Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>C1(C)C=CC=CC=1.CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH:19]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 115 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a distillation device and a dropping funnel and having an inner volume of 500 ml were charged 11.0 g (0.2 mol) of sodium methoxide and 30 ml of dimethyl sulfoxide under argon atmosphere, and the temperature of the mixture was raised to 110 to 120° C. while stirring, then, 27.0 g (0.2 mol) of dimethyl malonate with a purity of 98% was gradually added dropwise to the mixture over 30 minutes, and the resulting mixture was stirred for 2 hours while removing methanol under reduced pressure of 0.010 to 0.013 MPa. Subsequently, the mixture was cooled to 100° C. under the same pressure, 16.2 g (0.1 mol) of 2,4-di-fluoronitrobenzene with a purity of 98% was gradually added dropwise to the mixture over 30 minutes, and the mixture was further reacted at the same pressure and the same temperature for one hour. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of toluene was added to the mixture and 40 ml (0.2 mol) of 5 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 50 ml of water and 50 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. This organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it can be found that 20.6 g (yield: 76%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:39][N:40]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:40][CH3:39])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCO[C@@H]1CN(c2nc(C(=O)O)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCO[C@@H]1CN(c2nc(C(=O)NC)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 77 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (74c) (223 mg, 0.43 mmol), methylamine hydrochloride (60 mg, 0.89 mmol), WSC hydrochloride (260 mg, 1.36 mmol) and HOBT (60 mg, 0.44 mmol), to obtain 142.5 mg of the title compound as a white solid (77%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[O:7])=[C:4]([O:21][CH3:22])[CH:3]=1.C1COCC1.CCO>[Fe].CC(O)=O>[NH2:1][C:2]1[C:17]([NH2:18])=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[O:7])=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc(Br)cc1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(N)c(N)cc1C(=O)Nc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-amino-N-(4-bromophenyl)-2-methoxy-5-nitrobenzamide (1.30 g; 3.55 mmol), THF (80 mL) and EtOH (50 mL) was treated with AcOH (3 mL) and stirred for 15 min at 100° C. To the warm mixture, Fe (1.30 g; 23.3 mmol) was carefully added in portions and the resulting mixture was heated for 2 h at 100° C. The mixture was cooled, filtered through celite and concentrated to give the crude sub-title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.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+]>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].C(Cl)Cl.O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][N:12]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN1CCC(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Temperature: 100 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, 130b (1.08 g, 5.65 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.26 g, 8.47 mmol), Pd2(dba)3 (517 mg, 0.565 mmol), XantPhos (523 mg, 0.903 mmol), Cs2CO3 (6.07 g, 18.6 mmol) and dioxane (28.3 mL) were added. The reaction mixture was heated at 100° C. overnight. CH2Cl2 (200 mL) was added to the resulting mixture was washed with water (30 mL×3). CH2Cl2 (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. CH2Cl2/ether (1:2, 5 mL) were added followed by sonication, the precipitation was filtered and dried. Compound 130c was obtained as a green solid, 784 mg (37%).
Reaction SMILES: CC([S@]([NH:7][C@H:8]1[C:17]2[C:12](=[C:13]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)C>C(Cl)Cl.O1CCOCC1.Cl>[F:21][C:20]([F:22])([F:23])[CH2:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:7]
Reactant: CC(C)(C)[S@@](=O)N[C@@H]1CCCc2c(OCC(F)(F)F)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@@H]1CCCc2c(OCC(F)(F)F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of Intermediate 14A (206 mg, 0.590 mmol) in DCM (1 mL) was added 4 N HCl (147 μl, 0.590 mmol) in dioxane. The resulting mixture was stirred at rt for 0.5 h. The solvents were evaporated and DCM (3×) was added and evaporated. The resulting white solid was vacuum dried for 1 h to give Intermediate 14 (0.13 mg, 0.51 mmol, 86% yield) in HCl salt which was used directly without further purification. LCMS=1.55 min [M+1-17]=229 (Method B).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Br:9][CH2:10][C:11](C1C=CC(C)=CN=1)=[O:12]>>[Br:9][CH2:10][C:11]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:12]
Reactant: Cc1ccc(C(=O)CBr)nc1
Reactant: Clc1ccc(Br)nc1
Product: O=C(CBr)c1ccc(Cl)cn1

