Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:16]=1[CH3:44])(=O)C.Cl.[Cl:46][CH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[ClH:46].[CH3:23][O:22][C:19]1[C:18]([O:24][CH3:25])=[C:17]([OH:26])[C:16]([CH3:44])=[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[C:20]=1[O:21][CH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1
Reactant: COc1c(O)c(CCCCCCCCCCOC(C)=O)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(O)c(C)c(CCCCCCCCCCO)c(OCc2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
A mixture of 6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol (3.70 g) obtained in Example B-1, 4-chloromethylpyridine hydrochloride (1.96 g), potassium carbonate (5.00 g) and dimethylformamide (30 ml) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (30 ml). Tetrabutylammonium fluoride trihydrate (1 g) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. Methanol (50 ml) and 1N sodium hydroxide solution (10 ml) were added to the residue, and the mixture was stirred at room temperature for 16 hours. After concentration, the residue was subjected to column chromatography on silica gel and eluted with ethyl acetate. The desired fraction was concentrated. The residue was dissolved in ethanol (30 ml), and conc. hydrochloric acid (0.7 ml) was added. The crystals obtained after concentration under reduced pressure were separated by filtration and washed with ether to obtain the desired compound (1.2 g).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][C:19]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccc(Br)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc(C#C[Si](C)(C)C)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Under N2, a mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-bromo-N-methylpyridin-2-amine (0.22 g, 0.58 mmol), ethynyltrimethylsilane (0.22 mL, 1.6 mmol), Et3N (0.24 mL, 1.5 mmol), CuI (5.0 mg, 0.03 mmol), PdCl2(PPh3)2 (8.0 mg, 0.01 mmol) and PPh3 (3.0 mg, 0.01 mmol) in DMF (3.0 mL) was stirred at 90° C. for 4 h. The reaction was then cooled to ambient temperature, diluted with water (3 mL), extracted with ethyl acetate (2×10 mL). The combined extracts was washed with brine (2×6 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel to give the titled compound. MS (m/z): 295 (M+H)+.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]([F:13])([F:12])[S:8][CH:9]([CH3:11])[CH3:10])=[N:5][N:6]=1.N([O-])=O.[Na+].[ClH:18]>C(O)(=O)C.O>[Cl:18][C:2]1[S:3][C:4]([C:7]([F:13])([F:12])[S:8][CH:9]([CH3:11])[CH3:10])=[N:5][N:6]=1
Reactant: Cl
Reactant: CC(C)SC(F)(F)c1nnc(N)s1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)SC(F)(F)c1nnc(Cl)s1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
2-Amino-5-[difluoro(isopropylthio)methyl]-1,3,4-thiadiazole (190 g) was dissolved in a mixture of acetic acid (880 ml) and concentrated hydrochloric acid (216.5 ml) at 60° C. A solution of sodium nitrite (171.3 g) in water (300 ml) was then added dropwise over 30 minutes at 65°-70° C. The mixture was stirred at 65° C. for 15 minutes and then allowed to cool. It was then poured onto water (3 L) and extracted with ether, the combined extracts being washed with water, dried (MgSO4) and evaporated to give an orange liquid, which was distilled under vacuum to give 150 g of 2-chloro-5-[difluoro(isopropylthio)methyl]-1,3,4-thiadiazole, bp 75°-77° C. at 0.7 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:21]([OH:23])[CH3:22].Br[CH2:25][N+:26]([O-:28])=[O:27]>C1COCC1.C(#N)C>[NH2:8][C:3]1[C:2]2[CH:7]=[CH:22][C:21](=[O:23])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[S:10][C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: CCO
Reactant: S=C=Nc1ccccc1Cl
Reactant: O=[N+]([O-])CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Nc1c([N+](=O)[O-])sc2c1ccc(=O)n2-c1ccccc1Cl
Temperature: -78 °C
Yield: 41 %

