Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:21])=[O:1]
Reactant: O=C1Cc2cccc(OCc3ccccc3)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1OCc1ccccc1

Procedure:
A mixture of 2-oxo-7-benzyloxyindoline (2.15 g.), sodium hydroxide (0.84 g.), dioxane (20 ml.) and water (20 ml.) was refluxed under heating for 72 hours with stirring. After cooling, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water and the solution was washed with ethyl acetate. Diethyl ether was added to the solution and adjusted to pH 4 to 5 with 5% sulfuric acid. The diethyl ether layer was separated, washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was crystallized with a mixture of ethyl acetate and n-hexane to give 2-(2-amino-3-benzyloxyphenyl)acetic acid (2.2 g.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]([CH2:28][C:29]#[C:30][CH3:31])([S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[C:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH2:34][C@@H:35]([C:37]1[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=1)[OH:36]>>[C:1]([O:5][C:6](=[O:32])[C:7]([CH2:8][C:9]#[C:10][CH3:11])([S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][CH:24]([NH:33][CH2:34][C@H:35]([OH:36])[C:37]3[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])[CH2:28][C:29]#[C:30][CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 from 0.37 g (0.8 mmol) of Reference Example 27, 2-But-2-ynyl-2-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-hex-4-ynoic acid tert-butyl ester, and 0.24 g (1.0 mmol) of (R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl)-methanesulfonamide, yielding 0.54 g of an off-white solid; m.p. 93-95° C.; MS (ES) m/z 688.2 (MH+); HRMS (ES) Calcd. for C34H46N3O8S2 (MH+): 688.2721, Found: 688.2722.
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH2:38][C@H:39]([N:43]2[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44]2)[C:40]([OH:42])=O)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH2:38][C@H:39]([N:43]2[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44]2)[C:40]([NH:2][OH:1])=[O:42])(=[O:35])=[O:36])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC[C@@H](C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
120 mg (0.9 mmol) of 1-hydroxybenzotriazole and 170 mg (0.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added to a solution of 340 mg (0.7 mmol) of (S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid in 8 ml of dimethylformamide. The reaction medium is stirred for 30 min, and then 120 mg (0.8 mmol) of O-tert-butyldimethysilylhydroxylamine in 3 ml of dimethylformamide are added. The reaction medium is then stirred at ambient temperature for 20 h, and then hydrolyzed with 2 ml of water and 2 ml of a 5% aqueous solution of citric acid. After stirring for 30 min, a saturated aqueous solution of sodium hydrogen carbonate is added to pH=8, and then the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is taken up in dichloromethane, filtered, and then dried under vacuum. 80 mg (23%) of (S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide are obtained in the form of a white solid with a melting point of 150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[CH2:28].CCN(CC)CC>CCOCC.CN(C=O)C.CCOC(C)=O.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>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:5]2[CH:4]=[CH:3][C:2](/[CH:28]=[CH:27]/[C:26]([O:30][CH2:31][CH3:32])=[O:29])=[CH:7][CH:6]=2)=[CH:14][CH:13]=1
Reactant: C=CC(=O)OCC
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 110 °C
Yield: 75.1 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (10.2 g, 0.0255 mol), ethyl acrylate (28 mL, 0.255 mol.), dichlorobis(triphenylphosphine)palladium(II) (0.895 g, 1.28 mmol, 5 mol %), Et3N (17.6 mL, 0.128 mol), and DMF (50 mL). The stirred reaction mixture was heated to 110° C. for 18 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then diluted with Et2O (200 mL). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude product. The crude reaction mixture in DMF was diluted with EtOAc (400 mL), washed with water (2×100 mL), brine (1×100 mL), dried (Na2SO4), filtered, and then concentrated under reduced pressure to afford the crude product as an oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (19:1 to 1:1) as an eluent to give 8.02 g (75%) of compound 15 as a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 0.88 (s, 6H), 0.91 (s, 6H), 1.31 (s, 2H), 1.35 (t, J=7.2 Hz, 3H), 1.99 (s, 2H), 2.00 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 5.35 (broad s, 1H), 6.41 (d, J=16.2 Hz, 1H), 6.77 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.10 Hz, 1H), 7.44 (d, J=8.40 Hz, 2H), 7.68 (d, J=16.2 Hz, 1H). HRMS (EI) Calcd for C28H34O3: 418.57 (M+.). Found: 419.17. Note: Excess ethyl acrylate can be distilled from the reaction mixture before work-up.
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][OH:30])[CH:23]=[N:24][CH:25]=1)=O)(C)(C)C>CO>[ClH:1].[NH:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][OH:30])[CH:23]=[N:24][CH:25]=1.[ClH:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CO)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OC[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M anhydrous HCl/ether (2.0 mL) was added to a stirred solution of (1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropylmethanol (200 mg, 0.59 mmol) in dry MeOH (2.0 mL) at 0° C. The resulting mixture was stirred at room temperature for 12 h, concentrated, and purified by HPLC to give the title compound as its hydrochloride (106 mg). 1H NMR (CD3OD, 300 MHz) δ 8.36 (s, 1H), 8.28 (s, 1H), 7.70 (s, 1H), 4.98-4.92 (m, 1H), 4.52-4.47 (m, 2H), 4.16-4.02 (m, 2H), 3.76-3.68 (m, 1H), 3.53-3.45 (m, 1H), 3.33-3.29 (m, 2H), 2.10-2.02 (m, 1H), 1.64-1.49 (m, 1H), 1.17 (t, 1H, J=7.2 Hz); MS (ESI) m/z 257 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].[O:23]1[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:24]1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:24][C:25]3([OH:23])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:10])[CH3:11])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(=O)NCC2CCNCC2)c(=O)n1C(C)C
Reactant: C1CCC2(CC1)CO2
Solvent: CO
Product: Cc1c(Cl)cc(C(=O)NCC2CCN(CC3(O)CCCCC3)CC2)c(=O)n1C(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of 5-chloro-1-isopropyl-6-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide as prepared in Example 6(2) (484 mg, 1.49 mmol) and 1-oxaspiro[2.5]octane (200 mg, 1.78 mmol, prepared according to Blake, Alexander J et al., J. Chem. Soc. Dalton Trans., 1998, 14, 2335) in methanol (5 mL) was stirred at 50° C. for 16 h. Then, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1) to give 751 mg (99%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][C:42]=1[N+:50]([O-:52])=[O:51].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:30][CH2:31]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)=[CH:43][C:42]=1[N+:50]([O-:52])=[O:51]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 44.8 %