Procedure:
* 2-Bromoacetyl-5-chloropyridine was prepared from 2-bromo-5-chloropyridine (Case, J. Am. Chem. Soc., 1946, 68, 2574) according to the procedure for preparing 2-bromoacetyl-5-methylpyridine described in step 1 of Example 32.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:12][CH2:13][O:14][C:15]([CH:17]([C:21]([CH3:23])=O)[C:18]([CH3:20])=O)=[O:16]>>[CH2:13]([O:14][C:15]([C:17]1[C:18]([CH3:20])=[N:11][N:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[C:21]=1[CH3:23])=[O:16])[CH3:12]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CCOC(=O)c1c(C)nn(-c2ccc(Cl)c(Cl)c2)c1C
Yield: 32 %

Procedure:
In analogy to the procedure described in Example 38A], 3,4-dichlorophenylhydrazine hydrochloride and ethyl diacetoacetate gave the title compound in 32% yield as yellow solid. MS: 313.0 (MH+, 2 Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:11]=[C:12]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])C>C(O)C>[C:2]1([NH:1][CH:11]=[C:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Solvent: CCO
Product: O=S(=O)(C(=CNc1ccccc1)S(=O)(=O)c1ccccc1)c1ccccc1
Yield: 80.7 %

Procedure:
A mixture of aniline (1.0 g) and 2-ethoxy-1,1-bis(phenylsulphonyl)ethene (3.5 g) was heated at 160°-180° C. for 30 minutes, allowing any ethanol evolved to escape. After cooling, the residue was recrystallised by dissolving in a minimum of hot choroform and diluting with between 3 and 4 volumes of ethanol to give 1-phenylamino-2,2-bis(phenylsulphonyl)ethene (3.2 g), m.p. 199°-202° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(OCC)(=O)C.CCCCCC>ClCCl>[CH3:33][S:34]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:36])=[O:35]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a room temperature solution of 0.1 g (0.3 mmol) of material from Example 50 and 0.06 mL (0.4 mmol) of triethylamine in 2 mL of dichloromethane was added 0.03 mL (0.4 mmol) of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 16 hours. Chromatography (10 g silica gel, 50% ethyl acetate/hexane) of the reaction mixture afforded 0.1 g (94%) of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([Br:26])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([C:17]1[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[N:19][N:18]=1)[CH:13]=[CH:12]2)(=O)=O.[CH3:29][CH:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1.CN1C(=O)CCC1>O>[N:19]1[N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[C:7]([N:32]4[CH2:33][CH2:34][CH2:35][CH:30]([CH3:29])[CH2:31]4)[C:8]([Br:26])=[CH:9][CH:10]=3)[N:15]=2)[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=12
Reactant: O=S(=O)(Oc1c(Br)ccc2ccc(-c3nnc4ccccn34)nc12)C(F)(F)F
Reactant: CC1CCCNC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1CCCN(c2c(Br)ccc3ccc(-c4nnc5ccccn45)nc23)C1
Temperature: 25 °C