Procedure:
A mixture of (2-chlorophenyl)isothiocyanate (23.1 g, 136 mmol) and acetonitrile (30 ml) was dissolved in dry THF (200 ml) and cooled to −78° C. under a nitrogen atmosphere. A solution of sodium bis(trimethylsilyl)amide in THF (1.0M, 300 ml, 300 mmol) was added over 10 min and the reaction mixture then stirred with warming to r.t. over 2 h. Ethanol (250 ml) and N,N-dimethyluracil (19.4 g, 136 mmol) were added and the mixture heated to reflux for 24 h. The mixture was cooled and concentrated in vacuo to leave a thick brown oil. The residue was dissolved in acetonitrile (200 ml) and bromonitromethane (23.0 g, 164 mmol) added. The mixture was heated to 55° C. for 18 h then cooled to r.t. and diluted with ice/water (800 ml). The resultant solid was isolated by filtration to give a hard black solid. This was then purified by treatment with hot acetone/water (3:1, 300 ml). Cooling and filtration gave the title compound as a pale orange solid (18.0 g, 41%). δH (DMSO-d6) 8.78-8.52 (2H, br s), 8.31 (1H, d, J 9.7 Hz), 7.83-7.50 (4H, m), 6.64 (1H, d, J 9.7 Hz). LCMS (ES+) RT 3.02 minutes, 322 (M+H)+
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:35])[CH:7]=[C:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22](=[O:34])[NH:23][C:24]2[CH:28]=[C:27]([C:29]([O:31]C)=[O:30])[N:26]([CH3:33])[CH:25]=2)=[CH:16]3)=[O:12])[CH:9]=1)=[O:4].[OH-].[Na+]>O.CO>[OH:31][C:29]([C:27]1[N:26]([CH3:33])[CH:25]=[C:24]([NH:23][C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:11]([NH:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:35])[CH:7]=2)=[O:12])=[CH:21][CH:20]=3)=[O:34])[CH:28]=1)=[O:30]
Reactant: COC(=O)c1cc(NC(=O)c2ccc3[nH]c(C(=O)Nc4cc(C(=O)OC)n(C)c4)cc3c2)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(NC(=O)c2ccc3[nH]c(C(=O)Nc4cc(C(=O)O)n(C)c4)cc3c2)cc1C(=O)O
Temperature: 50 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
A solution of 4-({1-[2-(5-methoxycarbonyl-1-methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2carboxylic acid methyl ester 8 (1.04 g, 2.18 mmole) and NaOH (10 mmole) in a mixture of water/MeOH (1/4) (25 ml) was stirred at 50° C. for 6 h and then overnight at ambient temperature. The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in water (50 ml) and acidified with 1M HCl up to pH=3. The precipitate was collected on the filter and washed with water (3×50 ml) and dried over phosphorus pentoxide in dessicator to give 0.85 g (87%) of 4-({1-[2-(5-hydroxycarbonyl-1-methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2-carboxylic acid 9 as white crystalline material. MS: 448.08 (M−H). 1H-NMR (DMSO-d6): δ 11.96 (s, 1H, H-1, indole); 10.45,10.25 (s,s, 1H,1H, —C(═O)NH); 8.30 (m, 1H, H-6, indole); 7.48 (m, 3H, H-7, indole); 7.49,7.46 (d,d, H-3 or H-5, Py1,Py2); 7.39 (s, 1H, H-3, indole); 6.91 (m, 2H, H-3 or H-5, Py1,Py2); 3.84,3.83 (s,s, 6H, NCH3, Py1,Py2).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][C:50]=1[S:59](Cl)(=[O:61])=[O:60].O>ClCCl>[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][C:50]=1[S:59]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[NH:8][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:60])=[O:61]
Reactant: CC(C)(C)OC(=O)[C@@H](CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](CCCOS(=O)(=O)c1ccc2ccccc2c1)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of di-tert-butyl (4S)-4-(3-hydroxypropyl)-N-trityl-L-glutamate (217.5 mg, 0.39 mmol) and triethylamine (160 μL, 1.17 mmol) in dichloromethane (5.0 mL) was added naphthalene-2-sulfonyl chloride (155.4 mg, 0.58 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/n-hexane=12/88) to give the desired product (289 mg, 82%) as a white solid (m.p.=119.3° C.).
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:14])[CH:10]=2)[O:5][CH:4]=1)#N.N([O-])=[O:16].[Na+].[OH2:19]>S(=O)(=O)(O)O>[Br:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:19][CH:1]=[C:3]([C:4]([OH:16])=[O:5])[C:12]2=[O:13]
Reactant: O
Reactant: O=N[O-]
Reactant: N#Cc1coc2ccc(Br)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1coc2ccc(Br)cc2c1=O

Procedure:
26 g of the product of step (b) are stirred overnight in 150 ml of conc. sulphuric acid at room temperature. The mixture is then diluted with 10 ml of water and cooled to 0°. Under stirring, a solution of 15 g of sodium nitrite in 30 ml of water is introduced slowly under the liquid surface, the temperature being maintained by cooling at 15°. After addition, the mixture is warmed at 70° for 1 hour and poured over ice and the precipitate is suction filtered off, suspended in 600 ml of acetone, refluxed, hot-filtered and the filtrate then evaporated on a rotary evaporator. The residue is recrystallised from chloroform, to obtain the heading compound, m.p. 260°-264°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[CH2:21](N)[CH:22]([CH3:24])[CH3:23].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: CC(C)CN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(CC(C)C)c1C