Procedure:
To 300.0 mg (0.49 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 12 ml toluene were added 11.4 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 109.2 mg (0.59 mmol) (4-fluoro-3-nitro-phenyl)boronic acid in 3.0 ml ethanol and 88.7 mg (1.53 mmol) potassium fluoride in 3.0 ml water. The mixture was stirred at 100° C. for 9 hours and at 60° C. for 20 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 147 mg (40%) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-fluoro-3-nitrophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.[Na].[H-].[Na+].N1C=CN=C1>CN(C=O)C>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ccnc2)nc1
Temperature: 120 °C

Procedure:
A solution of the methyl ester obtained in Step 1. above (16.29 g) in DMF is added dropwise to a DMF suspension of sodium imidazole [prepared from NaH (4.19 g) and imidazole 6.49 g)] at RT. The reaction mixture is heated to 120° C. for nineteen hours. The cooled reaction mixture is partitioned between water and chloroform, the organic layer separated, washed with water, dried over Na2SO4, filtered, evaporated, and residual DMF removed under high vacuum yielding the desired product as a tan solid which is recrystalized from methanol (M.P. 183°-184.5° C.) before use in the next step.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:18]([Br:29])=[CH:17][N:16]=2)[S:12][CH:13]=1)(=[O:3])[CH3:2].O=P(Cl)(Cl)Cl>C(#N)C>[CH2:22]([O:21][C:20]1[C:15]([NH:14][C:11]2[S:12][CH:13]=[C:9]([CH2:8][CH2:7][C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)[N:10]=2)=[N:16][CH:17]=[C:18]([Br:29])[CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)NNC(=O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nnc(CCc2csc(Nc3ncc(Br)cc3OCc3ccccc3)n2)o1
Temperature: 50 °C
Reaction time: 72 h
Yield: 28.2 %

