Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[C:19]([N:36]4[CH2:41][CH2:40][CH2:39][CH:38]([C:42]([NH2:44])=[O:43])[CH2:37]4)[C:20]4[CH:25]=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[K+]>CO>[N:7]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[C:19]([N:36]4[CH2:41][CH2:40][CH2:39][CH:38]([C:42]([NH2:44])=[O:43])[CH2:37]4)[C:20]4[CH:25]=[CH:24][NH:23][C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1.[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[C:19]([N:36]4[CH2:41][CH2:40][CH2:39][CH:38]([C:42]([NH2:44])=[O:43])[CH2:37]4)[C:20]4[CH:25]=[CH:24][NH:23][C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(N)=O)C4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(N)=O)C4)c4cc[nH]c4n3)cc2)CC1
Product: NC(=O)C1CCCN(c2nc(Nc3ccc(N4CCNCC4)cc3)nc3[nH]ccc23)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3-carboxamide (12 mg, 0.019 mmol) in MeOH (2 mL), aq. 1N KOH (1 mL) was added. It was stirred at 60° C. for 2 h. After being concentrated in vacuo, the residue was acidified with HOAc (1 mL). The mixture was then purified by HPLC to give 1-(2-(4-(piperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3-carboxamide (2 mg) (MS 421.5 (M+H)) and 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3-carboxamide (8 mg) (MS 463.6 (M+H)); UV 202.6, 274.6 nm).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O1CCOCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccccn1
Solvent: C1COCCO1
Product: Nc1ccccc1C(=O)Nc1ccccn1
Yield: 53.1 %

Procedure:
A mixture of isatoic anhydride 71 (8.7 g, 0.053 mol) and 2-aminopyridine (5 g, 0.06 mol) was heated in dioxane (30 mL) for 6-7 hours. After cooling, the solvent was evaporated in vacuo, the residue treated with water and recrystallized from EtOH/H2O to yield 72 (6 g, 54%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].CC#N.[N:27]1([CH2:33][CH2:34][OH:35])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[I-].[Na+]>Cl.CO>[NH2:23][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:21])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:30]1[CH2:31][CH2:32][N:27]([CH2:33][CH2:34][OH:35])[CH2:28][CH2:29]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: OCCN1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCN3CCN(CCO)CC3)c2n1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
An aliquot (0.2 mL, 0.1 mmol) of a solution of 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine (for example, as prepared for Intermediate 44) in MeCN (prepared by dissolving 410 mg, 1.2 mmol in MeCN (2.4 mL)) was added to 2-(1-piperazinyl)ethanol (commercially available, for example, from Aldrich) (0.1 mmol) in a test tube. DIPEA (50 μl, 3 equivalents) and sodium iodide (5 mg) were added. The reaction mixture was heated to 60° C. for 18 hours in a Radleys greenhouse. The samples were filtered then DMSO (0.3 mL) was added and the solution and purified MDAP on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier. The solvent was evaporated in vacuo using the Genevac to give an intermediate. 2N HCl/MeOH (200 μL) added to each vial, capped and stood at room temperature for 4 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The residue was redissolved in methanol (0.5 mL) and applied to top of an aminopropyl SPE (0.1 g, 3 mL, preconditioned in methanol (1.5 mL)). The cartridge was washed methanol (2×1.5 mL). The solvent was removed to give the title compound (0.0175 g).
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.[CH3:15][O:16]C1C=C(C=CC=1)/C=C/C(Cl)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1/[CH:43]=[CH:44]/[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1/[CH:43]=[CH:44]/[C:45]1[CH:46]=[CH:47][C:48]([O:16][CH3:15])=[CH:49][CH:50]=1
Reactant: COc1cccc(/C=C/C(=O)Cl)c1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Nc1ccccc1Nc1ccccn1
Product: COc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-methoxycinnamoyl chloride (Wiesler, W. T.; Nakanishi, K. J. Am. Chem. Soc., 1990, 112, 5574) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 327.39; mp: 145.5-146.5° C.; 1H-NMR (CDCl3) δ: 8.81-8.76 (1H, m), 8.04-7.96 (1H, m), 7.98 (1H, d, J=16.1 Hz), 7.85-7.79 (1H, m), 7.56-7.41 (5H, m), 7.37-7.22 (3H, m), 7.00 (1H, d, J=16.1 Hz), 6.88 (1H, d, J=8.4 Hz), 3.83 (3H, s).
