Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[C:7]([C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[C:7]([C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:34])=[O:33]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(N(CCO)CCO)c1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c([N+](=O)[O-])ccc(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A solution of methyl 3-[bis(2-hydroxyethyl)amino]-2,6-dinitrobenzoate [Palmer et al., J. Med. Chem. 1996, 39, 2518] (7.24 g, 22 mmol) in CH2Cl2 (120 mL) was cooled in an ice-bath and Et3N (15 mL) and MsCl (8 mL) were added in one portion. After stirred for 10 min, satd. NaHCO3 (100 mL) was added, and after a further 30 min the aqueous phase was extracted with CH2Cl2 (2×70 mL), the combined organic phase were dried, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel. Elution with EtOAc/petroleum ether (1:1 to 1:0), gave crude methyl 3-(bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,6-dinitrobenzoate (16) (10.67 g, 100%) as a yellow oil;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:34]([O:36][CH2:37][CH2:38][NH2:39])[CH3:35]>>[CH2:34]([O:36][CH2:37][CH2:38][NH:39][C:28]([C:14]1[C:15](=[O:27])[N:16]([CH2:19][C:20](=[O:26])[N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]2[C:12]([C:13]=1[OH:33])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:29])[CH3:35]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Reactant: CCOCCN
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-l -[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.18 (1H, br m), 8.53 (1H, d, J=1 Hz), 7.15 (2H, dd, J=8.6, 5.5 Hz), 7.08 (1H, s), 7.02 (2H, m), 4.87 (2H, s), 4.11 (2H, s), 3.61 (4H, m), 3.59-3.44 (6H, m), 2.04 (2H, m, J=7 Hz), 1.89 (2H, m, J=7 Hz), 1.22 (3H, t, J=7 Hz); HRMS calcd for C26H29FN4O5+H+: 497.2200. Found: 497.2190.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1>CS(C)=O.O>[O:9]1[C:10]2([CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)[CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)C1CCCC(=O)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1CCCC2(CO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of trimethylsulfoxonium iodide (53.3 g, 242 mmol) in dry DMSO (300 mL) under N2, was added sodium hydride (9.69 g, 242 mmol) portionwise over 30 min. This light yellow mixture was stirred at RT for 1 h. The reaction mixture was then cooled in an ice bath and treated with methyl 3-oxocyclohexanecarboxylate (29.0 g, 186 mmol) dropwise while maintaining a temperature at or below 27° C. The resulting reaction mixture was allowed to warm slowly to RT and stir overnight. The reaction was diluted with water and extracted with DCM. The combined organics were washed with water, dried over MgSO4, filtered, and concentrated to provide methyl 1-oxaspiro[2.5]octane-5-carboxylate (31.8 g, 85% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.71 (m, 1H), 2.65 (d, J=1.76 Hz, 2H), 2.00 (dd J=11.8, 13.6 Hz, 2H), 1.74-1.85 (m, 2H), 1.60-1.74 (m, 1H), 1.40-1.56 (m, 2H), 1.17-1.32 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Br:11])[C:3]=1[OH:12].[C:13](=[O:16])([O-])[O-].[K+].[K+].BrCCCCCC[C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:29]([NH:31][C:32](=[O:33])[C:27]=12)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Br:11])[C:3]=1[O:12][CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][CH2:29][N:31]1[C:32](=[O:33])[C:27]2[C:26](=[CH:36][CH:35]=[CH:34][CH:28]=2)[C:13]1=[O:16]
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)c2c(CCCCCCBr)cccc21
Reactant: O=[N+]([O-])c1cc(Br)c(O)c(Br)c1
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCCCOc1c(Br)cc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-dibromo-4-nitrophenol (2.00 g, 6.74 mmol) in acetonitrile (10 mL) was added potassium carbonate (2.79 g, 20.22 mmol). The resulting mixture was stirred for 0.5 h under reflux conditions. To this was added 6-bromohexylphthalimide (2.30 g, 7.41 mmol) and continued stirring for another 72 hours at 80° C. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo. MPLC purification (Hexanes:EtOAc/80:20) of the residue gave 12 as a white amorphous solid (1.10 g, 60%). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 2H), 7.82-7.84 (m, 2H), 7.69-7.72 (m, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.70 (t, J=7.2 Hz, 2H), 1.87-1.91 (m, 2H), 1.72-1.75 (m, 2H), 1.58-1.62 (m, 2H), and 1.43-1.47 (m, 2H).
