27]2)=[O:6]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2.5 h
Yield: 80.5 %

Procedure:
To a solution of 2-chloro-5-nitrobenzoic acid (1.22 g) in N,N-dimethylformamide (1.5 ml) was added carbonyldiimidazole (1.0 g). The resulting reaction mixture was stirred for 2.5 h and then 1-adamantanemethylamine (1.0 g) was added. After 14 h the reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water and brine and then dried over sodium sulphate (Na2SO4). The organic layer was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 3-10% methanol in dichloromethane) to yield the subtitle compound as a yellow solid (1.7 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.N1CCCCC1>CN(C=O)C>[CH2:35]([O:34][C:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:30][CH:29]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and ethyl 4-aminophenylacetate in DMF and subsequent treatment with piperidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](F)[N:30]=1>CCCCCC.C1C=CC=CC=1.O1CCCC1>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[N:30]=1
Reactant: Fc1cccc(F)n1
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(-c3cccc(F)n3)cc2)cc1
Yield: 25.5 %

Procedure:
24.00 g (66.60 mmol) of 4-bromo-4'-octyloxybiphenyl in 500 ml of hexane and 160 ml of benzene are stirred at room temperature with 49 ml (78.70 mmol) of a 1.6-molar n-butyllithium solution in hexane under argon for 18 hours. The reaction mixture is then slowly added dropwise at 0° C. under argon to a solution of 5.5 ml (60 mmol) of 2,6-difluoropyridine in 200 ml of tetrahydrofuran. After a reaction time of 5 hours at 0° C., the reaction mixture is evaporated to dryness, the residue is taken up in toluene, and solid components are filtered off. The filtrate is washed with water, dried over sodium sulfate, filtered and freed from solvent. Recrystallization from 8:2 hexane/ethyl acetate gives 5.77 g of 2-fluoro-6-[4-(4-octyloxyphenyl)phenyl]pyridine. ##STR24##
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5](=[O:21])[C@@H:6]1[CH2:10][C@H:9]([O:11]C=O)[CH2:8][N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>O1CCCC1>[CH3:3][O:4][C:5](=[O:21])[C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15]
Reactant: COC(=O)[C@@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
A solution of 1 N aqueous sodium hydroxide (6 mL) was added to a cold (0†° C.) stirred solution of N-tert-butoxycarbonyl-cis-4-formyloxy-L-proline methyl ester (I, 4.07 g) in tetrahydrofuran (6 mL). After stirring at 0° C. for 3 hr, a solution of 1 N aqueous sodium hydroxide (3 mL) was added and additionally stirred at 0° C. for 30 min. The mixture was evaporated in vacuo. The residue was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=1:5 to 1:1, v/v) to give the title compound (2.77 g) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.35-1.54 (m, 9H), 1.78 (br s, 1H), 2.00-2.15 (m, 1H), 2.27-2.39 (m, 1H), 3.50-3.59 (m, 1H), 3.61-3.71 (m, 1H), 3.63-3.77 (m, 1H), 3.78-3.80 (m, 3H), 4.29 (dd, J=1.5, 9.8 Hz, 1H), and 4.33-4.39 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1>CN(C)C=O>[CH2:3]([O:10][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[N:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 5 g) was added portionwise to a mixture of benzyl alcohol (12.4 g) and dimethylformamide (150 ml) which had been cooled to 0° C. The mixture was allowed to warm to ambient temperature and was stirred for 1 hour. 3,5-Dibromopyridine (25.2 g) was added and the mixture was heated to 60° C. for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and a dilute aqueous potassium carbonate solution. The organic layer was washed with a dilute aqueous hydrochloric acid solution and with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was a red oil which on trituration under petroleum ether (b.p. 60°-80° C.) gave 5-benzyloxy-3-bromopyridine (18.6 g, 67%), m.p. 65°-67° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:4]1[C:3]([C:2]([F:13])([F:14])[F:1])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:12])[CH3:11])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1
Product: CC(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 27.74 %

Procedure:
N-(3-trifluoromethyl-phenyl)-acetamide (2.8 g, 13.7 mmol) was added in small portions to the cold fuming nitric acid (10 mL) taken in a dry round bottom flask at −10° C. The reaction mixture was stirred for another 10 minutes at the same temperature then quenched with water (50 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated to dryness. The obtained residue was purified by column chromatography using 20% ethylacetate in hexane to get the title compound as yellow solid (0.9 g, 27.74%).
Reaction SMILES: C(OC(=O)C[CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:18]=2)=[C:14]([CH3:16])[N:15]=1)=[O:9])C.[CH2:30]([O:32][C:33](=[O:40])[CH2:34][CH2:35]CN=C=O)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:40])[CH2:34][CH2:35][CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:18]=2)=[C:14]([CH3:16])[N:15]=1)=[O:9])[CH3:31]
Reactant: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)c2)s1
Reactant: CCOC(=O)CCCN=C=O
Product: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)c2)s1

Procedure:
The titled compound is prepared by an analogous procedure to 3-{3-[4-Methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-yl]-ureido}-propionic acid ethyl ester (Example 14) by replacing ethyl 3-isocyanatopropionate with 4-isocyanato-butyric acid ethyl ester.
Reaction SMILES: C([C:3]([C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([O:17]S(C(F)(F)F)(=O)=O)=[CH:14]2)=[CH:9][CH:8]=1)([OH:6])CC)C.CCN(CC)CC.CS(C)=O.[C]=O.[CH3:38][OH:39]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CCOCC>[CH3:38][O:39][C:3]([C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][C:13]([OH:17])=[CH:12][CH:11]=2)[CH:16]=1)=[O:6]
Reactant: CO
Reactant: CCC(O)(CC)c1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)c1ccc2ccc(O)cc2c1

Procedure:
Treat a mixture containing trifluoromethanesulfonic acid 7-(1-ethyl-1-hydroxypropyl)naphthalen-2-yl ester (0.41 g, 14.1 mmol), Pd(OAc)2 (0.30 g, 1.38 mmol), bis-(diphenylphosphino)ferrocene (0.705 g, 1.27 mmol), Et3N (10.2 mL, 73.2 mmol), in MeOH (12 mL) and DMSO (18 mL) with carbon monoxide at 100 psi at 80° C. for 4 h. Pour the reaction mixture into ether (300 mL) and wash with brine (5×100 mL). Add EtOAc (250 mL), wash the organic layer with brine, dry over Na2SO4, and filter. Concentrate the filtrate to give the title compound as a tan solid (2.84 g, quant). 1H NMR (400 MHz, CDCl3) δ 3.98 (s, 3H), 7.23-7.29 (m, 2H), 7.78 (t, J=8.3 Hz, 2H), 7.88-7.90 (m, 1H), 8.43 (d, J=0.88 Hz, 1H).