Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[C:12]([OH:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[O:27])=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[C:12]([OH:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2ccc(C(C)(C)C)c(O)c2c1C
Reactant: O=C(Cl)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3cccs3)cc(C(C)(C)C)c(O)c2c1C
Temperature: 25 °C

Procedure:
To a solution of ethyl-3-methyl-4-hydroxy-5-tert-butyl-benzofuran-2-carboxylate 12a (0.760 g, 2.75 mmol) in 30 mL dry (4A sieves) 1,2-dichloroethane at 5° C. under nitrogen was added a solution of thiophene-2-carbonyl-chloride (806 mg, 5.49 mmol) in 5 mL 1,2-dichloroethane followed by the portionwise addition of AlCl3 (0.733 g, 5.59 mmol). The cooling bath was removed and the reaction mixture allowed to warm to room temperature and then refluxed for 1.5 hours. The reaction mixture was then cooled and poured into 100 mL ice cold 2N HCl. The organic layer was removed and the aqueous layer extracted with methylene chloride (3×30 mL). The combined organic layers were washed with 5% NaHCO3 (50 mL), water (50 mL) and saturated NaCl (50 mL) and dried over Na2SO4. Concentration followed by flash chromatography (30% EtOAc in hexane) afforded compound 13 as an oil sufficiently pure for further use; 1H NMR d 1.41 (3H, t, J=6 Hz), 1.55 (9H, s), 2.90 (3H, s), 4.42 (2H, q, J=6 Hz), 7.19 (1H, dd, J=4 Hz), 7.75 (2H, d, J=4 Hz), 7.90 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([NH:10][C@@H:11]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C:12]2[C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])[CH:4]=[CH:3]1.[H][H]>[Pd].CCOC(C)=O>[CH2:18]([C:17]1[C:12]([C@H:11]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[NH:10][C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:1])[NH:7][CH:6]=2)=[O:9])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: C=Cc1cccnc1[C@@H](NC(=O)c1ccc(=O)[nH]c1)c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cccnc1[C@@H](NC(=O)c1ccc(=O)[nH]c1)c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 100 mL round bottom flask containing (S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)-1,6-dihydropyridine-3-carboxamide (40 mg, 0.100 mmol, Example 363) was added EtOAc (20 mL). The resulting mixture was then stirred at 23° C. for 2 min. At this time, Pd/C (10%, 20 mg) was added before a balloon of hydrogen was bubbled through the mixture. The reaction was stirred for 2 h under hydrogen (1 atm) and was then filtered though a plug of Celite® brand filter agent and eluted with EtOAc (50 mL). The solvent was removed, and the material was placed on high vacuum for 1 h to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.67 (d, J=6.9 Hz, 1H), 8.53 (d, J=4.7 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.94 (dd, J=9.6, 2.4 Hz, 1H), 7.36-7.67 (m, 5H), 7.27-7.36 (m, 1H), 6.60 (d, J=9.5 Hz, 1H), 6.50 (d, J=6.7 Hz, 1H), 2.63-2.82 (m, 1H), 2.36-2.62 (m, 1H), 1.11 (t, J=7.5 Hz, 3H). MS (ESI, positive ion) m/z: 402.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][CH:13]=[N:12][CH:11]=1)[NH2:6].[C:15]([C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1)#[N:16]>C(Cl)Cl>[C:15]([C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:10]3[O:14][CH:13]=[N:12][CH:11]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:25])[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: ClCCl
Product: COc1cc(NC(=O)Nc2cccc(C#N)c2)ccc1-c1cnco1
Yield: 89 %

Procedure:
3-Methoxy-4-(5-oxazolyl)aniline, 1D (1.00 g, 5.26 mmol) and 3-cyanophenyl isocyanate (1.17 g, 7.89 mmol) in DCM (40 mL) were stirred at rt for 20 h. The precipitate formed was collected by filtration, followed by washing with dichlorometnane to provide 1E (1.57 g, 89% yield) as a yellow solid. (LC/MS retention time=3.67 min.; M+=335. Column: YMC S5 ODS 4.6×5.0 mm Ballistic. Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Cl[C:7]1([C:13]([O:15][CH3:16])=[O:14])[C:11](=[O:12])[CH:10]=[CH:9][S:8]1.S(=O)(=O)(O)O>C(O)(=O)C>[OH:12][C:11]1[CH:10]=[C:9]([S:2]([CH3:1])(=[O:4])=[O:3])[S:8][C:7]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: CS(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1sc(S(C)(=O)=O)cc1O
Reaction time: 24 h

