Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C@@H:22]([OH:25])[CH2:23][OH:24])[C:16](=[O:26])[CH:15]2[CH3:27])[CH:10]=[CH:11][C:12]=1[Cl:13].CC1C=C(C)C=C(C)N=1>CC(N(C)C)=O>[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C@@H:22]([OH:25])[CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[C:16](=[O:26])[CH:15]2[CH3:27])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC1C(=O)N(CC[C@@H](O)CO)CCN1c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)N(C)C
Solvent: Cc1cc(C)nc(C)c1
Product: CC1C(=O)N(CC[C@@H](O)COS(C)(=O)=O)CCN1c1ccc(Cl)c(Cl)c1
Yield: 129.8 %

Procedure:
A solution of methanesulfonyl chloride (53 mg, 0.46 mmol) in DMA (0.5 mL) was added at 0° C. to a solution of 4-(3,4-dichloro-phenyl)-1-((R)-3,4-dihydroxy-butyl)-3-methyl-piperazin-2-one (160 mg, 0.46 mmol) and 2,4,6-trimethylpyridine (279 mg, 2.30 mmol) in DMA (2 mL), then after 2½ h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford crude methanesulfonic acid (R)-4-[4-(3,4-dichloro-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-2-hydroxy-butyl ester (254 mg) as a light yellow gum. This was dissolved in DMA (2 mL), cooled to 0° C., and treated with NaH (55% dispersion in mineral oil, 41 mg, 0.94 mmol). After 15 min, as the methanesulfonate intermediate had disappeared, with mass spectrometry confirming the formation of the epoxide intermediate, 4-(3,4-dichloro-phenyl)-3-methyl-1-((R)-2-oxiranyl-ethyl)-piperazin-2-one [m/e=329, (M+H)+)], cesium carbonate (184 mg, 0.56 mmol) and a solution of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 77 mg, 0.47 mmol) and N,N-diisopropylethylamine (152 mg, 1.2 mmol) in DMA (1 mL) were added. The reaction mixture was heated at 80° C. for 20 h, then diluted with EtOAc/MeOH 4:1 and filtered through diatomaceous earth. The filtrate was chromatographed (IST Isolute® Flash NH2; EtOAc/MeOH gradient) to produce the title compound (101 mg, 47%). Light yellow foam, MS: 456.2 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(F)c2)C1
Agent: B
Solvent: C1CCOC1
Product: Fc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 111.4 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-fluorophenyl)piperidin-1-yl]methanone (1.21 g, 3.51 mmol) was treated with BH3THF according to the above general procedure. 1.28 g crude product was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:19][C:5]2=[N:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[C:4]2[CH:3]=1.I[C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])[N:27]=2)=[CH:24][N:23]([CH:37]([CH3:39])[CH3:38])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH:37]([N:23]1[CH:24]=[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])[N:27]=2)[C:21]([C:8]2[CH:9]=[C:4]3[CH:3]=[C:2]([CH3:1])[NH:19][C:5]3=[N:6][CH:7]=2)=[N:22]1)([CH3:39])[CH3:38]
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)cnc2[nH]1
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1cc2cc(-c3nn(C(C)C)cc3-c3ccnc(NC[C@H](C)O)n3)cnc2[nH]1
Temperature: 80 °C
Reaction time: 30 h
Yield: 18.6 %

Procedure:
To a suspension of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (B-7-7) (1.8 g, 2.3 mmol in the theory) and (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (0.45 g, 1.2 mmol) in toluene/EtOH (3:1, 50 mL) was added aq. Na2CO3 (1.7 mL, 2 M). The mixture was degassed under N2 for 2 minutes, Pd(PPh3)4 (0.05 g, 0.042 mmol) was added into the mixture and degassed again. The mixture was stirred at 80° C. for 30 hours. TLC (CH2Cl2: MeOH=20:1) showed that the reaction was complete. Water (50 mL) and EtOAc (50 mL×3) were added into the mixture. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give crude product which was purified via prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-7) (0.169 g, 18.6%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1.Cl.O1CCOCC1>CCOC(C)=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COc1ccc2c(Cl)ncnc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2c1

