Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]1[CH:21]=[C:22](O)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([F:26])[CH:25]=1)[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cc(F)cc(F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 3,5-difluorophenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[C:25]1([C:31]2[O:35][CH:34]=[N:33][C:32]=2[C:36](Cl)=[O:37])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)[C:36]([C:32]1[N:33]=[CH:34][O:35][C:31]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:37])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ncoc1-c1ccccc1
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncoc2-c2ccccc2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (65 mg, 0.23 mL) in THF (2.0 mL) was added to a suspension of NaH (12 mg, 0.28 mmol) in THF (1.0 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 5-phenyl-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 16 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1→2:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.39. LC-MS-conditions 02: tR=1.06 min, [M+H]+=454.20.
Reaction SMILES: Cl[CH:2]([C:36]1([CH3:41])[CH2:40][CH2:39][CH2:38][CH2:37]1)[C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:17]([CH:24]3[CH2:26][CH2:25]3)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][C:4]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH:24]1([CH:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][O:9][C:7]3[CH:6]=[CH:5][C:4]([C:27]4[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=4[F:35])=[C:3]([CH2:2][C:36]4([CH3:41])[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:8]=3)[CH:12]=2)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:25][CH2:26]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(C(Cl)C3(C)CCCC3)c2)c1)C1CC1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC3(C)CCCC3)c2)c1)C1CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a solution of ethyl 3-(3-(((2-(chloro(1-methylcyclopentyl)methyl)-2′-fluoro-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)-3-cyclopropylpropanoate (92 mg) and 2,2-azobisbutyronitrile (3 mg) in toluene (3 mL) was added tributyltin hydride (0.13 mL), and the mixture was stirred at 100° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (32 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(c2ccc(N)cc2)CCOCC1
Yield: 90 %

Procedure:
A mixture of 4-(4-nitro-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 2.12 g, 8.00 mmol) and 10% Pd/C (1.06 g, 50 wt %) in 20 ml, of MeOH was stirred at RT under H2 (balloon pressure) for 2 h. The Pd catalyst was removed by filtration on Celite and the filtrate was concentrated to give 1.69 g (90%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C13H17NO3, 236.1 (M+H). found 236.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[CH2:17][CH:18]([CH2:24][C:25]([O:27]C)=[O:26])[C:19](=[O:23])[N:20]([CH3:22])[CH2:21][C:15]=3[CH:14]=2)[CH:3]=1.N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OCC)=O)C(=O)NCC=2C=1>>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[CH2:17][CH:18]([CH2:24][C:25]([OH:27])=[O:26])[C:19](=[O:23])[N:20]([CH3:22])[CH2:21][C:15]=3[CH:14]=2)[CH:3]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3cc(N)ccn3)cc2CN(C)C1=O
Agent: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Product: CN1Cc2cc(OCCCNc3cc(N)ccn3)ccc2CC(CC(=O)O)C1=O

Procedure:
According to the procedure of Example 1(c), except substituting methyl (±)-8-[3-(4-aminopyridin-2-ylamino)-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the ethyl (±)-8-[3-[2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound was prepared as a white solid: MS (ES) m/e 399 (M+H)+. Anal. Calcd for C21H26N4O4.1.5CF3CO2H.0.125H2O: C, 50.62: H, 4.91; N, 9.83. Found: C, 50.63; H 5.26; N, 9.90.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:19].[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>C1COCC1>[CH3:9][CH:10]1[CH:18]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([S:21][CH3:20])=[CH:23][CH:24]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:19]
Reactant: CC1Cc2ccccc2C1=O
Reactant: CSc1ccc(CCl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(CC2c3ccccc3C(=O)C2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled solution (-70° C.) of LDA (1 M) in THF (37 mL) was added dropwise a solution of 2-methyl-1-indanone (J.A.C.S. Vol. 98, 8119-8124 (1976)) (2.5 g, 17 mmol) in THF (20 mL). The resulting dark red solution was stirred at room temperature for 3 hours, then cooled to -20° C. and a solution for 4-methylthiobenzyl chloride (3.1 g, 18 mmol) in THF (15 mL) was added slowly. The addition completed, the reaction mixture was stirred at -20° C. for 30 minutes before being quenched with 3N aqueous HCl (50 mL) and brine (50 mL). The product was extracted with ether, dried over MgSO4 and evaporated to dryness. The oily residue was chromatographed on silica gel eluting with a 1:5 mixture of ethyl acetate-hexane to afford the pure title compound as an oil.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1)[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][C:4]1[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[O:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ccc(C(=O)OC)o1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCc1oc(C(=O)OC)cc1Br
Temperature: 70 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a solution of methyl 5-ethyl-2-furancarboxylate (1.2 g, 7.78 mmol) and aluminum trichloride (1.56 g, 11.68 mmol) in chloroform (15 ml) at 25° C. was added bromine (0.56 ml, 10.90 mmol). The resulting solution stirred at 70° C. in a sealed tube for 2 h and the solution was cooled, concentrated and purified via column chromatography (silica, 5% EtOAc in hexanes) affording methyl 4-bromo-5-ethyl-2-furancarboxylate (1.1 g, 3.26 mmol, 41.8% yield) as a white solid; LCMS (ES) m/z=233, 235 (M, M+2)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[H-].[Na+].C(Cl)(=O)C(C)(C)C.C([Li])CCC.[CH3:27][C@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:27][C@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[N:29]1[C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1CC(=O)O
Reactant: C[C@@H]1NC(=O)O[C@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccccc1CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 74.1 %

