Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[OH:8][CH:9]([CH2:15][NH:16][OH:17])[CH2:10][P:11](=[O:14])([OH:13])[OH:12]>C(O)=O>[CH:1]([N:16]([CH2:15][CH:9]([OH:8])[CH2:10][P:11](=[O:13])([OH:12])[OH:14])[OH:17])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=P(O)(O)CC(O)CNO
Solvent: O=CO
Product: O=CN(O)CC(O)CP(=O)(O)O
Yield: 16 %

Procedure:
Formic acid (300 mg.) was added dropwise to acetic anhydride (330 mg.) with stirring and the mixture was stirred for half an hour. To this solution were added 2-hydroxy-3-(N-hydroxyamino)propylphosphonic acid (430 mg.) and then formic acid (0.5 ml.), and the mixture was stirred for 1.5 hours at ambient temperature and then evaporated to dryness under reduced pressure. The oily residue was dissolved in methanol (10 ml.) and adjusted to pH 6-7 with conc. aqueous ammonium hydroxide solution to give oily precipitates which was collected by decantation and pulverized by triturating with methanol to give monoammonium salt of 3-(N-formyl-N-hydroxyamino)-2-hydroxypropylphosphonic acid (80 mg.).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7]O)[CH2:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH3:9][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][N:33]2[C:29](=[O:39])[C:30]3[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:34])[CH2:4][CH2:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1(C)CC[C@@H](CO)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC[C@@H](CN2C(=O)c3ccccc3C2=O)O1
Temperature: 8 °C

Procedure:
To a stirred solution of (S)-(5,5-dimethyltetrahydrofuran-2-yl)methanol (14 g, 108 mmol) and PPh3 (33.8 g, 129 mmol) in THF (140 ml) under N2 was added phthalimide (17.40 g, 118 mmol) to give a suspension. The mixture was cooled to 8° C. and DIAD (27.2 ml, 140 mmol) was added dropwise over 30 mins keeping internal T<10° C. The resulting white slurry was diluted with water (100 ml) and extracted with EtOAc (100 ml). The organics were washed with sat. NaHCO3 (100 ml), brine (100 ml) and dried (MgSO4) and concentrated under reduced pressure. Purification by chromatography on silica eluting with 0-20% EtOAc/iso-hexane afforded the title compound as a white crystalline solid;
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([O:18]C)=[O:17])[CH:11]=2)[O:6][C:5]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>CO.C1COCC1.CCOC(C)=O>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([OH:18])=[O:17])[CH:11]=2)[O:6][C:5]=1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1cnc2oc(-c3ccc(F)cc3)c(Br)c2c1
Reaction time: 1 h
Yield: 96.6 %

Procedure:
NaOH (3.3 mL, 3.3 mmol, 1M aq) was added to a stirring solution of methyl 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (294 mg, 0.668 mmol) in MeOH (7 mL) and THF (7 mL) at 60° C. It was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoic acid (275 mg, 0.645 mmol, 97% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.90 (1H, br. s.), 8.40 (1H, d, J=2.26 Hz), 8.18-8.25 (2H, m), 8.05 (1H, d, J=2.26 Hz), 7.92 (1H, dd, J=7.78, 1.76 Hz), 7.85 (1H, d, J=1.76 Hz), 7.43-7.54 (3H, m), 2.35 (3H, s). LC-MS retention time: 2.42 min; m/z (MH+): 426, 428. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16])[CH2:3][CH2:4][CH3:5]>ClCCl.[O-2].[O-2].[Mn+4]>[C:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16])(=[O:1])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1ccc(C(=O)OC)cc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCC(=O)c1ccc(C(=O)OC)cc1C
Temperature: 30 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a solution of (+/−)-methyl 4-(1-hydroxybutyl)-3-methylbenzoate (0.8 g, 4 mmol) in dichloromethane (15 mL) was added manganese dioxide (3.13 g, 36.0 mmol). The reaction was stirred at 30° C. overnight. TLC showed starting material remained and the reaction was heated to reflux for 5 hours. The reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated and purified by flash column chromatography to give methyl 4-butyryl-3-methylbenzoate (290 mg) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.90 (d, J=7.6 Hz, 2H), 7.59 (d, J=7.6 Hz, 1H), 3.93 (s, 3H), 2.86 (t, J=7.6 Hz, 2H), 2.49 (s, 3H), 1.69-1.78 (m, 2H), 0.99 (t, J=7.6 Hz, 3H).
Reaction SMILES: N1C=CC=CC=1.[P:7]([Cl:10])(Cl)[Cl:8].[CH:11]([NH:14][CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>CCOCC>[Cl:8][P:7]([Cl:10])[N:14]([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12]
Reactant: ClP(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)N(C(C)C)P(Cl)Cl
Temperature: -70 °C
Yield: 36.3 %

