Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].[CH3:8][O:9][C:10](=[O:19])[CH2:11][C:12](=O)[CH2:13][C:14](OC)=[O:15].Cl.C(OCC)(=O)C>C[O-].[Na+].CO.C(Cl)Cl>[OH:15][C:14]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:5]=[C:12]([CH2:11][C:10]([O:9][CH3:8])=[O:19])[CH:13]=1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: N=C(N)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1cc(O)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,2,2-Trifluoroethanimidamide (6.7 g, 50. mmol, Oakwood) was dissolved in 0.5 M sodium methoxide in methanol (120 mL, 60. mmol) and 3-oxo-pentanedioic acid dimethyl ester (8.4 mL, 55 mmol, Aldrich) was added. The reaction solution was stirred at room temperature for 72 hours, followed by heating to 50° C. for 42 hours. The solvent was removed in vacuo. 1N HCl (50 mL) was added, this resulted in pH 5. After stirring overnight, 4M HCl (10 mL) and ethyl acetate were added, and layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, on 120 g silica gel cartridge, eluting with a gradient (solvent A=hexane; solvent B=3% iPrOH/EtOAc) from 0-30% solvent B in A over 40 minutes and hold at 30% for 20 minutes at a flow rate of 60 mL/min. The residue obtained on evaporation of product-containing fractions was mixed with DCM and the resulting white ppt (impurity) was removed by filtration. The filtrate was evaporated and the resulting residue was repurified (A=hexane; solvent B=iPrOH) on a 120 g silica gel cartridge, eluting with a gradient from 0-20% B in A over 25 minutes and hold at 20% B at a flow rate of 60 mL/min. Evaporated to afford an oil which crystallized on standing (5.2 g, 75% pure). A portion of the material was purified via preparative HPLC-MS (C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA) to afford product used in the subsequent step. 1H NMR (300 MHz, CDCl3) δ 6.76 (s, 1H), 3.76 (s, 3H), 3.75 (s, 2H).
Reaction SMILES: [O:1]1CCC[CH2:2]1.C[Li].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][CH:17]1[C:37](=[O:38])[N:19]2[C:20]([C:29]([O:31][CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:30])=[C:21]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:22][S:23][C@H:18]12)=[O:15].C(OCl)(C)(C)C>CCOCC.C(O)(=O)C.CO>[CH3:2][O:1][C:17]1([NH:16][C:14](=[O:15])[CH2:13][C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[C:37](=[O:38])[N:19]2[C:20]([C:29]([O:31][CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:30])=[C:21]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:22][S:23][C@H:18]12
Reactant: C1CCOC1
Reactant: CC(=O)OCOC(=O)C1=C(COC(C)=O)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Agent: CC(C)(C)OCl
Agent: [Li]C
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OCOC(C)=O)=C(COC(C)=O)CS[C@@H]21
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To 25 ml of tetrahydrofuran was added 2 ml of a 1.8 molar solution of methyl lithium in ether. The solution was cooled to 0° C. and 4 ml of methanol were added to the solution. The solution was then cooled to -80° C and 468 mg of acetoxymethyl 7-[2-(2-thienyl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate were added, followed by the addition of 0.143 ml of t-butylhypochlorite. The cold reaction mixture was stirred for 25 minutes and was thereafter diluted with 4 ml of glacial acetic acid. The acidified reaction mixture was evaporated to dryness and the residual reaction product mixture was dissolved in dichloromethane. The solution was washed consecutively with a saturated solution of sodium chloride, a dilute solution of sodium thiosulfate, a saturated solution of sodium bicarbonate, and finally with a saturated solution of sodium chloride. The washed solution was dried and was then evaporated to dryness. The residue was chromatographed on preparative thin layer silica gel plates using benzene-ethyl acetate (7:3). The location of separated materials on the chromatogram was determined with an ultraviolet lamp. The reaction product was eluted from the silica gel with acetone. The acetone was evaporated to yield 202 mg of acetoxymethyl 7-methoxy-7-[2-(2-thienyl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=[CH2:17].O[CH:28]([CH3:41])[CH2:29][C:30]([CH:32]1[C:37]([CH3:39])([CH3:38])[CH2:36][CH:35]=[CH:34][CH:33]1[CH3:40])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][CH:28]([CH3:41])[CH2:29][C:30](=[O:31])[CH:32]2[C:37]([CH3:39])([CH3:38])[CH2:36][CH:35]=[CH:34][CH:33]2[CH3:40])=[O:23])=[CH:20][CH:19]=1)=[CH2:17]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: CC(O)CC(=O)C1C(C)C=CCC1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1ccc(C(=O)OC(C)CC(=O)C2C(C)C=CCC2(C)C)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 74.3 %