Procedure:
9.38 g of 2-methoxyphenylacetic acid are added to a suspension of 1.89 g of sodium hydride (80% 25 dispersion in vaseline) in 200 cm3 of dry tetrahydrofuran, at room temperature. This suspension is cooled to -30° C., 7.77 cm3 of pivaloyl chloride are added and then a solution, cooled to -78° C., which is obtained by adding 35.27 cm3 of a 1.6M solution of butyllithium in hexane to a solution, cooled to -78° C., of 10 g of (4S,5S)-4-methyl-5-phenyl-2-oxazolidinone in 200 cm3 of dry tetrahydrofuran is finally added. The reaction mixture is stirred for 45 minutes at -30° C. and then after re-equilibrating to room temperature, 200 cm3 of a saturated aqueous solution of ammonium chloride are added followed by 500 cm3 of ethyl acetate; after decantation, the organic phase is washed twice with 100 cm3 of water and then twice with 100 cm3 of a saturated aqueous solution of sodium chloride; dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 36 cm), eluting under a nitrogen pressure of 0.6 bar with a cyclohexane and ethyl acetate mixture (85/15 followed by 80/20 by volume) and collecting fractions of 50 cm3. Fractions 14 to 31 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 13.6 g of (4S,5S)-4-methyl-5-phenyl-3-(2-methoxyphenylacetyl)-2-oxazolidinone are obtained in the form of a yellow oil.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[CH:6]([OH:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH:6]([OH:12])[CH2:5][OH:4]
Reactant: COC(=O)CC(O)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Product: COC(=O)CC(O)CO

Procedure:
The process of claim 18 wherein about one equivalent of the lithium borohydride is reacted with the hydroxy butane dioic acid dimethyl ester to produce the 3,4-dihydroxybutyric acid -1-methyl ester.
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][N:5]1[C:19](=[O:21])[CH3:20].CN(C=[O:26])C>>[C:19]([N:5]1[CH2:6][C:7]2[C:8](=[O:26])[C:9]3[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=3[NH:15][C:16]=2[C:4]1=[CH2:3])(=[O:21])[CH3:20]
Reactant: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(C)=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C=C1c2[nH]c3ccc(OC)cc3c(=O)c2CN1C(C)=O
Reaction time: 8 h

Procedure:
NaH (1.5 eq; 60% suspension in oil) is added to a solution of 1-methylene-2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (1 g; 3.9 mmol) in DMF (5 ml). The mixture is stirred under an oxygen atmosphere overnight. The DMF is then distilled off under reduced pressure. The crude product is washed successively with ethyl acetate, methanol and then ether. After drying, 2-acetyl-7-methoxy-3-methylene-9-oxo-1,3,4,9-tetrahydropyrrolo[3,4-b]quinoline is obtained.
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:26][C@H:27]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl.OC1C2N=NNC=2C=CC=1.Cl.CNC(N=C=NCC)CCNC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13]([NH:26][C@H:27]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: CCN=C=NC(CCNC)NC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 94.7 %