Procedure:
300 ml abs. ether, 81 ml anhydrous pyridine and 87.5 ml PCl3 (1 Mol) are pre-cooled with stirring to -70° C. in a 2 l three-neck, round-bottomed flask with a 500 ml dropping funnel, KPG stirrer, thermometer and acetone/dry ice bath. 142 ml diisopropylamine (1 Mol) in 250 ml abs. ether are added dropwise to it within 2 hours and the temperature is maintained at ca -60° to -65° C. After completing the addition, the thickened pulpy reaction mixture is allowed to reach room temperature and is diluted with about 600 ml abs. ether to make it more easily stirrable. After a further 3 hours stirring at room temperature the precipitate which forms is aspirated over a glass filter and washed several times with ether. After drawing off the ether at normal pressure, it is freed of unreacted PCl3, diisopropylamine and pyridine in a water-jet vacuum and then the remaining oil is fractionally distilled under an oil-pump vacuum (Kp 46° C./0.35 Torr). 73.4 g of the phosphane is obtained which corresponds to 36% of the theoretical yield.
Reaction SMILES: [F:1][C:2]([C:5]1[C:6](=[O:19])[C:7]([OH:18])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[CH3:11])([F:4])[F:3].[CH2:20]([O:22]CC)[CH3:21]>C(OC(=O)C)(=O)C>[F:3][C:2]([C:5]1[C:6](=[O:19])[C:7]([O:18][C:20](=[O:22])[CH3:21])=[N:8][N:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]=1[CH3:11])([F:1])[F:4]
Reactant: Cc1c(C(F)(F)F)c(=O)c(O)nn1-c1ccccc1
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1nn(-c2ccccc2)c(C)c(C(F)(F)F)c1=O
Temperature: 50 °C
Yield: 70 %

Procedure:
A suspension of Compound 1 (2.36 grams) in acetic anhydride is heated for six hours at 50° C. The recooled solution is concentrated under vacuum. There is obtained, after the addition of diethyl ether, filtration, washing with ether and drying, the Compound 3 (1.91 grams; yield=70%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([O:32][CH3:33])=[CH:9][C:10]2[C:11]3[C:12]4[C:29](=[O:30])[NH:28][C:27](=[O:31])[C:13]=4[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:15][C:16]=3[NH:17][C:18]=2[CH:19]=1)(=O)=O.C([Sn](CCCC)(CCCC)/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])CCC.[Cl-].[Li+].C(OCC)(=O)C>CN(C=O)C.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>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[C:13]2[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:12]=2[C:11]2[C:10]3[CH:9]=[C:8]([O:32][CH3:33])[C:7](/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])=[CH:19][C:18]=3[NH:17][C:16]=2[CH:15]=1
Reactant: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reactant: CCCC[Sn](/C=C/CCO)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1/C=C/CCO)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 95.9 %

Procedure:
A solution of the triflate (169) (0.20 g, 0.35 mmol) prepared as described in example 308, (3E)-4-(tributylstannyl)-3-buten-1-ol (0.19 g, 0.53 mmol) and lithium chloride (29 mg, 0.70 mmol) in DMF (10 mL) was purged by bubbling nitrogen through the liquid for 10 min. Bis(triphenylphosphine)palladium dichloride (12 mg, 0.017 mmol) was added last and the solution was flushed with nitrogen for 2 min more, then warmed under an atmosphere of nitrogen for 3 h. The mixture was diluted with brine, extracted with ethyl acetate and worked up to give an oil which was chromatographed on silica. Elution with ethyl acetate/petroleum ether (1:5) gave foreruns, while ethyl acetate/petroleum ether (1:1) increasing to pure ethyl acetate gave (170) as a yellow solid (0.15 g, 95%), mp 271–275° C. 1H NMR δ [(CD3)2SO] 11.86 (br s, 1H), 11.07 (br s, 1H), 8.45 (s, 1H), 7.70 (s, 1H), 7.58 (dd, J=8.1, 2.2 Hz, 1H), 7.55 (s, 1H), 7.51–7.41 (m, 3H), 6.87 (d, J=16.0 Hz, 1H), 6.44 (dt, J=16.0, 7.1 Hz, 1H), 4.62 (t, J=5.3 Hz, 1H), 3.94 (s, 3H), 3.58 (m, 2H), 2.42 (m, 2H). Found: C, 67.09; H, 4.36; N, 5.98. C25H19ClN2O4 requires C, 67.19; H, 4.28; N, 6.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([Cl:19])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2ccc(C(=O)O)s2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(=O)Cl)s2)cc1
Temperature: 100 °C