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].[CH3:11][Si:12]([CH3:18])([CH3:17])[C:13]#[C:14][CH:15]=O.C[Si](Cl)(C)C.[C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH3:25]>CC(OC)(C)C>[NH2:5][CH:15]([C:14]#[C:13][Si:12]([CH3:18])([CH3:17])[CH3:11])[CH2:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C#CC=O
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)CC(N)C#C[Si](C)(C)C
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a 500 mL, 3-neck round bottom flask equipped with a mechanical stirrer and under a blanket of nitrogen was charged 110 mL of lithium bis(trimethylsilyl)amide (1.0M solution in THF) while maintaining the internal temperature at -20° C. using an isopropanol/dry ice bath. Once the desired temperature was attained, 20.14 g of 3-(trimethylsilyl)-2-propynal (a 62.7% solution in MTBE) was added to the reaction flask over 2 h. Upon completing the addition, the reaction mixture was stirred for 10 min at -20° C. followed by the addition of 10.3 g of trimethyl silyl chloride over a period of 20 min while maintaining the batch temperature at -20° C. Upon completing the addition the reaction mixture was stirred for 10 min at which time 69.7 g of t-butyl acetate was added to the reaction mixture over 15 min while maintaining the batch temperature at -20° C. The reaction mixture was stirred for 10 min at -20° C. at which time 19.2 mL of lithium bis(trimethylsilyl)amide (1.0M solution in THF) was added over a period of 40 min while maintaining the batch temperature at -20° C. An in-process check was performed on an aliquot using GC Method C to ensure that the area % of the desired product was >55%. The reaction mixture was added to an ammonium chloride solution (prepared by adding 5.0 g of ammonium chloride in 25 mL of water) and the mixture was allowed to reach ambient temperature with stirring (25° C.). The mixture was stirred at ambient temperature (25° C.) for 1 h. The mixture was transferred to a separatory funnel and the phases were separated. An in-process check was performed using GC Method C to determine the presence of desired product. This material was used without further purification. The solvent from the organic phase was removed under reduced pressure to give 34.5 g of the title compound as a brown oil (49.52 wt %, a molar yield of 70.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:27]=[CH:26]C3C(=CC=C(C=O)C=3)N=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C[Mg]Br.O.C([O:37][CH2:38][CH3:39])(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:5]3[C:4](=[CH:3][CH:2]=[C:7]([CH:38]([OH:37])[CH3:39])[CH:6]=3)[N:17]=[CH:26][N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc2nc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncc2c1
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
In 30 mL of tetrahydrofuran was dissolved 620 mg of 4 (3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1), the solution was cooled to 0° C. under the nitrogen atmosphere, and 4.9 mL of methylmagnesium bromide (0.93M tetrahydrofuran solution) was added dropwise. After the reaction at 0° C. for 1 hour under the nitrogen atmosphere, water and ethyl acetate were added to separate the layers. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, the resulting crystal was washed with chloroform to obtain 330 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-hydroxyethan-1-yl)quinazoline (VI-1).
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][C:3]1=[O:13].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[H-].[Na+].[Na+].[Cl-]>CN(C)C=O>[CH2:19]([O:18][C:16]([CH2:15][N:4]1[C:3](=[O:13])[CH:2]([CH3:1])[S:6][CH:5]1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: CC1SC(c2cccnc2)NC1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(C)SC1c1cccnc1
Reaction time: 1 h
Yield: 55 %

Procedure:
5-Methyl-2-(3-pyridyl)thiazolidin-4-one (10 g, 51.5 mmol) and ethyl bromoacetate (6.85 ml, 61.8 mmol) were dissolved in dry dimethylformamide (50 ml), and 60% sodium hydride (2.16 g, 54.1 mmol) was added in limited amounts to the solution at 0° to 10° C. This reaction mixture was kept between those temperatures for 1 hour. The mixture, after addition of aqueous NaCl, was extracted with ethyl acetate. The extract was washed with aqueous NaCl, dried, and the solvent was removed in vacuo. The residue was chromatographed on silica gel, giving the cis-isomer (5.8 g) (compound No. 9) and the trans-isomer (2.1 g) (compound No. 10) of the title compound (55% yield). Compound No. 9: cis-isomer NMR (CDCl3, δ) [ppm]; 1.24 (3 H, t, J=7.2 Hz), 1.67 (3 H, d, J=7.1 Hz), 5.81 (1 H, s). IR (CHCl3) [cm-1 ]; 2950, 1740, 1683, 1587, 1575, 1441, 1370, 1014. Compound No. 10: trans-isomer NMR (CDCl3, δ) [ppm]; 1.25 (3 H, t, J=7.2 Hz), 1.68 (3 H, d, J=7.1 Hz), 5.83 (1 H, d, J=1.7 Hz). IR (CHCl3) [cm-1 ]; 2950, 1739, 1685, 1585, 1572, 1370, 1345, 1012.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=O)[N:5]1[CH3:11].P(Cl)(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].C([O-])(=O)/C=C/C([O-])=O>C(Cl)(Cl)Cl.C(O)(C)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]1[CH3:11]
Reactant: CN1CC(CCCl)N(C)C1=O
Reactant: Nc1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CC(CCCl)N(C)C1=Nc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
To 8.0 g (0.045 mole) of 4-(2-chloroethyl)-1,3-dimethyl-2-oxo-imidazolidine was added 50 ml of phosphorus oxychloride, and the solution was refluxed for 18 hours, and concentrated in vacuo. The residue was dissolved in 25 ml of methylene chloride and added dropwise to 4.2 g (0.045 mole) of aniline stirring at room temperature. Stirring was continued for two hours. The solution was diluted with chloroform and washed with dilute sodium hydroxide solution. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in isopropyl alcohol and treated with 5.2 g. (0.045 mole) fumaric acid, and the resulting fumarate was recrystallized from isopropyl alcohol and weighed 9.0 g (50% yield); m.p. 109°-112° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C@@H:21]([OH:23])[CH3:22])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1>>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C@@H:21]([OH:23])[CH3:22])=[O:18])[CH:14]=[N:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: C[C@H](O)CNC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: C[C@H](O)CNC(=O)c1cncc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with (S)-(+)-1-amino-2-propanol via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 7.6 mg of 342. MS (Q1) 516.5. (M)+.