Procedure:
To a solution of 406 mg of CBZ-D-Trp-OH (1.2 mmol), 302 mg of Lys(BOC)-OtBu HCl (1.0 mmol), 202 mg of hydroxybenzotriazole (1.5 mmol) and 366 mg of 4-dimethylaminopyridine (3 mmol) in 60 mL of methylene chloride was added 448 mg (1.5 mmol) of 1,3dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC). After stirring for 3 hours 100 mL more methylene chloride was added to the reaction, and it was washed four times with 25 mL portions of 0.1 N hydrochloric acid solution, twice with 25 mL of 50% saturated sodium bicarbonate solution, once with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield 590 mg (100%) of CBZ-D-Trp-Lys(BOC)-OtBu.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[N:15]=[C:16]([S:23][CH3:24])[S:17][C:18]=1[C:19]([O:21][CH3:22])=[O:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[N:15]=[C:16]([S:23][CH3:24])[S:17][C:18]=2[C:19]([O:21][CH3:22])=[O:20])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: COC(=O)c1sc(SC)nc1N
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1sc(SC)nc1Nc1cc(Cl)ncc1C(F)(F)F

Procedure:
Method A was applied to a mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (156 mg, 0.51 mmol) and methyl 4-amino-2-(methylthio)thiazole-5-carboxylate (86 mg, 0.42 mmol), Pd2(dba)3 (26 mg, 0.028 mmol), xantphos (21 mg, 0.036 mmol) and cesium carbonate (270 mg, 0.83 mmol) in dioxane (4.5 ml).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:13](C(OCC)=O)[C:12]2=[O:30])=[CH:2]1.[OH-].[K+]>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(F)ccc1NC1=CC(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of the compound (0.15 g, 0.37 mmol) of Example 97 in ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. Water was added to this residue, the mixture was washed with ethyl acetate then 1M hydrochloric acid was added to adjust pH to acidic. The precipitate was collected by filtration, washed with water, diethyl ether, ethyl acetate and hexane then dried to afford the titled compound as solid (0.12 g, y. 93%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][N:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:18]=[CH:17][N:16]=1
Reactant: COc1cc(C=O)ccn1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(C=C2N=C(c3cccs3)OC2=O)ccn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A mixture of N-(2-thienylcarbonyl)glycine (454 mg, 2.45 mmol), 2-methoxy-4-pyridinecarboxaldehyde (370 mg, 2.7 mmol), sodium acetate (201 mg, 2.45 mmol) and acetic anhydride (3.0 mL) was stirred at 90° C. for 3 hours in a sealed tube. Thereafter, the temperature of the reaction solution was returned to room temperature, and water (15 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1 hour. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (50 mL) and was then dried under reduced pressure, so as to obtain 572 mg of the above-captioned compound.
Reaction SMILES: Cl.C(OC(=O)NC)(C)(C)C.O1[C:15]2([CH2:20][CH2:19][N:18]([S:21]([C:24]3([CH2:27][C:28]4[C:33]([CH3:34])=[CH:32][C:31]([NH:35][CH3:36])=[CH:30][C:29]=4[CH3:37])[CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[O:14]CC1.[OH-].[Na+]>CCO>[CH3:37][C:29]1[CH:30]=[C:31]([NH:35][CH3:36])[CH:32]=[C:33]([CH3:34])[C:28]=1[CH2:27][C:24]1([S:21]([N:18]2[CH2:17][CH2:16][C:15](=[O:14])[CH2:20][CH2:19]2)(=[O:23])=[O:22])[CH2:26][CH2:25]1
Reactant: CNc1cc(C)c(CC2(S(=O)(=O)N3CCC4(CC3)OCCO4)CC2)c(C)c1
Agent: CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CNc1cc(C)c(CC2(S(=O)(=O)N3CCC(=O)CC3)CC2)c(C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 286.8 %