Procedure:
To a solution of 5-(4-methoxyphenyl)thiophene-2-carboxylic acid (0.60 g, 2.5 mmol) in toluene (4 mL) was added thionylchloride (560 mL, 7.7 mmol) and the reaction mixture was heated at 100° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated to afford the desire product (642 mg, crude): ESI MS m/z 253 [C12H9ClO2S+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc(I)cn1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 179 mg (0.66 mmol) of 5-iodo-2-trifluoromethyl-pyridine in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 76 mg of a white powder. LC-MSD, m/z for C22H13BrF3N3O2 [M+H]+=488.0, 490.0; HPLC retention time: 2.5 min.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27](C)=[CH2:28])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.I([O-])(=O)(=O)=[O:31].[Na+].O.[BH4-].[Na+]>C1COCC1.O.[Os]=O>[OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][CH:27]([OH:31])[CH3:28])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(C)Cc1ccccc1-c1cc2ccc(N3C[C@H](CO)OC3=O)cc2c(=O)[nH]1
Agent: O=[Os]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)Cc1ccccc1-c1cc2ccc(N3C[C@H](CO)OC3=O)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
The 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-[2-(2-methylallyl)phenyl]-2H-isoquinolin-1-one (25 mg, 0.064 mmol) obtained in Example 2-40 was dissolved in THF-water (3 ml-1 ml). Thereafter, an osmium oxide aqueous solution (0.1 mmol/ml, 0.032 ml, 0.0032 mmol) and sodium periodate (55 mg, 0.26 mmol) were added to the solution, and the obtained mixture was then stirred at a room temperature for 15 hours. Thereafter, water was added to the reaction mixture, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate, and was then concentrated under reduced pressure. The thus obtained ketone body (24 mg) that was a roughly purified product was dissolved in methanol (2 ml) without being further purified. Thereafter, sodium borohydride (7.3 mg, 0.19 mmol) was added to the obtained solution under cooling on ice. The obtained mixture was stirred at a room temperature for 2 hours. Thereafter, the reaction solution was concentrated, and was then purified by preparative TLC (methylene chloride:methanol=10:1), so as to obtain 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-[2-(2-hydroxypropyl)phenyl]-2H-isoquinolin-1-one (15.3 mg, 61%, two-stage) in the form of white powders.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:17][CH2:16][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC=C(C(=O)OC)c1cccc(Cl)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1cccc(Cl)c1CBr
Temperature: 25 °C

Procedure:
27.0 g of methyl α-(3-chloro-2-methylphenyl)-β-methoxyacrylate and 21.5 g of N-bromosuccinimide were stirred in 300 ml of anhydrous tetrachloromethane. After 1 g of Porofor N had been added, the mixture was refluxed for 4 hours. After cooling to room temperature (=25° C.), the succinimide was removed. The combined organic phases were washed with water, dried over sodium sulfate and concentrated. This gave 23 g of the title compound as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1.CO.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
To a mixture of tert-butyl 4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)piperidine-1-carboxylate (63 mg) and methanol (1.3 mL) were added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.15 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized by the addition of saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-piperidin-4-ylpyrimidin-2-amine (27 mg) as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C>[C:13]([O:12][C:11]([NH:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:3][CH:4]=1)[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][CH:25]=[CH:24]2)=[O:19])=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-(4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenoxy)acetate (E250) was prepared from E249 according to the scheme in FIG. 14. To tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E249) in DMF cooled to −35° C. was added NaH, and the solution was stirred at −35° C. for 30 min. Then, methyl bromoacetate was added and the solution was warmed and stirred at 0° C. for 1 h. The solution was poured into NaHCO3(sat)/EtOAc and further extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3-4% MeOH/CH2Cl2) gave pure methyl 2-(4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenoxy)acetate (E250).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([CH:21]=1)[C:19]#[N:20].O>CN(C)C=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:18]([CH:21]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: OCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Br)ccc1OCCCc1ccccc1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
3-Phenylpropanol (2.17 g) was dissolved in N,N-dimethylformamide (32 ml), and sodium hydride (60%, 0.638 g) was added at room temperature. After stirring for 1 hr, 5-bromo-2-fluorobenzonitrile (1.60 g) was added, and the mixture was further stirred at 40-50° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (2.30 g) as a colorless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([N:22]2[C@H:26]([CH3:27])[C@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])=[O:21])=[CH:14][CH:13]=1.[C:35]([O:39][C:40](=[O:43])[CH2:41]Br)([CH3:38])([CH3:37])[CH3:36]>C1COCC1>[C:35]([O:39][C:40](=[O:43])[CH2:41][C@H:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[C:20]([N:22]1[C@H:26]([CH3:27])[C@H:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:24][C:23]1=[O:34])=[O:21])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 79.5 %