Procedure:
A solution of DCC (3.60 g, 17.5 mmol) in 10 ml of CH2Cl2 was added to an ice-cold solution of 4-vinylbenzoic acid (2.35 g, 15.9 mmol), DMAP (1.55 g, 12.7 mmol) and 3-hydroxy-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone (4.00 g, 19.1 mmol) in 30 ml of CH2Cl2. The reaction mixture was stirred at room temperature for 5 days. The precipitate was filtered off and the filtrate taken up in CH2Cl2, washed twice with 10% aqueous HCl, saturated aqueous Na2CO3 and saturated aqueous NaCl. The organic phases were dried over Na2SO4 and concentrated. Flash-chromatography over SiO2 (heptane/ether 9:1) gave 4.02 g of the desired compound (yield: 74%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:2][NH2:3])[N:8]=[CH:7][N:6]=1
Reactant: NN
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: O
Product: NNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
11.8 ml (12.1 g, 241.6 mmol) hydrazine hydrate are added dropwise to a solution of 20.0 g (134.3 mmol) 4,6-dichloropyrimidine in ethanol at RT, while stiffing. If clouding of the solution occurs during metering in of the hydrazine hydrate, further ethanol (approx. 400 ml) is added. The reaction solution is subsequently stirred at RT for 12 h. For working up, the solid which has precipitated out is filtered off, the residue on the filter is washed twice with 150 ml water each time and twice with 100 ml diethyl ether each time and the product is dried in vacuo. A further crystalline product fraction is obtained from the concentrated mother liquor.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH2:7]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:25]2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([N:33]3[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10](=[O:11])[C:9]5([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)[S:8][CH2:7]4)[CH2:37][CH2:38]3)=[CH:25]2)=[CH:20][CH:19]=1
Reactant: O=C1N(CCCCBr)CSC12CCCCC2
Reactant: Fc1ccc(-n2cc(N3CCNCC3)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1N(CCCCN2CCN(c3cn(-c4ccc(F)cc4)c4ccccc34)CC2)CSC12CCCCC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]decan-4-one (3.8 g), 1-(4-fluorophenyl)-3-piperazino-1H-indole (3.7 g), K2CO3 (3.5 g), NaI (200 mg) and anhydrous CH3CN (150 ml) was heated to 80° C. with stirring under nitrogen. After 18 hours, no starting amine remained as judged by TLC. The mixture was cooled to room temperature and filtered, and the filtrate concentrated in vacuo. The residue was chromatographed on silica using EtOAc as an eluent. The fractions containing the desired product were combined and concentrated to provide a foam which was recrystallized from ether to provide 2.816 g of crystals, m.p. 134°-136° C., homogeneous by TLC.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(I)c3)c2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(I)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.2 %

Procedure:
A solution of 6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1H-quinolin-2-one (9.68 g, 19.9 mmol), prepared as described in PCT international patent application publication number WO 97/21701 (published Jun. 19, 1997) (3.10 g, 7.87 mmol) in DMF (70 mL) was treated with cesium carbonate (23.1 g, 19.9 mmol) and (bromomethyl)cyclopropane (5.37 g, 39.8 mmol). The reaction mixture was stirred at room temperature for 12 hours, diluted with dichloromethane (75 mL), and washed with 1N HCl (2×50 mL) and brine (100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a black residue. Purification by flash column chromatography (silica, ethyl acetate:petroleum ether 1:9-3:7) gave 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl4-(3-iodo-phenyl)-1H-quinolin-2-one (6.79 g, 63%) as a yellow solid.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([CH2:12][OH:13])[CH2:3][O:4]CC1C=CC=CC=1.[H-].[Na+].C(Br)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([CH2:12][OH:13])[CH2:3][OH:4]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Agent: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CO)CO
Reaction time: 0.5 h