Procedure:
Sodium methane sulphinate (16 mmol) was added to a solution of 2-chloro-2-methoxycarbonylthiophene-3(2H)-one in acetic acid (20 ml) containing sulphuric acid (1.3 ml). After standing for 24 hours the precipitate was filtered, m.p. 138°-140° C. (acetic acid).
Reaction SMILES: B(O)O.[F:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13](CC(C(O)(C)C)(C)O)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.Cl[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>O.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.C(O)C>[Cl:34][C:29]1[CH:30]=[C:31]([Cl:33])[CH:32]=[C:27]([C:13]2[CH:12]=[CH:11][C:10]([O:9][C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)[N:28]=1
Reactant: CC(C)(O)C(C)(O)Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(Oc2ccc(-c3cc(Cl)cc(Cl)n3)cc2)cc1
Temperature: 80 °C

Procedure:
As described in Scheme 7, in a 50-mL vial with a screw-top septum, 4-(4′-fluorophenoxy)phenyl pinacol boronate (compound A) (3 g, 9.55 mmol) was reacted with 2,4,6-trichloropyridine (compound B) (1.73 grams, 9.55 mmol, Sigma Aldrich), sodium carbonate (2 g, 19.1 mmol), and PdCl2(PPh3)2 (335 mg, 0.48 mmol, Sigma Aldrich), in a 20-mL solution of 2 parts dimethoxyethane, 1 part ethanol, and 2 parts water. The reaction mixture was heated to 80° C. overnight. When the reaction was complete as indicated by LC/MS, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over sodium sulfate, and concentrated. The residue was chromatographed by CombiFlash® (220-gram silica gel, 0-100% EtOAc/Hexane) to provide 2,4-dichloro-6-[4-(4-fluoro-phenoxy)-phenyl]-pyridine (compound C) as a waxy solid (1 g, 3 mmol). 1H NMR (CHCl3): 7.97-7.92 (m, 2 H), 7.60-7.57 (m, 1 H), 7.27-7.24 (m, 1 H), 7.11-6.99 (m, 6H). LC/MS: m/z 333.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])O[C:3]1([O:17]C)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:19][C:2]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:17]
Reactant: COC1(c2ccc(N3CCCCC3)cc2)OC1(C)C
Reactant: C1COCCN1
Product: CC(C)(C(=O)c1ccc(N2CCCCC2)cc1)N1CCOCC1
Temperature: 130 °C

Procedure:
12.1 g (46.3 mmol) of 3,3-dimethyl-2-methoxy-2-(4-piperidinophenyl)-oxirane and 26.1 g (0.30 mol) of morpholine are added together, and the mixture is heated to the refluxing temperature (about 130° C.). After 6 hours the mixture is cooled down and the morpholine is distilled off under reduced pressure. The residue is taken up in toluene and is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and is extracted with toluene. The toluene solution is dried with K2CO3 and concentrated. The residue is recrystallised from methanol. Melting point 159°-162° C.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:27]3[NH:26][C:25]2=[O:33])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:27]3[N:26]([CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[C:25]2=[O:33])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21

Procedure:
[2-(Chloromethoxy)ethyl](trimethyl)silane (1.673 mL) was added to a solution of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g) and sodium hydride (0.504 g) (60% in mineral oil) in DMF (5.0 ml) at 0° C. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. After the reaction, the reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.75 g) as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].[C:25]([O:28][CH:29]=[CH2:30])(=[O:27])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[C:25]([O:28][CH:29]1[CH2:30][N:1]1[C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])(=[O:27])[CH3:26]
Reactant: C=COC(C)=O
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC1CN1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Reaction time: 48 h
Yield: 41 %