Procedure:
A 5 N aqueous HCl solution (2.0 ml, 10 mmol) was added to a solution of a mixture of 4-[1-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-cyclopropylmethyl]-3,5-dimethyl-phenyl}-methyl-carbamic acid tert-butyl ester (54.7 mg, 0.111 mmol) and {4-[1-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-cyclopropylmethyl]-3,5-dimethyl-phenyl}-methyl-amine (23.1 mg, 0.0585 mmol) in EtOH (2.0 mL), and the mixture was stirred at 80° C. for two hours. The reaction mixture was neutralized by adding a 5 N aqueous NaOH solution (1.9 ml) and then extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give 1-[1-(2,6-dimethyl-4-methylamino-benzyl)-cyclopropanesulfonyl]-4-piperidinone (58.8 mg, 99%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[Cl:24][C:25]1[N:30]=[C:29]([C:31]([NH2:33])=O)[CH:28]=[C:27]([N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:41]([C:43]3[NH:44][C:45]([CH3:50])=[C:46]([Cl:49])[C:47]=3[Cl:48])=[O:42])[CH2:36][CH2:35]2)[N:26]=1.[CH3:51][Si:52]([O:55][P:56](=[O:58])=[O:57])([CH3:54])[CH3:53]>C1(C)C=CC=CC=1>[CH3:51][Si:52]([O:55][P:56](=[O:58])=[O:57])([CH3:54])[CH3:53].[Cl:48][C:47]1[C:46]([Cl:49])=[C:45]([CH3:50])[NH:44][C:43]=1[C:41]([NH:40][CH:37]1[CH2:38][CH2:39][N:34]([C:27]2[CH:28]=[C:29]([C:31]#[N:33])[N:30]=[C:25]([Cl:24])[N:26]=2)[CH2:35][CH2:36]1)=[O:42]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)nc(Cl)n3)CC2)c(Cl)c1Cl
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)nc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 60 h

Procedure:
A stock solution of trimethylsilyl polyphosphate (prepared according to Yokoyama, Masataka; Yoshida, Sayaka; Imamoto, Tsuneo. Synthesis, 1982, 7, 591-592) was prepared by combining P2O5 (10 g) and hexamethyldisiloxane (25 ml) in anhydrous toluene (50 ml) and heating the mixture at 80° C. until it became a clear solution (about 45 minutes). 2-Chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxamide (Example 37, 2.1 g, 4.8 mmol) was treated with trimethylsilyl polyphosphate (80 ml), and the reaction was heated at 80° C. for 5 h, after which the reaction was about 50% complete. No further reaction was apparent after adding more trimethylsilyl polyphosphate and letting the reaction stir an additional 2.5 days. Upon cooling to room temperature, the reaction was concentrated under reduced pressure until most of the solvent was removed. The remaining liquid was triturated with EtOAc and water to form a brown precipitate, which was mostly the amide precursor. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid. About 20 mg was purified by preparatory HPLC, using a gradient of 35-75% acetonitrile/water (0.1% TFA), while the rest was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[N:34]=[C:33]([NH:35][CH2:36][CH2:37][CH3:38])[C:32]([C:39](O)=[O:40])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)#[N:21]>>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[N:34]=[C:33]([NH:35][CH2:36][CH2:37][CH3:38])[C:32]([C:39]([NH:1][C:2]3[CH:3]=[C:4]([NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:5]=[CH:6][CH:7]=3)=[O:40])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)#[N:21]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(N)c1
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1

Procedure:
By using tert-butyl (2-((3-aminophenyl)amino)-2-oxoethyl)carbamate (B1) and 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C5), tert-butyl (2-((3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-2-oxoethyl)carbamate (D8) was obtained in the same manner as that of Example 12, (1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:26][CH:25]=1)[CH3:22]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: CCOc1ccc(-c2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-ethoxy-phenylboronic acid to give [1-(4-ethoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 375(MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][CH2:10][CH2:11][CH2:12][N:13]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1cccc(C2OCCO2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCOc1cccc(C2OCCO2)c1
Yield: 74.5 %

Procedure:
A solution of N-{3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl}phthalimide (119.4 g, 0.3 mole) and hydrazine hydrate (78.6 mL, 1.62 mole) in 95% ethyl alcohol (1.5 L) was heated at reflux temperature for 17.5 hours. The thick white mixture was cooled in an ice-water bath, filtered and the solid washed with ice cold 95% ethyl alcohol. The combined filtrate and washings were evaporated under reduced pressure and the residue was partitioned between 940 mL of 5% aqueous sodium hydroxide and 500 mL of dichloromethane. The aqueous phase was extracted with 500 mL of dichloromethane and the combined organic phase was extracted with 300 mL of saturated aqueous sodium chloride. The organic phase was dried, evaporated under reduced pressure and the residue was distilled under high vacuum to give 49.9 g of the title compound; bp=143°-147° C. at 0.25 mmHg.