Procedure:
To 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (137 mg, 0.5 mmol) was added 4-chloro-7-methoxyquinazoline (97 mg, 0.5 mmol) according to the procedure described in Example 1B. The resulting compound was dissolved in EtOAc (5 mL) and 4N HCl in dioxane (0.2 mL, 0.8 mmol) was added. The mixture was sonicated, stirred and concentrated in vacuo to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-yloxy)phenyl)urea as the mono-hydrochloride (103 mg, 0.22 mmol, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.15 (s, 1H), 8.69 (s, 1H), 8.28 (d, 1H), 7.58 (s, 1H), 7.45-7.35 (m, 3H), 7.27 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 3.98 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:24]([O:31][CH2:32][C:33](Cl)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH2:24]([O:31][CH2:32][C:33]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C=C2/C(=N/OC(=O)COCc3ccccc3)CCc3ccccc32)cc1
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (50 mg, 0.15 mmol) and benzyloxyacetylchloride (0.029 ml, 0.18 mmol) were added into dichloromethane (5.0 ml). Then, at 0-5° C. triethylamine (0.026 ml, 0.18 mmol) was added, stirred for 15 minutes so as to complete the reaction. Afterward, an organic layer was separated by blending water, washed again with water and saturated brine and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and made to crystal by using diisopropylether. As a result, 40.7 mg of the present compound (productive yield 56%) was obtained as a white solid crystal.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20].[OH-:21].[K+].Cl>>[F:12][C:11]1[C:2]([OH:21])=[C:3]2[C:8]3=[C:9]([C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[N:6]([CH3:20])[CH2:5][CH2:4]2)[CH:10]=1
Reactant: [OH-]
Reactant: CN1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Agent: [K+]
Product: CN1CCc2c(O)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
2.78 g of the compound (8) obtained in Example 3 was added to 10 ml of aqueous 30% potassium hydroxide solution, and the solution was heated at reflux for 6 hours. After air-cooling, the solution was acidified with 6N hydrochloric acid, and the deposited solids were filtered off and washed with water, ethanol and isopropyl ether in this order to obtain 2.60 g of the subject compound (166).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][N:21]=2)=[CH:13][CH:12]=1.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.O>[Br:8][C:4]1[N:3]=[C:2]([C:19]2[S:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=3)=[N:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2ccc(OC)cc2)s1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ncc(-c3cccc(Br)n3)s2)cc1
Reaction time: 24 h
Yield: 59 %

Procedure:
A sealed tube was charged with 2,6-dibromopyridine (474 mg, 2.00 mmol), 2-(4-methoxyphenyl)-5-(tributylstannyl)thiazole (920 mg, 2.00 mmol), Pd(PPh3)4 (231 mg, 0.20 mmol), and anhydrous and degazed toluene (9 ml) and heated to 120° C. with stirring for 24 hours. The cooled reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure before purification by dry flash chromatography over SiO2 eluting with EtOAc/cyclohexane 20/80 to give 5-(6-bromopyridin-2-yl)-2-(4-methoxyphenyl)thiazole (410 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.82 (t, J=7.8 Hz, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.07 (d, J=8.5 Hz, 2H), 3.83 (s, 3H).
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:13][C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH:24](O)[CH3:25])=[CH:16][CH:15]=1)[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH2:24][CH2:25][O:2][CH:1]=[O:3])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccc2c(=O)c(C(=O)O)cn(C(C)O)c2n1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Reaction time: 0.75 h

Procedure:
Formic acid (1 ml) was added to acetic anhydride (2 ml) which was cooled to 0°. The mixture was warmed to 50° for 15 minutes, cooled to 0° and added to a suspension of 7-ethoxy-1,4-dihydro-1-hydroxyethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.78 g) in dry pyridine (10 ml). The mixture was stirred at 0° for 45 minutes and then for 1 hour at room temperature. The solid was collected and washed with water and dried, m.p. 208.5°-210° (d). (71%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[N:10]=[C:1]=[O:2])=[O:15]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1N=C=O
Yield: 100 %