Procedure:
A mixture of p-nitrobenzyl 2-azido-carbapen-2-em-3-carboxylate (11.3 mg, 34 micromol), vinyl acetate (0.1 ml), and solid sodium bicarbonate in dry dichloromethane was kept 2 days at ambient temperature, filtered through fluorisil, and evaporated under vacuum. The residue was chromatographed on one 15 cm×20 cm 250 micron silica gel preparative thin layer chromatography plate developed with 5:1 (v/v) diethyl ether-ethyl acetate. The band centered at Rf 0.20 was eluted with ethyl acetate and the eluate was evaporated under vacuum to provide 5.5 mg (41%) p-nitrobenzyl 2-(2-acetoxyaziridin-1-yl)-carbapen-2-em-3-carboxylate; IR (CH2Cl2): 1770, 1735 cm-1 ; NMR (CDCl3): δ 1.90 dd (J1 =6 Hz, J2 =7 Hz, 1H), 2.10 t (J=7 Hz, 1H), 2.13 s (3H), 2.76 bd (J=5 Hz, 2H), 2.85 dd (J 1 =2.5 Hz, J2 =15 Hz, 1H), 3.25 dd (J1 =5 Hz, J2 =15 Hz, 1H), 4.12 m (1H), 4.87 dd (J1 =6 Hz, J2 =7 Hz, 1H), 5.27 s (2H), 7.49 d (J=9 Hz, 2H), 8.25 d (J=9 Hz, 2H).
Reaction SMILES: [Br-].[CH2:2]([O:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O.[CH2:36]([OH:38])[CH3:37]>>[OH:38][CH2:36][C:37]1[CH:34]=[CH:33][C:12](/[CH:13]=[CH:13]/[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:34][CH:33]=2)=[CH:11][CH:10]=1
Reactant: CCCCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCO
Agent: [Br-]
Solvent: O
Product: CCCCCCOc1ccc(/C=C/c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
115 mg (16.5 mmole) of Li were dissolved in 75 ml of ethanol under a nitrogen atmosphere. Then 2.05 g (15 mmole) of aldehyde 4-hydroxymethylbenzaldehyde were added and the mixture was cooled in an ice bath. Then 5.148 g (15 mmole) of (4-hexyloxy-benzyl)-triphenylphosphonium bromide were added. The mixture was stirred in the ice bath under nitrogen for 0.5 hour, and then stirred at room temperature for 3 hours. 2.5 ml of water were added and the precipitate was collected on a filter and washed with 10 ml of ethanol. After drying over silica in a dessicator, 1.75 g of a white powder were obtained. Yield 37%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl>CCOC(C)=O.[OH-].[Na+]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.4 %

Procedure:
To a solution of (S)-methyl 1-((4-nitrophenyl)sulfonyl)pyrrolidine-2-carboxylate (642 mg, 2.0 mmol) in EtOAc (10 mL) was added SnCl2.2H2O (2.02 g, 9.0 mmol). The resulting mixture was stirred at room temperature for 2 d and diluted with EtOAc (50 mL) and 1 N NaOH (10 mL). The layers were separated and the aqueous phase re-extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (30 mL) and dried over MgSO4. The mixture was filtered and the solvent was removed in vacuo to yield the title compound as a white solid (531 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]1>>[Br:1][C:2]1[C:3]([NH:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: Clc1ncc(Br)c(NC2CCOCC2)n1
Yield: 83 %