Procedure:
Boc—Ser(Bzl)-ol (300 mg, 1.07 mmol) was dissolved in DMF (2 ml), and NaH (50% oil suspension; 77.3 mg, 1.61 mmol) was added under ice-cooling thereto followed by stirring for 30 minutes. After addition of benzyl bromide (165 μl, 1.39 mmol), the mixture was stirred for 10 minutes under ice-cooling, and stirred for 1 hour at room temperature. Aqueous solution of 10% citric acid was added to the reaction mixture, and ethyl acetate added for extraction. The ethyl acetate layer was washed with saturated aqueous solution of sodium hydrogen carbonate, then saturated aqueous solution of NaCl, dried over magnesium sulfate, and concentrated under reduced pressure, yielding the dibenzyl derivative of Boc—Ser-ol. The Boc group of this compound was removed and sequentially coupled to Boc—Val—OH and then to Boc—Ala—OH. The Boc group of the product was removed. The product (9.5 mg, 16.9 μmol) obtained was coupled to the compound (5.7 mg, 11.1 μmol) obtained in the step 1) of the synthesis of compound (4), and the protecting groups were removed by an ordinary method, yielding compound (8) (0.5 mg) shown in Table 1 as colorless oil.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[Cl:14])=[N+:2]=[N-:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:14][C:5]1[CH:6]=[C:7]([C:10]([F:12])([F:13])[F:11])[CH:8]=[CH:9][C:4]=1[N:1]1[C:24]([NH2:25])=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:3]=[N:2]1
Reactant: COc1ccc(CC#N)cc1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2-chloro-4-trifluoromethyl-benzene (1.00 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.797 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.366 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (20 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow solid residue (1.20 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 15% ethylacetate in hexane, to afford the title compound as a white solid (0.324 g, 30% yield). M.p. 130.0-130.7° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:12]1([NH:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:17]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[O-:18])[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: ONC1CCCC1
Product: CCOc1ccccc1C=[N+]([O-])C1CCCC1
Yield: 72.6 %

Procedure:
Using 2-ethoxybenzaldehyde and N-cyclopentylhydroxylamine and following the procedures described herein, the title compound was obtained in 72.6% yield as white crystals, m.p. 87.3° C. (Rf=0.43 on a silica gel plate using hexanes:EtOAc, 2: 1, v:v, as an eluant).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:37][CH2:36][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCN(CCc4ccccc4)CC3)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.8 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole (53.9 mg, 0.132 mmol) in 1,2-dichloroethane was treated sequentially with phenylacetaldehyde (0.17 mL, 1.5 mmol) and acetic acid (1.7 mL, 3.0 mmol), stirred at ambient temperature for 1.5 hours, treated with sodium triacetoxyborohydride (66.9 mg, 0.316 mmol), stirred at ambient temperature for 3-19 hours, diluted with chloroform and washed with 1.0 N sodium hydroxide and brine. (Methanol was added to the organic phase to aid in solubility.) The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.1-0.5% ammonium hydroxide/1.0-5.0% methanol in chloroform to yield 3-(1-naphthylsulfonyl)-5-{[1-(2-phenylethyl)piperidin-4-yl]oxy}-1H-indazole as an orange foam (45.8 mg, 67.8%). The foam was dissolved in methanol and chloroform, treated with isopropanolic HCl and concentrated in vacuo for 13 hours at 86° C. to give the title product as an orange foam (43.4 mg); Mass spectrum (+EI, [M+H]+) m/z 512. 1HNMR (500 MHz, DMSO-d6): δ14.16 (d, 1H, J=4.52 Hz), 10.19-10.30 (m*, 1H), 8.70-8.76 (m, 1H), 8.56 (dd, 1H, J=7.32 Hz and 1.10 Hz), 8.27 (d, 1H, J=8.18 Hz), 8.04 (d, 1H, J=7.68 Hz), 7.70-7.75 (m, 1H), 7.55-7.63 (m, 3H), 7.10-7.39 (m*, 7H), 4.60-4.82 (m*, 1H), 3.60-3.65 (m, 1H), 3.38-3.45 (m, 1H), 3.30-3.36 (m*, 1H), 3.15-3.24 (m, 2H), 3.01-3.07 (m, 2H), 2.01-2.28 (m*, 3H), 1.80-1.95 ppm (m*, 1H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([O:11]C(=O)C)[CH:9]([O:15]C(=O)C)[CH:8]([O:19]C(=O)C)[CH:7]([O:23][CH2:24][C:25]([CH3:63])([C:27]2[O:31][N:30]=[C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[N:43]=[C:44]5[N:48]([CH:49]=4)[C:47]4[CH:50]=[CH:51][C:52]([O:54][CH2:55][CH2:56][N:57]6[CH2:62][CH2:61][O:60][CH2:59][CH2:58]6)=[CH:53][C:46]=4[S:45]5)=[CH:38][CH:37]=3)=[O:34])[CH:28]=2)[CH3:26])[O:6]1)=[O:4].CO.O.[OH-].[K+]>C(O)(=O)C>[OH:11][CH:10]1[CH:9]([OH:15])[CH:8]([OH:19])[CH:7]([O:23][CH2:24][C:25]([CH3:63])([C:27]2[O:31][N:30]=[C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[N:43]=[C:44]5[N:48]([CH:49]=4)[C:47]4[CH:50]=[CH:51][C:52]([O:54][CH2:55][CH2:56][N:57]6[CH2:58][CH2:59][O:60][CH2:61][CH2:62]6)=[CH:53][C:46]=4[S:45]5)=[CH:38][CH:37]=3)=[O:34])[CH:28]=2)[CH3:26])[O:6][CH:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1OC(OCC(C)(C)c2cc(NC(=O)Nc3ccc(-c4cn5c(n4)sc4cc(OCCN6CCOCC6)ccc45)cc3)no2)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(COC1OC(C(=O)O)C(O)C(O)C1O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C