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:10]([Cl:13])([Cl:12])[Cl:11].C(#N)C.[CH2:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:26]([NH:34][CH:9]([NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:10]([Cl:13])([Cl:12])[Cl:11])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccncc1
Reactant: NCCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NC(NCCc1ccccc1)C(Cl)(Cl)Cl)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
3.7 g of triethylamine was added dropwise to a liquid mixture of 6.0 g of N-(1,2,2,2-tetrachloroethyl)isonicotinamide. 100 ml of acetonitrile and 2.2 g of phenethylamine at a temperature of up to 5° C. The mixture was stirred at room temperature for 2 h and the obtained reaction solution was heated to 50° to 60° C. to carry out the reaction for 3 h, cooled to room temperature and poured in water to precipitate crystals. The crystals were filtered, washed with water, dried and recrystallized from a solvent mixture of n-hexane and ethyl acetate to obtain 3.2 g of N-[1-(phenethylamino)-2,2,2-trichloroethyl]isonicotinamide. m.p. 115° to 117° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][NH:19][CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][N:19]([CH3:20])[C:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 15 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (5.0 g, 23 mmol), O,N-dimethylhydroxylamine hydrochloride (4.51 g, 46.5 mmol), DIPEA (9.00 g, 69.6 mmol), and HATU (17.6 g, 46.5 mmol) in DMF (50 mL) was stirred at 15° C. for 16 h. DMF was removed, the residue was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and evaporated to give the crude product, which was purified by silica gel chromatography eluting with a 0-30% gradient of EtOAc in petroleum ether to afford tert-butyl 3-(N-methoxy-N-methylcarbamoyl)pyrrolidine-1-carboxylate (6.3 g, 90% yield) as pale yellow oil. LCMS (ESI) m/z: 203.2 [M-56+H+].
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=C[CH:35]=1)CCC.C[N:45](C=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.C(OCC)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:33]5[S:32][CH:31]=[CH:35][N:45]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4nccs4)ccc32)n1)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution containing 28 mg of 2-[(S)-1-phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine, 60 μL 2-(tributylstannyl)-thiophene, 0.7 mg Pd(PPh3)4 and 3 mL DMF was stirred under nitrogen at 100° C. for 2 hours. The solution was cooled to room temperature, added to 100 mL of ethyl ether, washed three times with water and then once with brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in methylene chloride to give 11.1 mg of the title compound. RF: 0.5 (5% MeOH in CH2Cl2). 1H NMR (500 MHz, CD3OD): δ 1.59 (d, J=7.1 Hz, 3H), 5.13 (m, 1H), 6.90 (d, J=5.7 Hz, 1H), 7.06 (dd, J=5.0, 3.7 Hz, 1H), 7.22 (t, J=7.3 Hz, 1H), 7.29-7.54 (m, 7H), 7.76 (m, 1H), 7.86 (br s, 1H), 8.31 (br s, J=5.2 Hz, 1H), 8.68 (m, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 398.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][CH:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].C(OCC)(=O)C.O>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][CH:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:36]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.3 g) and rhodium acetate (dimer, 0.075 g) in methylene chloride (15 mL) was added dropwise a solution of ethyl diazoacetate (3.1 mL) in methylene chloride (5 mL), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (2.1 g, 53%).