Procedure:
A modification of the method described in Part A of Example 4 was used to treat 2,4-dichloro-5,6-dimethyl-3-nitropyridine (Dellaria et al, U.S. Pat. No. 6,545,016, Example 7, Part A, 50.0 g, 0.194 mol) with triethylamine (47 mL, 0.34 mol) and isobutylamine (27 mL, 0.27 mol) in anhydrous DMF (500 mL). The work-up procedure was as follows. The reaction mixture was poured into hot water (1 L). The resulting mixture was extracted with chloroform (2×800 mL), and the combined extracts were dried over magnesium sulfate, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure to provide 60.78 g of 2-chloro-5,6-dimethyl-4-(2-methylpropyl)-3-nitropyridine as a bright orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)cn1
Yield: 59.8 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 6-methoxypyridin-3-ylboronic acid (66 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-50% ethyl acetate in hexanes) to yield the product (72 mg, 62%). ESI-MS m/z calc. 401.17. found 402.5 (M+1)+. Retention time 1.86 minutes.
Reaction SMILES: C[O:2][C:3](=[O:35])/[C:4](/[NH:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:18][C:17]=1[Cl:33])=[CH:5]/[C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12].O.[OH-].[Li+]>CO.O1CCCC1.O>[Cl:33][C:17]1[CH:18]=[C:19]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])[CH:20]=[CH:21][C:16]=1[C:15]([NH:14]/[C:4](=[CH:5]\[C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12])/[C:3]([OH:35])=[O:2])=[O:34]
Reactant: COC(=O)/C(=C/c1scnc1C(C)C)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ncsc1/C=C(\NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
A mixture of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-(1-methylethyl)thiazol-5-yl]propenoic acid methyl ester (Example 232; 75 mg, 0.146 mmol) and lithium hydroxide monohydrate (24 mg, 0.572 mmol) in methanol/tetrahydrofuran/water (2:2:1; 1.25 mL) was stirred at room temperature for 90 min. A further potion of lithium hydroxide monohydrate (6 mg, 0.143 mmol) was added and the reaction mixture was allowed to stir at room temperature for 65 h. After the reaction mixture was evaporated to dryness, water was added, followed by 1N hydrochloric acid solution (0.72 mL). The resulting colorless precipitate was filtered off, then was purified by reverse phase HPLC and lyophilized to afford (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-(1-methylethyl)thiazol-5-yl]propenoic acid (42 mg, 58% yield) as a colorless powder.
Reaction SMILES: [C:1]([O:9][CH:10]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:30].[NH4+].[OH-]>C(O)(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:30]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:9][C:10]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: O=C(OC(C(=O)c1ccc(F)cc1)c1ccncc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc(-c3ccccc3)oc2-c2ccncc2)cc1
Yield: 7.3 %

Procedure:
A solution of 2-benzoyloxy-1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (0.131 g, 0.391 mmol) and ammonium acetate (0.28 g, 3.63 mmol) in glacial acetic acid (3 mL) was heated at reflux for 1.5 h. After cooling, the mixture was neutralized with conc. NH4OH and the solvent was removed in vacuo to give a yellow oil. Purification by flash chromatography (15-25% EtOAc/Hex) afforded the title compound as a white solid (9.0 mg): ESMS (m/z): 317 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].C([Li])(CC)C.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[OH:8][C:4]1[CH:3]=[C:2]([B:16]([OH:19])[OH:17])[CH:7]=[CH:6][CH:5]=1
Reactant: COB(OC)OC
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: OB(O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
3-Bromophenol (8.65 g, 50 mmol) in dry THF (150 mL) was treated with sodium hydride (60%, 2.4 g, 60 mmol) at r.t. After 1 h, sec-butyllithium (1.3 M, 50 mL, 65 mmoL) was added dropwise to the reaction solution at −78° C. The reaction mixture was then allowed to stir at the same temperature for 30 min prior to addition of trimethyl borate (15 mL). After warming up to r.t. for 2 hrs, the reaction mixture was quenched with water (50 mL), and extracted with dichloromethane (2×100 mL). The combined organic phases were dried over MgSO4 and evaporated to give the title compound as a white solid (4.0 g, 58%), which was used in the Suzuki coupling reactions without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9](Cl)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[CH:15][CH:14]=1.[NH2:22][C:23]1[N:24]=[C:25]([CH3:28])[S:26][CH:27]=1>>[CH3:28][C:25]1[S:26][CH:27]=[C:23]([NH:22][C:9]2[N:10]=[CH:11][C:2]([C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)[N:24]=1
Reactant: Clc1ncc(Br)c2cccnc12
Reactant: Cc1nc(N)cs1
Reactant: OB(O)c1cccnc1
Product: Cc1nc(Nc2ncc(-c3cccnc3)c3cccnc23)cs1