Procedure:
Final compound 3,4,5-trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6) is prepared by following a general procedure given in J. Med. Chem. 1995, 38, 1911). To a stirred mixture of 3,4,5-triacetoxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid methyl ester (1 equivalent) in 4:1 MeOH:water at rt, is added dropwise aq potassium hydroxide (1-4 equivalents) and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is acidified with glacial acetic acid and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 3,4,5-trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:35])[CH2:29][C:30](OCC)=[O:31])[CH:24]=[CH:25][CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.N#N.[Li+].[Br-].[BH4-].[Na+]>C1COCC1.O.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:35])[CH2:29][CH2:30][OH:31])[CH:24]=[CH:25][CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Agent: N#N
Agent: [BH4-]
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)CCO)c3)n2)cc1

Procedure:
To a solution of ethyl 3-((3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)amino)-3-oxopropanoate (0.17 g) in THF (5 mL), in a 25 mL 3-necked RBF equipped with N2 bubbler, were added LiBr (0.182 g) and NaBH4 (0.081 g). The reaction mixture was stirred at reflux temperature for 3 hr. The reaction was monitored on TLC using ethyl acetate:hexane (8:2) as mobile phase. After completion, the reaction mixture was poured into water. The product was extracted with ethyl acetate and the organic layer was washed with brine and concentrated completely under reduce pressure at 40° C. The obtained solid was purified by column chromatography. Product was eluted with 100% ethyl acetate to give, after concentration, 10.2 mg of N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-3-hydroxypropanamide. 1H NMR: DMSO-d6 (400 MHz): 2.50 (s, 2H), 3.30 (s, 3H), 3.63 (t, 2H, J=4.4), 3.70 (t, 2H, J=5.2), 4.01 (t, 2H, J=4), 4.67 (t, 1H, J=5.2), 6.79 (m, 2H), 7.24 (t, 1H, J=8), 7.33 (d, 1H, J=7.6), 7.51 (m, 3H), 7.85 (s, 1H), 8.05 (d, 1H, J=3.6), 8.94 (s, 1H), 9.34 (s, 1H), 9.87 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2CCCCC2)CCCCC1.Br[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[F:37])[CH:30]=[CH:29][CH:28]=1.[C:38]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:41]([O:40][C:38]([N:45]1[CH2:50][CH2:49][N:48]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][C:35]=3[F:37])[CH:30]=[CH:29][CH:28]=2)[CH2:47][CH2:46]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: Fc1cccc2cccc(Br)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cccc(F)c23)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 38.2 %

Procedure:
A third intermediate compound, 1-(8-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A solution of Pd(OAc)2 (0.25 g, 1.11 mmol, 0.1 equiv)) and dicyclohexylphosphino-biphenyl (0.39 g, 1.11 mmol, 0.1 equiv) in toluene (20 mL) was degassed by bubbling N2 gas for 1 h. 1-Bromo-8-fluoro-naphthalene (2.5 g, 11.1 mmol) in toluene (10 mL) and 1-Boc-piperazine (2.5 g, 13.3 mmol, 1.2 equiv) were added followed by NaOtBu (1.6 g, 16.66 mmol, 1.5 equiv). The mixture was stirred at 80° C. for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane and filtered through a celite pad. The celite was rinsed with dichloromethane and the combined filtrates were concentrated. The residue was purified by silica gel chromatography (20% ethyl acetate in hexane) to give 4-(8-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl ester as a dark oil (1.4 g, 38%). 1H NMR (400 MHz, CDCl3): δ 7.60 (d, 1H), 7.50 (d, 1H), 7.40 (m, 1H), 7.10 (m, 2H), 6.95 (d, 1H), 4.50–4.00 (br s, 2H), 3.40–3.20 (m, 4H), 2.80–2.60 (m, 2H), 1.50 (s, 9H). MS (ES+): 331.08 (M+H)+.