Reaction SMILES: COC(=O)C1C=CC(NC(=O)CS[CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=NC=1.[H-].[Na+].Br[CH2:36][C:37]([O:39][CH2:40]C)=[O:38].C1C[O:45]CC1>>[CH3:40][O:39][C:37](=[O:38])[CH2:36][O:21][CH:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:14](=[O:45])[N:15]1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COC1C(C)=C(C)C(=O)N1Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 1, Part B (400 mg, 1.6 mmol) in 15 mL THF was cooled to 0° C. under N2. Sodium hydride (58 mg, 2.4 mmol) was added in two portions and stirring continued for 0.5 h. Ethyl bromoacetate (400 mg, 2.4 mmol) in 5 mL THF was added dropwise over 5 min, and stirring continued at room temperature for 24 h. Solvent was evaporated, the mixture was cooled to 0° C., EtOAc was added, followed by cold water. The aqueous phase was washed with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. The title compound was isolated as an oil and used without further purification (450 mg, 83%).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([O:34]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:26]=2)=[CH:21][CH:20]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10].O.C(OCC)(=O)C>CN(C)C=O>[CH2:9]([O:11]/[C:12](=[CH:18]\[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:34])[CH:26]=2)=[CH:23][CH:24]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:10]
Reactant: CCCCCCCN
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
0.31 mL (2.10 mmol) of heptylamine is added to a solution of 0.51 g (1.05 mmol) of ethyl (Z)-2-ethoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate in 15 mL of dimethylformamide. The tube is sealed and rapidly placed in an oil bath preheated to 80° C. The reaction mixture is stirred at 80° C. for 1 hour 30 minutes. After cooling, the reaction is worked up by addition of 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 75/25 heptane/ethyl acetate mixture to give 0.38 g (77%) of ethyl (Z)-2-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in the form of a colorless oil.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:45]([CH3:47])[CH3:46])[C:11]([N:13]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:14][C:15]([NH:17][C@H:18]([C:23]([C:25]1[O:26][CH:27]=[C:28](C2C(Cl)=CC=CC=2Cl)[N:29]=1)=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](N[C@@H](C(C)C)C(N(CC(O)=O)CC1C=CC=CC=1)=O)(=O)[C:49]1C=CC=CC=1.C(OC(=O)C[C@H](NC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=CC=1)C(C1OC=C([C:90]2[C:95]([Cl:96])=[CH:94][CH:93]=[CH:92][C:91]=2[Cl:97])N=1)O)(C)(C)C>>[C:1]([NH:9][C@@H:10]([CH:45]([CH3:47])[CH3:46])[C:11]([N:13]([CH:38]1[CH2:39][C:40]2[C:49](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:48]1)[CH2:14][C:15]([NH:17][C@H:18]([C:23]([C:25]1[O:26][CH:27]=[C:28]([C:93]2[CH:94]=[C:95]([Cl:96])[CH:90]=[C:91]([Cl:97])[CH:92]=2)[N:29]=1)=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc(-c2cc(Cl)cc(Cl)c2)co1)C1Cc2ccccc2C1

Procedure:
Compound 727 was prepared by a method similar to the method use to prepare compound 710, except compound 704 is replaced with compound 724 in the preparation of compound 708: 1H NMR (500 MHz, CD3OD) δ 8.73 (d), 8.38-8.21 (m), 8.20-8.11 (m), 7.81-7.72 (m), 7.50-7.32 (m), 7.14-6.93 (m), 5.52-5.40 (m), 5.22-5.13 (m), 5.08 (m), 4.96 (d), 4.56 (d), 4.48-4.37 (m), 4.21-4.10 (m), 3.98 (t), 3.82 (d), 3.26-3.11 (m), 3.10-2.88 (m), 2.25-2.12 (m), 1.04-0.83 (m). ##STR106##
Reaction SMILES: N1CCCCC1.[CH2:7]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:7]([O:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])=[CH:16][C:15]=1[O:22][CH3:23])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: C#CCCCCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C#CCCCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 73.4 %

Procedure:
Piperidine (0.30 mL, 3.0 mmol) was added to a suspension of 4-(hex-5-ynyloxy)-3-methoxybenzaldehyde (0.70 g, 3.0 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.61 g, 2.7 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-(Hex-5-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.78 g, 73%) as a yellow crystalline solid; mp 148-150° C.; δH (400 MHz, DMSO-d6) 1.59 (p, J=7.6 Hz, 2H, CH2), 1.81 (p, J=7.6 Hz, 2H, CH2), 2.24 (dt, J=7.6, 2.4 Hz, 2H, CH2CCH), 2.78 (t, J=2.4 Hz, 1H, CCH), 3.83 (s, 3H, OCH3), 4.01 (t, J=7.6 Hz, 2H, OCH2), 6.77 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.37 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 17.4, 24.6, 27.8, 55.7, 67.6, 71.4, 84.3, 110.7, 112.6, 