Procedure:
NaHMDS (1.0M, 17 mL, 17 mmol) was added to a stirred solution of (4R,5S)-3-[3-(4-Chlorophenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one (4.8 g, 14 mmol) in THF (200 mL) at −78° C. under N2. Stirred at −78° C. for 45 minutes and then Bromo-acetic acid tert-butyl ester (2.5 mL, 17 mmol) was added dropwise over 10 minutes. The solution was allowed to warm to −20° C. over 4 hours and then quenched with saturated aqueous NH4Cl. The product was extracted into EtOAc (2×300 mL), dried over Na2SO4, concentrated in vacuo and purified by column chromatography on silica (20% EtOAc/hexanes) to give (3S)-3-(4-Chlorobenzyl)-4-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-4-oxo-butyric acid tert-butyl ester (5.1 g, 80%.) 1H NMR (CDCl3, 400 MHz) δ 7.44-7.21 (9H, m), 5.45 (1H, d, J 7.3 Hz), 4.68-4.62 (1H, m), 4.51-4.42 (1H, m), 3.01 (1H, dd, J 13.0 and 6.2 Hz), 2.78 (1H, dd, J 16.7 and 10.6 Hz), 2.63 (1H, dd, J 13.2 and 9.0 Hz), 2.32 (1H, dd, J 6.7 and 4.3 Hz), 1.38 (9H, s), 0.89 (3H, d, J 6.6 Hz.)
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.CCCCCC>[C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH:12]([O:14][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])[CH2:11]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCC1CC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CC(ON2C(=O)c3ccccc3C2=O)C1

Procedure:
Analogously to Example 1 b, but using ethyl acetate/hexane mixtures (1:3 and 1:1) in the flash chromatography, starting from 15.24 g (0.0757 mol) of 3-(N-BOC-aminomethyl)-cyclobutanol, 12.35 g (0.0757 mol) of N-hydroxyphthalimide, 19.85 g (0.0757 mol) of triphenylphosphine and 13.3 ml (0.0795 mol) of diethyl azodicarboxylate (93%), the title compound, which melts at 161°-162° C. after recrystallization from ethyl acetate, is obtained. Evaporation of the mother liquor and recrystallization of the residue from ethyl acetate/hexane gives a further batch of the title compound, m.p. 145°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([OH:34])=O)=[N:10]2)=[CH:5][CH:4]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:57][S:58]([NH2:61])(=[O:60])=[O:59]>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([NH:61][S:58]([CH3:57])(=[O:60])=[O:59])=[O:34])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(-n2nc(C(=O)O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)NS(C)(=O)=O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Reaction time: 0.25 h

Procedure:
To 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (0.2 g, 0.43 mmol) in CH2Cl2 (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.1 g, 0.5 mmol) and TEA (0.18 mL, 1.3 mmol) and the reaction was stirred for 15 min. 1-Hydroxybenzotriazole (71 mg, 0.5 mmol) was added and the reaction was stirred for 15 min. Methane sulfonamide (0.125 g, 1.3 mmol) and DMF (1 mL) were added and the reaction was stirred for 72 h. The solvents were removed and after purification by HPLC and freeze-drying 75 mg (33%) white solid was obtained; High Resolution Mass Spec (M+H)+ for C26H24N5O6S 534.1468.