Procedure:
The crude N′-acetyl-3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanehydrazide (0.339 g, 0.691 mmol) was added acetonitrile (25 mL), POCl3 (0.380 ml, 4.15 mmol) and the mixture heated at 50° C. overnight. Additional POCl3 (0.5 mL) was added and the reaction was stirred for 3 days 50° C. Additional 0.5 ml POCl3 (0.5 mL) was added and the reaction was stirred at 50° C. for an additional 18 hours. The reaction was then concentrated to dryness, diluted with water, extracted with DCM, dried over Na2SO4, filtered, concentrated to a residue and purified by prep HPLC and then on a silica gel column, eluting with 75% EtOAc/Hexanes, to give 3-(benzyloxy)-5-bromo-N-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)thiazol-2-yl)pyridin-2-amine (0.092 g, 28% yield) as a white solid. 1H NMR (DMSO-d6) δ 2.44 (s, 3H), 3.01 (t, J=7.6 Hz, 2H), 3.17 (t, J=7.6 Hz, 2H), 5.29 (s, 2H), 6.73 (s, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.42 (t, J=7.2 Hz, 2H), 7.59 (d, J=7.2 Hz, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 10.31 (s, 1H); Mass Spectrum (apci) 472 (M+H).
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:15]([O:17]C)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.O.[OH-].[Li+]>CO.O>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution of Z-Tyr(3-tBu)-OMe (1.01 g, 2.62 mmol) in methanol/water (12 ml/3 ml), lithium hydroxide monohydrate (0.17 g, 3.93 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was washed with ether, rendered acidic by 2N hydrochloric acid and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure, giving crude Z-Tyr(3-tBu)-OH (0.98 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]([O:12]CC)=[O:11])[CH2:5][CH2:4]1)[CH3:2]>Cl>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CN1CCN(CC)CC1
Agent: Cl
Product: CCN1CCN(CC(=O)O)CC1
Yield: 54.5 %

Procedure:
The solution of ethyl 2-(4-ethylpiperazin-1-yl)acetate (1.3 g, 6.50 mmol, 1.0 eq) in 8 N HCl stirred at 95° C. for 16 h. The mixture was concentrated on vacuum pump, and quenched and extracted as in Intermediate Example 15(b). The solvent was distilled off to afford the product in 54.5% yield (0.6 g).
Reaction SMILES: COC[O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[N:10][CH:11]=1.Cl>CO>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[N:10][CH:11]=1
Reactant: COCOCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1ccc(OCCc2ccc(CO)cn2)cc1
Yield: 77.6 %

Procedure:
A mixture of 5-methoxymethoxymethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (14.5 g), 2N hydrochloric acid (50 ml) and methanol (50 ml) was stirred under reflux for 2 hours. The reaction mixture was concentrated and the residue was neutralized with saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 5-hydroxymethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (9.7 g, yield: 88%). This compound was recrystallized from ethyl acetate to obtain colorless prisms, m.p. 144°-145° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:51])=[C:9]([CH2:11][O:12][C:13]2[CH:50]=[CH:49][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[C:20]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]5[N:39]=[C:40]([C:44]6[O:45][CH:46]=[CH:47][CH:48]=6)[O:41][C:42]=5[CH3:43])=[CH:32][CH:31]=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:51])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[C:20]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]5[N:39]=[C:40]([C:44]6[O:45][CH:46]=[CH:47][CH:48]=6)[O:41][C:42]=5[CH3:43])=[CH:34][CH:35]=4)=[N:19]3)=[CH:49][CH:50]=2)[N:10]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccco5)oc4C)cc3)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
After a mixture of ethyl 1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazole-4-carboxylate (250 mg), 1N sodium hydroxide solution (1 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (1 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazole-4-carboxylic acid (230 mg, yield: 93%). This was recrystallized from acetone-hexane. Melting point: 144–145° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[S:42]([N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]1)(=[O:43])=[O:44]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(OC)c(S(=O)(=O)n2cc(C=O)c(C)c2-c2ccccc2)c1
Yield: 85.7 %