Procedure:
Phosgene was bubbled through a solution of 10 g (66 mmol) of methylanthranilate in 15 ml of anhydrous toluene for 2 hours at reflux. Then the solvent was distilled off under reduced pressure to give 11.7 g (100%) of 2-methoxycarbonylphenyl-isocyanate; NMR (CDCl3) 3.89 (s, 3H, CH3); 7.0-7.63 (m, 3H, phenyl H-3, -4, -5); 8.0 (dd, 1H, phenyl H-6). This was converted to the title compound, in 34% overall yield, by condensation with an equimolar amount of 2-pyridylcarbinol followed by saponification of the resulting ester with 1 N sodium hydroxide and acidification of the reaction mixture to pH 4. The crude product was purified by crystallization from ethyl acetate; melting point=172-175° C.; NMR (DMSO-d6) 5.2 (s, 2H, methoxy CH2); 6.8-8.8 (m, 9H, aromatic, NH); 10.8 (broad s, 1H, OH).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])[CH:2]([CH3:4])[CH3:3].Br[CH:17]([C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:14]=1[O:15][CH:17]([C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(O)c(CC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc(C(=O)OC)cc1CC(C)C)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a solution of 1.008 g (4.84 mmol) of methyl 3-iso-butyl-4-hydroxybenzoate and 1.737 g (6.05 mmol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate in 10 mL of acetone was added 1.338 g (10 mmol) of finely powdered potassium carbonate. The reaction mixture was magnetically stirred and refluxed for 4 hours, then cooled to room temperature, filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane; combination of the purified fractions and drying in vacuo afforded 1.518 g (76%) of the title compound as an amorphous powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:24][CH3:25])=[N:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(OCC)(=O)C>[CH:19]1([N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:18]=3)[C:14]([CH2:24][CH3:25])=[N:15]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCc1nn(C2CCCC2)c2cc(Br)ccc12
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1nn(C2CCCC2)c2cc(-c3cccs3)ccc12
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of 76 mg (0.598 mmol, 1.2 equiv) thiophene-2-boronic acid in 0.5 mL methanol was added to a room temperature suspension of 146 mg (0.498 mmol, 1.0 equiv) 6-bromo-1-cyclopentyl-3-ethyl-1H-indazole and 17 mg (0.0149 mmol, 0.03 equiv) Pd(PPh3)4in 2 mL toluene and 0.5 mL 2M aqueous Na2CO3. The mixture was heated to reflux for 4 h, then cooled to room temperature. The reaction mixture was diluted with 50 mL ethyl acetate, washed 1×10 mL each H2O, brine, and dried over MgSO4. The crude product was purified on a silica gel column (3% ethylacetate/hexanes, flash) to give 81 mg (55%) of a clear oil, which crystalized onstanding: mp 60-64° C.; HRMS calcd for C18H20N2S+H: 297.1427. Found: 297.1484.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:32])[C@H:13]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:14][N:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[O:17])[C:3]=1[F:33].[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:27]1([CH2:26][C@@H:13]([C:12]([NH:11][NH:10][C:4]2[C:3]([F:33])=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([CH2:34][CH3:35])[CH2:37][CH2:38]3)[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)=[O:32])[CH2:14][N:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[O:17])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCN1CCNCC1
Reactant: COc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN1CCN(c2nc(OC)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)CC1
Yield: 83.9 %

Procedure:
[(2R)-3-{2-[6-Chloro-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.150 g, 0.31 mmol), commercially available 1-ethylpiperazine (0.080 mL, 0.63 mmol) and diisopropylethylamine (0.054 mL, 0.31 mmol) were stirred in DMSO (2 mL) overnight at 65° C. The reaction mixture was then purified by RP-HPLC to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(4-ethyl-1-piperazinyl)-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-3-oxopropyl)[(phenylmethyl)oxy]formamide as a red solid (0.145 g, 83%). LCMS: (M+H)+=558.3.
Reaction SMILES: [C:1]1(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[O:9])O1.FC(F)(F)C(O)=O.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26]>C(O)(=O)C>[O:26]=[C:20]1[CH:19]([N:18]2[C:3](=[O:9])[C:4]3=[CH:8][S:7][CH:6]=[C:5]3[C:1]2=[O:10])[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1
Reactant: O=C1OC(=O)c2cscc21
Reactant: NC1CCC(=O)NC1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(N2C(=O)c3cscc3C2=O)C(=O)N1
Yield: 122.6 %