Procedure:
The product from Step G (0.025 g, 0.0528 mmol) and 3-methylpiperidine (0.0186 mL, 0.158 mmol) were added to a small microwave reaction vial followed by NMP (0.250 mL). The vessel was placed inside the center of the microwave oven and then it was exposed to microwave irradiation (250 W) for 20 minutes at a temperature of 195° C. After the irradiation, the reaction mixture was cooled to ambient temperature, poured into 10 mL of water and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with saturated brine and dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by column chromatography on silica gel to give the product as a dark orange semisolid which was 80% pure. This material was purified via Preparative TLC using 50% Acetone/hexane as eluent to provide 0.005 g (22%) of the product as an orange film. MS ESI (+) m/z 422.3 (M) detected.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[C:10]([NH:12][C@@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([C@:16]1([CH3:19])[CH2:18][O:17]1)=[O:15])=[O:11].[O:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]([NH:47][C@@H:48]([CH3:52])[C:49]([O-])=[O:50])=[O:46])[CH2:40][CH2:39]1.[K+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][C@H:9]([NH:8][C:49](=[O:50])[C@H:48]([NH:47][C:45](=[O:46])[CH2:44][N:41]2[CH2:42][CH2:43][O:38][CH2:39][CH2:40]2)[CH3:52])[C:10]([NH:12][C@@H:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C@:16]2([CH3:19])[CH2:18][O:17]2)=[O:15])=[O:11])[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@]2(C)CO2)cc1OC
Reactant: C[C@H](NC(=O)CN1CCOCC1)C(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)[C@@H](C)NC(=O)CN2CCOCC2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@]2(C)CO2)cc1OC
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
To (S)-2-amino-3-(3,4-dimethoxyphenyl)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (784 mg, 1.54 mmol) in DMF (5 mL) was added potassium (S)-2-(2-morpholinoacetamido)propanoate (470 mg, 1.85 mmol), HATU (702 mg, 1.85 mmol), DIEA (1.02 mL, 6.16 mmol). The mixture was allowed to stir for 15 min at which time it was quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) followed by trituration from ethyl acetate/heptane (1:1) provided (S)-3-(3,4-dimethoxyphenyl)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((R)-2-(2-morpholinoacetamido)propanamido)propanamide (322 mg, 34%) as a colorless amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=7.7 Hz, 1H), 7.26-7.20 (m, 2H), 6.99 (dd, J=7.5, 1.8 Hz, 2H), 6.86-6.68 (m, 3H), 6.64 (d, J=7.3 Hz, 1H), 6.16 (d, J=7.0 Hz, 1H), 4.78-4.64 (m, 1H), 4.48 (q, J=7.1, 7.1, 7.0 Hz, 1H), 4.42-4.28 (m, 1H), 3.86 (d, J=4.0 Hz, 6H), 3.69 (t, J=4.6, 4.6 Hz, 4H), 3.27 (d, J=5.0 Hz, 1H), 3.08 (dd, J=14.0, 4.9 Hz, 1H), 3.02-2.79 (m, 5H), 2.64 (dd, J=14.0, 8.3 Hz, 1H), 2.45 (q, J=4.0, 3.9, 3.9 Hz, 4H), 1.49 (s, 2H), 1.30 (d, J=7.1 Hz, 3H). MS (EI) for C32H42N4O8, found 611.3 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[O:14][C:13]1=[O:26])[CH3:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][C@H:15]1[O:14][C:13](=[O:26])[N:12]([C@H:10]([CH3:11])[CH2:9][OH:8])[CH2:16]1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 92.3 %

Procedure:
A procedure similar to that described in Preparation was repeated, except that 0.88 g of 3-(2-t-butyldimethylsilyloxy-1(R)-methylethyl)-5(S)-(3-chlorophenoxymethyl)oxazolidin-2-one (prepared as described in Preparation 27), 6.6 ml of tetrabutylammonium fluoride (26% w/v in tetrahydrofuran) and 10 ml of anhydrous tetrahydrofuran were used, to give 0.58 g of the title compound having an Rf value of 0.45 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent) and having [α]D =+45.6° (methanol, c=1.000).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([NH:9][CH:10]=[C:11]([C:17](=[O:28])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([Cl:26])[C:19]=2F)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.NC1C=C(NC=C(C(=O)C2C=C(F)C(F)=C(Cl)C=2F)C(OCC)=O)C(F)=CN=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([N:9]2[C:19]3[C:18](=[CH:23][C:22]([F:24])=[C:21]([F:25])[C:20]=3[Cl:26])[C:17](=[O:28])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10]2)[CH:3]=1
Reactant: CCOC(=O)C(=CNc1cc(N)c(F)cn1)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)C(=CNc1cc(N)ncc1F)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(N)c(F)cn2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To 150 mg of the mixture of ethyl 3-(4-amino-5-fluoropyridin-2-yl)amino-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate and ethyl 3-(2-amino-5-fluoropyridin-4-yl)amino-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate were added 230 mg of anhydrous potassium carbonate and 450 mg of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 20 minutes and allowed to cool. The solution was separated by adding 20 ml of chloroform and 100 ml of distilled water, and the chloroform layer was washed with 100 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 3.2 g; eluent: chloroform:methanol, 100:1), and the fraction containing the main product was concentrated under reduced pressure to obtain 35 mg of the title compound as a yellow solid residue.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:38])[CH:16]([CH3:37])[C:17](=[O:36])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][Si](C(C)(C)C)(C)C)=[C:22]([O:34][CH3:35])[CH:21]=2)=[CH:11][C:10]=1[O:39][CH3:40])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:38])[CH:16]([CH3:37])[C:17](=[O:36])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:34][CH3:35])[CH:21]=2)=[CH:11][C:10]=1[O:39][CH3:40]
Reactant: COc1cc(CCC(=O)C(C)C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(OC)c2)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)C(C)C(=O)c2ccc(O)c(OC)c2)ccc1O
Temperature: 25 °C
Yield: 66.2 %