Procedure:
Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 72 mg), 15-crown-5 (330 mg) and 2,5-dimethoxybenzenesulfonyl chloride (355 mg), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow powder (yield 330 mg, 86%).
Reaction SMILES: Br[C:2]1[C:25](=[O:26])[N:24]([CH2:27][CH3:28])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1.[B:29]1(B2OC(C)(C)C(C)(C)O2)[O:33]C(C)(C)C(C)(C)[O:30]1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.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>[CH2:27]([N:24]1[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:8]=[CH:9][C:4]=2[CH:3]=[C:2]([B:29]([OH:33])[OH:30])[C:25]1=[O:26])[CH3:28]
Reactant: CCn1c(=O)c(Br)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(B(O)O)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 18.2 %

Procedure:
6-Bromo-8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (5, 100 mg, 0.22 mmol), bis(pinacolato)diboron (63 mg, 0.25 mmol), potassium acetate (66 mg, 0.68 mmol) and PdCl2(PPh3)2 (16 mg, 0.02 mmol) were mixed under argon in degassed toluene (3 mL). The resulting suspension was irradiated for 30 min at 120° C. in a microwave reactor. After completion, the reaction mixture was evaporated and the residue was purified by column chromatography using dichloromethane:methanol:triethylamine (4:1:0→1:1:0→0:95:5) as eluent. The crude product was dissolved in dichloromethane (10 mL), washed with water (5 mL), and the organic layer was dried over sodium sulfate, filtered and evaporated. The title compound (15 mg, 0.04 mmol, 18%) was obtained as a yellow solid. ESMS m/z 409 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (br. s., 1H) 8.85 (s, 1H) 8.52 (s, 2H) 8.28 (s, 1H) 7.64 (br. s., 2H) 6.94 (d, J=9.0 Hz, 2H) 4.33 (q, J=6.9 Hz, 2H) 3.07-3.14 (m, 4H) 2.43-2.47 (m, 4H) 2.22 (s, 3H) 1.26 (t, J=6.9 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=1I.[CH3:15][Si:16]([C:19]#[C:20][Si](C)(C)C)([CH3:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:13][NH:12][S:9]([CH2:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:19]([Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:20]2)(=[O:11])=[O:10]
Reactant: CNS(=O)(=O)Cc1ccc(N)c(I)c1
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)cc2c1
Yield: 72.9 %

Procedure:
4-Amino-3-iodo-N-methyl-benzenemethanesulfonamide (1.63 g, 0.005 mol), bis(trimethylsilyl)acetylene (1.28 g, 0.0075 mol) and tetrakistriphenylphosphine Pd(O) (0.578 g, 0.0005 mol) were dissolved in DME (50 mL) and followed by the addition of saturated aqueous Na2CO3 (5 mL). The mixture was heated at reflux for 48 h. The solvent was removed in vacuo. The residue was dissolved in EtOAc and extracted with brine. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. Silica gel chromatography (10-100% EtOAc gradient in hexane) of the residue afforded the product (4) (1.08 g, 76.8%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][Si:28]([CH3:33])([CH3:32])[CH2:29][CH2:30]O>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]([O:10][CH2:30][CH2:29][Si:28]([CH3:33])([CH3:32])[CH3:27])=[O:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCO
Reactant: O=C(O)[C@H](Cc1ccc(O)cc1)Oc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Product: C[Si](C)(C)CCOC(=O)[C@H](Cc1ccc(O)cc1)Oc1ccc(F)cc1

Procedure:
The target compound (1.81 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(e) using the above carboxylic acid (2.30 g), oxalyl chloride (1.80 ml) and 2-trimethylsilylethanol (15.96 ml).