Procedure:
1.54 g thieno(3,4-c)furan-1,3-dione and 1.42 g of 3-aminopiperidine-2,6-dione trifluoroacetic acid were dissolved in 15 mL of acetic acid. The reaction mixture was refluxed overnight, cooled, and evaporated to remove the solvent. The residue was dissolved in 20 mL anhydrous THF, and 2 g of CDI, and a catalytic quantity of DMAP were added. The reaction mixture was refluxed for 6 h until a large amount of white solid precipitated. The solid was cooled and filtered to yield 1.9 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[C:4]([CH3:12])[N:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:8]([C:7]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[N:3][C:4]([CH3:12])=[C:5]([C:10]#[N:11])[CH:6]=1)#[N:9]
Reactant: Cc1nc(N)c(C#N)cc1C#N
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: Cc1nc(N=CN(C)C)c(C#N)cc1C#N
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of 2-Amino-6-methyl-pyridine-3,5-dicarbonitrile (0.158 g, 1.0 mmol) and N,N-Dimethylformamide dimethyl acetal (0.119 g, 1.0 mmol) in toluene (10 mL) was heated at reflux for 6 hours. After cooling to room temperature, the solution was concentrated under vacuum to provide the title compound as a brown solid (0.2 g, 94%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH3:21].[CH3:22][O:23][C:24](OC)([O:29]C)[CH2:25][CH2:26][CH2:27]Br>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][CH2:27][CH2:26][CH2:25][C:24]([O:23][CH3:22])=[O:29]
Reactant: Cc1cc(Cl)ccc1Cl
Reactant: COC(CCCBr)(OC)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCCc1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Diisopropylamine (841 μl, 6 mmol) was added to 20 ml of tetrahydrofuran under nitrogen atmosphere and cooled to 0° C. 5.5 ml of 2.5N n-butyllithium (13 mmol) was added and the reaction was stirred for 20 minutes. The reaction was then cooled to -78° C. 2,5-Dichlorotoluene (642 ul, 5 mmol) was added and stirring was continued for 2 hours at -78° C. Trimethyl 4-bromoorthobutyrate (1.14 g, 5 mmol) was added to the reaction mixture in 10 ml tetrahydrofuran. The reaction was stirred for 5 minutes at -78° C., allowed to come to room temperature and stirred overnight. The reaction was worked-up by adding 10 ml of saturated KH2PO4, removal of most of the tetrahydrofuran on a rotary evaporator followed by partitioning of the aqueous residue between ethyl acetate and 1N HCl. The organic phase was washed twice with 1N HCl, once with 5% sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to a residue. Flash chromatography (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.8 minutes) of a water white oil. 1H NMR (300 MHz, CDCl3) delta=7.24 (d, J=8.5 Hz, H3), 7.18 (d, J=2.5 Hz, H6), 7.09 (dd, J=2.5, 8.5 Hz, H4), 3.66 (s, --COOCH3), 2.69 (t, J=7.8 Hz, Ar--CH2 --), 2.35 (t, J=7.0 Hz, --CH2 --COO--), 1.70-1.55 (m, --CH2 --CH--CH2 --CH2 --).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12]([O:18][C@H:19]([CH3:23])[C:20](Cl)=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:20](=[O:21])[C@H:19]([O:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:23])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCO[C@H](C)C(=O)Cl
Product: CCCCCCO[C@H](C)C(=O)Oc1ccc(C(=O)O)cc1Cl

Procedure:
Using 3-chloro-4-hydroxybenzoic acid 1/2 hydrate (3.76 g, 20.7 mmol) and (R)-2-n-hexyloxypropanoyl chloride (3.98 g, 20.7 mmol), the reaction was carried out in the same manner as described in Example 4, (1), to give the title compound as a pale yellow oil; yield: 2.60 g.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([O:7][N:8]([CH:21]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:24]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH:23]=[C:22]1[CH2:43]OS(C)(=O)=O)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH2:6]>O.CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:4]([O:7][N:8]([CH:21]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C@H:24]([CH2:34][O:35][Si:36]([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:38])[CH3:37])[CH:23]=[C:22]1[CH2:43][C:1]#[N:2])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH:5]=[CH2:6]
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COS(C)(=O)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC#N)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of sodium cyanide (4.94 g, 100.85 mmol) in water (20.0 mL) was added (2S)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(((methylsulfonyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (crude, 20.17 mmol) in DMF (100 mL). The mixture was then stirred at room temperature for 15 h. It became a dark orange solution. It was then diluted with sat. NaHCO3 and water and extracted with ethyl acetate, dried over MgSO4. The crude was subjected to silica gel column eluting with 0-100% ethyl acetate/hexanes to give a pale yellow oil, 5.92 g, 47.1%.
Reaction SMILES: [OH-].[Na+:2].C1(C)C(C)=CC=CC=1.[CH:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=2[OH:21])[CH2:13][CH2:12]1>O>[CH:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=2[O-:21])[CH2:13][CH2:12]1.[Na+:2]
Reactant: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cccc(C2CC2)c1[O-]
Temperature: 50 °C
Yield: 67.3 %

Procedure:
115.4 g of pure water was added to 54.1 g (1.312 mol) of 97% sodium hydroxide and heated to 50° C. to dissolve sodium hydroxide, and then xylene (1,000 ml) was added to the resultant solution at room temperature. To the mixture was added dropwise 200 g (1.317 mol) of 2-cyclopropyl-6-methylphenol at room temperature over 20 minutes. The resultant two-phase solution was subjected to thermal dehydration at 140° C., and, after completion of the distilling off of water, the resultant solution was cooled to 5° C. to obtain a slurry. The obtained slurry was subjected to filtration under a reduced pressure, and the resultant solids were washed with 500 ml of hexane twice. The solids were dried under a reduced pressure, and the resultant solids were quantitatively determined by an HPLC internal standard analysis method, which showed that 150.2 g of sodium 2-cyclopropyl-6-methylphenoxide (yield: 67%) was obtained.