Procedure:
1,5-Bis(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)-2-methyl-pentane-1,3-dione (250 mg, 0.43 mmol) was dissolved in anhydrous THF (8 ml) and stirred at room temperature under a nitrogen atmosphere. Tetrabutylammonium fluoride (0.27 ml, 0.94 mmol) was added and the mixture was stirred for 2 h and monitored by TLC. After this time the solvents were removed under vacuum to leave a residue which was purified on silica gel column using dichloromethane/ethyl acetate (1:0 to 5:1) to give 1,5-bis(4-hydroxy-3-methoxyphenyl)-2-methylpentane-1,3-dione (102 mg, 67%) as a light green oil: LCMS (m/z) 359 (M+H)+, 381 (M+Na)+; 1H NMR (400 MHz, CDCl3) δ 1.40 (3H, d, J=7.2 Hz, CH3), 2.63-2.82 (4H, m, 2×CH2), 3.81 (3H, s, OCH3), 3.94 (3H, s, OCH3), 4.39 (1H, q, J=7.2 Hz, H-2), 5.45 (1H, brs, OH), 6.13 (1H, brs, OH), 6.58-6.60 (2H, m, 2×ArH), 6.76 (1H, d, J=8.4 Hz, ArH), 6.92 (1H, d, J=8.4 Hz, ArH), 7.44-7.48 (2H, m, 2×ArH) ppm; 13C NMR (100 MHz, CDCl3) δ 13.57, 29.34, 42.17, 55.73, 55.97, 56.13, 110.31, 110.97, 113.98, 114.20, 120.77, 124.08, 128.80, 132.57, 143.81, 146.27, 146.80, 150.95, 195.57, 206.67 ppm.
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[O:17]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19][CH2:18]1.Cl>C(Cl)Cl.CO>[CH:22]1([O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCC2(CC1)OCCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: OCCCOC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.8 %

Procedure:
14.0 ml (14.0 mmol) of a 1M hexane solution of diisobutylaluminum hydride were added dropwise over a period of 5 minutes to a solution of 1.01 g (647 mmol) of 1,5-dioxaspiro[5.5]-undecane in 5 ml of methylene chloride, and the resulting mixture was stirred for 1 hour at room temperature. At the end of this time, the reaction mixture was ice-cooled and 20 ml of methanol were added dropwise over a period of 5 minutes in order to stop the reaction. The mixture was stirred for 20 minutes at room temperature, and then 2N aqueous hydrochloric acid was added to dissolve the precipitate. The mixture was then extracted with diethyl ether. The extract was washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 25 g of silica gel, using a 3:1 by volume mixture of diethyl ether and hexane as the eluent, to give 774 mg (yield 76%) of the title alcohol derivative as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=3[CH3:28])=[N:14][C:13](Cl)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>O>[CH2:1]([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=3[CH3:28])=[N:14][C:13]([NH:30][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1nc(Cl)nc2ccn(Cc3ccccc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(Cc3ccccc3)c12
Temperature: 90 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
In a sealed tube was added 5-benzyl-2-chloro-4-(2,6-dimethyl-4-nitrophenoxy)-5H-pyrrolo[3,2-d]pyrimidine (598 mg, 1.46 mmol), 4-aminobenzonitrile (691 mg, 5.85 mmol), TFE (9.1 mL) and TFA (1.97 mL, 11.7 mmol). The reaction mixture was stirred at 90° C. for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1-1:1), to give the product (442 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]([O:33]CC4C=CC=CC=4)=[O:32])[CH2:25][CH2:24]3)=[O:22])[O:18][C:17]2=[O:41])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.CO>CN(C=O)C.[Pd].C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:25][CH2:24]3)=[O:22])[O:18][C:17]2=[O:41])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CC(C(=O)N3CCN(CCC(=O)OCc4ccccc4)CC3)OC2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(N2CC(C(=O)N3CCN(CCC(=O)O)CC3)OC2=O)cc1

Procedure:
1.5 g of benzyl 3-{1-[3-(4-tert-butoxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperazinyl}propionate are hydrogenated in 50 ml of DMF over 5% Pd/charcoal. After customary workup, the crude product is dissolved in a solvent mixture consisting of dichloromethane/methanol/glacial acetic acid (70:30:2) and chromatographed over silica gel. Trituration of the product with ether gives 3-{1-[3-(4-tert-butoxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperazinyl}propionic acid, m.p. 76°-78°.