Procedure:
In the reaction of 5-bromo-2,4-dichloropyrimidine (300 mg, 1.32 mmol) with tetrahydropyran-4-ylamine (144 mg, 1.42 mmol) according to GP 2, the desired product is obtained in 83% yield (320 mg) after chromatographic purification (silica gel, ethyl acetate/hexane with ethyl acetate: 0-100%).
Reaction SMILES: [CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH3:29])=[CH:23][CH:22]=3)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH3:29])=[CH:23][CH:22]=3)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(OC)ccc4[nH]3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2[nH]c(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(5-methoxy-1H-indol-2-yl)quinoxaline-6-carboxylate (100.0 mg, 0.25 mmol) in methanol (30 mL) was added sodium hydroxide (20.0 mg, 0.50 mmol) in water (1 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (3N). The solid was precipitated and filtered to afford 3-(isopropyl(methyl)amino)-2-(5-methoxy-1H-indol-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid as a light yellow solid (23.5 mg, 24%).
Reaction SMILES: [F:1][CH:2]([F:28])[CH2:3][N:4]1[CH2:21][CH:20]([C:22](=[O:27])N(OC)C)[O:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5]1.[CH2:29]([Mg]Br)[CH3:30]>C1COCC1>[F:28][CH:2]([F:1])[CH2:3][N:4]1[CH2:21][CH:20]([C:22](=[O:27])[CH2:29][CH3:30])[O:19][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[CH2:5]1
Reactant: CON(C)C(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To tert-butyl 8-(2,2-difluoroethyl)-10-[methoxy(methyl)carbamoyl]-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (295 mg, 0.72 mmol) in THF (3 mL) at −78° C. under an atmosphere of nitrogen, was added ethylmagnesium bromide (1.7 mL of 1 M in THF, 1.7 mmol) dropwise. The reaction mixture was stirred at the same temperature for 0.5 hours, then at 0° C. for 1 hour. The reaction mixture was quenched with ethyl acetate (20 mL) and sat. aq. NaHCO3 (10 mL). The aqueous layer was further extracted with EtOAc (2×20 mL), and the combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate/hexane) to give tert-butyl 8-(2,2-difluoroethyl)-10-propanoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (227 mg, 83%) as a colorless oil. ESI-MS m/z calc. 376.2. Found 377.3 (M+1)+; Retention time: 1.76 minutes. 1H NMR (400 MHz, CDCl3) δ 6.01-5.70 (m, 1H), 4.21-4.15 (m, 1H), 3.91-3.75 (m, 2H), 3.33-3.22 (m, 1H), 3.15-2.98 (m, 2H), 2.79-2.57 (m, 5H), 2.43-2.35 (m, 1H), 2.19-2.06 (m, 2H), 1.61-1.39 (m, 12H), 1.06 (t, J=7.3 Hz, 3H).
Reaction SMILES: ClC1C=C2C(CCN)=C([Si](CC)(CC)CC)NC2=[N:6]C=1.[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30]([NH2:6])=[O:31])[CH:26]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine (0.128 g; 0.413 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.104 g; 0.434 mmol), HATU (N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.165 g: 0.434 mmol) and N,N-diisopropylethylamine (0.108 mL; 0.619 mmol) in DMF (3 mL) was stirred overnight at room temperature and concentrated under reduced pressure. The crude material was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) to give 0.108 g (49%) of N-(2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2, 3-1)]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.CN(C)C=O.S(OC)(OC)(=O)=O.C[O-].[Na+].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]1[N:45]=[C:44]([O:46][CH3:47])[C:43]([F:48])=[CH:42][C:33]=1[C:34]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:35]>C(OCC)C.O.C(OCC)(=O)C>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]1[C:32]2[C:33](=[CH:42][C:43]([F:48])=[C:44]([O:46][CH3:47])[N:45]=2)[C:34](=[O:35])[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:1]1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC)c(F)cc2c1=O
Yield: 82.8 %

Procedure:
To 4 ml of toluene was added 540 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 85 mg of sodium methoxide was added thereto at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour. Subsequently, 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate was further added to the reaction mixture, and the resulting mixture was subjected to reaction under reflux for 1.5 hours. The reaction mixture was added to a mixture of 8 ml of ethyl acetate and 8 ml of water, and the organic layer was separated, washed with 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 1 ml of diethyl ether, after which crystals were collected by filtration to obtain 170 mg (yield 82.8%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([Cl:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>CCOC(C)=O>[Cl:40][C:34]1[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=[C:32]([NH:31][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])[CH:33]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-methyl-1H-pyrazole-3-carboxylate (Step 55.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.76 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 573/575 [M+H]+ (LC-MS 2); Rf=0.18 (EtOAc).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 124.8 %

Procedure:
A solution of 3-(Trifluoromethyl)phenol (2.0 g, 12.34 mmol), 4-Fluorobenzaldehyde (2.0 g, 16.11 mmol), and Cs2CO3 (5.0 g, 15.35 mmol) in N,N-Dimethylformamide (DMF) (20 mL) was heated at 100° C. for 2 h, then cooled to rt. The solid suspension was removed by filtration over silica pad, and concentrated to afford crude title product (4.1 g) as a yellow liquid. LC-MS (ESI): m/z 267 [M+H]+; 3.60 min (ret time).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][OH:5]>>[CH2:4]([OH:5])[C@@H:1]([C@H:4]([C@@H:1]([C@@H:4]([CH2:1][OH:2])[OH:5])[OH:2])[OH:5])[OH:2]
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S)-2,3,4,6-Tetra-0-acetyl-1,5-anhydro-1-[5-(1-benzothiophene-2-ylmethyl)-2-(cyclopentyloxy)phenyl]-D-glucitol (381 mg) was dissolved in methanol (10 ml). Sodium methoxide (32 mg) was added to the solution, and the mixture was stirred for three hours at room temperature. The reaction mixture was neutralized with acid ion-exchange resin, and the resin was separated by filtration. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(1-benzothien-2-yl)methyl]-2-(cyclopentyloxy)phenyl]-D-glucitol (215 mg).