116.6, 119.8, 120.3, 122.6, 122.7, 127.2, 131.1, 134.0, 141.1, 141.6, 149.1, 150.0, 164.2, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1649; vmax 755, 1237, 1508, 1609, 1669, 2944, 3424, 3567 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>C1COCC1>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Br)cnc1NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cnc1N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (5-bromo-3-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (409 mg) in THF (20 mL) was added sodium hydride (68 mg) and the reaction was stirred at room temperature for 20 min. Then, iodomethane (0.11 mL) was added and the reaction was stirred at room temperature for 16 h. The reaction was quenched with water (30 mL) and extracted into ethylacetate (2×20 mL). The organic layers were washed with brine (2×40 mL), dried (MgSO4) and reduced in vacuo to give (5-bromo-3-methyl-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: NC1C=CC=CC=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:25])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:10][CH:9]=1.Cl.[N:27]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C:37]1([CH3:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O>[C:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:25])[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[CH:10][CH:9]=1)#[N:27]
Reactant: O=N[O-]
Reactant: Cc1ccccc1
Reactant: Nc1ccccc1-c1ccc(C(O)C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccccc1-c1ccc(C(O)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 29.4 g. (0.1 moles) of benzyl 2'-amino-4-biphenylylglycolate in 35 ml. of 28% hydrochloric acid and 100 ml. of cracked ice to maintain the temperature at 0°C is added a solution of 7.1 g (0.102 moles) of sodium nitrite in 20 ml. of water. The reaction mixture is then neutralized with sodium carbonate. This diazonium mixture is added to a cuprous cyanide solution (prepared from 31.5 g. of copper sulfate and 16.2 of sodium cyanide in 75 ml. of water). 250 ml. of toluene is also added and the mixture is stirred for 1/2 hour. The reaction is then allowed to stir an additional 2 hours while warming gradually to 50°C. This is then cooled and the toluene separated, dried over sodium sulfate and evaporated to dryness to obtain benzyl 2'-cyano-4-biphenylylglycolate.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]([O:8][CH2:9][CH3:10])=[CH2:7].P([O-])([O-])([O-])=O.C(OCC)(=O)C>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:6]([O:8][CH:9]([S:1][CH2:2][C:3]([OH:5])=[O:4])[CH3:10])[CH3:7]
Reactant: O=C(O)CS
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(C)SCC(=O)O
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of mercaptoacetic acid (17.4 mL, 250 mmol) in 125 mL of dichloromethane containing p-toluenesulfonic acid monohydrate (0.24 g, 1.26 mmol) was cooled to -18° to -25° C. with stirring. Ethyl vinyl ether (23.9 mL, 250 mmol) in 125 mL of dichloromethane was added dropwise to the cold solution over a period of 90 minutes. The stirring was continued for an additional 30 minutes with the temperature maintained in the -18° to -25° C. range. Then 200 mL of pH=7 phosphate buffer was added, and the reaction mixture was allowed to warm with stirring for 10 to 15 minutes. The mixture was then poured into a flask containing 900 mL of ethyl acetate and 200 mL of water. Layers were separated and the aqueous portion extracted twice with ethyl acetate. The organic layers were combined, washed with brine and dried (MgSO4). Removal of the solvent left 31.4 g of S-(1-ethoxyethyl)mercaptoacetic acid 41 as a colorless oil (77% yield): 1H NMR (CDCl3) 1.15 (t, J=7.0Hz, 3H), 1.52 (d, J=6.4Hz, 3H), 3.36 (s, 2H), 3.60 (m, 2H), 4.84 (q, J=6.4Hz, 1H), 11.65 (s, 1H). The material was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([NH2:17])[C:8]=1[O:18][CH:19]([CH3:21])[CH3:20].N1C=CC=CC=1>ClCCl>[NH2:6][C:7]1[C:8]([O:18][CH:19]([CH3:21])[CH3:20])=[C:9]([NH:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:14])[CH3:15])[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1c(N)cc(C(C)(C)C)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At ambient temperature 0.20 ml methanesulphonic acid chloride are added dropwise to a solution of 0.48 g 1,3-diamino-5-tert-butyl-2-isopropoxy-benzene and 0.35 ml of pyridine in 5 ml dichloromethane. The solution is stirred for 2 h at ambient temperature and then evaporated down. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (90:10→40:60) as eluant.