Procedure:
The title compound, MS: m/e=320.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 5-bromo-8-chloro-[1,7]naphthyridine (Example H), 5-pyridineboronic acid and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: [Mg].II.[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17]Br)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23].Cl.C([O:41]CC)C>>[CH2:19]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34](=[O:41])[CH2:17][CH2:16][CH2:15][C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Reactant: CCOCC
Agent: Cl
Agent: II
Agent: [Mg]
Product: CCCCC[C@H]1CC[C@H](CCCC(=O)c2ccc([C@H]3CC[C@H](CCCCC)CC3)cc2)CC1

Procedure:
0.6 g of magnesium shavings was covered with 5 ml of absolute diethyl ether while gassing with nitrogen and then, after the addition of a crystal of iodine, treated with a solution of 7 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide in 50 ml of absolute diethyl ether. After completion of the addition the mixture was heated to reflux for a further 30 minutes. The reaction mixture was then treated with a solution of 2.6 g of 4-(trans-4-pentylcyclohexyl)benzonitrile in 50 ml of absolute diethyl ether and subsequently heated overnight under slight reflux. The cooled reaction mixture was treated with 200 ml of 25% hydrochloric acid and the organic phase was separated. The aqueous phase was extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, 250 ml of concentrated potassium carbonate solution and again with 500 ml of water, dried over magnesium sulfate, filtered and then concentrated. Recrystallization of the residue from ethanol gave 4.1 g of 1-(trans-4-pentylcyclohexyl)-4-[4-(trans-4-pentylcyclohexyl)butanoyl]benzene with m.p. (C-SB) 75° C., SB -N 89° C. and cl.p. (N-I) 116° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O1CCOCC1.O.[OH-].[Na+].Cl>C(OCC)(=O)C>[CH2:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.2 %

Procedure:
To a mixture of N-benzyloxycarbonyl-L-leucine (2.7 g, 10.2 mmol), L-phenylalanine methyl ester hydrochloride (2.2 g, 10.2 mmol), and triethylamine (1.4 mL, 10.2 mmol) in dry THF (150 mL) was added N-ethyl-N'-dimethylaminopropyl-carbodiimide (EDCI) (2.2 g, 11.2 mmol) with stirring at room temperature. After the mixture was stirred overnight at room temperature, it was rotary evaporated. The residue was mixed with ethyl acetate and then washed successively with water, 1N HCl, and brine; the solution was dried (MgSO4) and evaporated to give a white solid residue. Recrystallization (EtOAc-hexane) gave 2.9 g (66%) of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine methyl ester, m.p. 91°-93° C. A mixture of this ester (2.8 g, 6.6 mmol) in 2:1 dioxane-water (150 mL) was treated at 0° C. with 1N NaOH solution (7.3 mmol). After stirring the solution for 2-3 hours at room temperature, it was acidified at 0° C. by the addition of 1N HCl, and then rotary evaporated. The residue was mixed with ethyl acetate and then washed successively with water, 1N HCl, and brine; the solution was dried (MgSO4) and evaporated to give 2.7 g of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine as a white solid, m.p. 120°-122° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:23][C:24]1[C:25]([Cl:33])=[CH:26][C:27]([C:30]([OH:32])=O)=[N:28][CH:29]=1.[F:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH2:39][CH2:38]2.O>CN(C=O)C>[Br:23][C:24]1[C:25]([Cl:33])=[CH:26][C:27]([C:30]([N:40]2[C:41]3[C:37](=[CH:36][C:35]([F:34])=[CH:43][CH:42]=3)[CH2:38][CH2:39]2)=[O:32])=[N:28][CH:29]=1
Reactant: O=C(O)c1cc(Cl)c(Br)cn1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Cl)c(Br)cn1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.75 mg (2.3 mmol) TBTU were added to 0.50 g (2.1 mmol) 5-bromo-4-chloro-pyridine-2-carboxylic acid, 0.29 g (2.1 mmol) 5-fluoro-2,3-dihydro-1H-indole and 0.62 mL (4.4 mmol) TEA in 11 mL DMF and the mixture was stirred overnight at RT. Then the reaction mixture was combined with water, the precipitate formed was suction filtered and dried.