Reaction SMILES: C(S(O)=O)C(N)C(O)=O.[CH2:10]([N:21]([CH2:26][C:27]([O-:29])=[O:28])[CH2:22][C:23]([O-:25])=[O:24])[CH2:11][N:12]([CH2:17][C:18]([O-:20])=[O:19])[CH2:13][C:14]([O-:16])=[O:15].CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-]>O>[CH2:11]([N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH2:10][N:21]([CH2:26][C:27]([OH:29])=[O:28])[CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: NC(CS(=O)O)C(=O)O
Agent: [Cl-]
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O

Procedure:
To prepare 100 ml of the substrate solution: dissolve 0.765 gm of cysteine sulfinic acid in 100 ml of deionized water. Add 0.186 gm of ethylenediaminetetraacetate (EDTA) and 60 mg of TRITON X-100 detergent (TX-100). Mix well.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:32])[C:17]([CH2:29][C:30]#[N:31])=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:32][C:16]1[C:17]([CH2:29][C:30]#[N:31])=[C:18]([C:27]#[N:28])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Temperature: 90 °C
Yield: 34.3 %

Procedure:
A mixture of 6-bromo-9H-purine (22 mg, 0.11 mmol), 6-(1-aminoethyl)-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile (17 mg, 0.054 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (8 mg, 30%). LCMS calculated for C22H16ClFN7 (M+H)+: m/z=432.1. found: 432.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[CH:14]1([CH:20]=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C>C(O)C>[CH:14]1([CH:20]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=2[CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CC1CCCCC1
Reactant: COc1cccc(C(=O)NN)c1C
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc(C(=O)NN=CC2CCCCC2)c1C
Reaction time: 18 h

Procedure:
10.0 g (55.5 mmol) of 3-methoxy-2-methyl-benzoic acid hydrazide was dissolved in 200 mL of absolute ethyl alcohol. Cyclohexanecarbaldehyde (6.85 g, 61.0 mmol) and glacial acetic acid (3 mL) were added, and the reaction mixture was stirred for 18 h while monitoring by TLC. The precipitate was collected by filtration and washed with hexane. Product 3-methoxy-2-methyl-benzoic acid cyclohexylmethylene-hydrazide was obtained as a white solid (9.36 g, yield 61%): Rf=0.20 (3:1 EtOAc:n-Hexane); 1H NMR (400 MHz, CDCl3) δ 11.17 (s, 1H), 7.91 (s, 1H), 7.50 (d, J=4.8 Hz, 1H), 7.25 (t, J=6.4 Hz, 1H), 6.99 (t, J=5.6 Hz, 1H), 3.89 (s, 3H), 2.28 (s, 3H), 1.92-1.62 (m, 5H), 1.38-1.14 (m, 6H); HRMS (ESI) m/z calcd for C16H23N2O2 [M+H]+ 275.1760. found 275.1752, calcd for C16H22N2NaO2 [M+Na]+ 297.1579. found 297.1568.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[O:18].[Br-].[CH2:20]1COC[CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2([CH:20]=[CH2:21])[OH:18]
Reactant: C1CCOC1
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: [Br-]
Product: C=CC1(O)CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-2-phenylchroman-4-one (2.021 g, 6.67 mmol) in anhydrous THF (35 mL) at −78° C. is added a solution of vinylmagnesiun bromide in THF (1 M, 10 mL, 10 mmol) dropwise within 30 min. The reaction temperature is allowed to warm to rt and stirred for another 2 h. The reaction is chilled to 0° C. and quenched with sat. aq. NH4Cl and extracted with ethyl acetate (2×40 mL). The combined organic phases are washed with H2O, brine, and dried over Na2SO4, and filtered. The filtrate is concentrated and the residue is purified through flash chromatography on silica gel to afford 6-bromo-2-phenyl-4-vinylchroman-4-ol as an oil (1.961 g. 89%). MS ESI+ve m/z 313 (M+H—H2O)+.
Reaction SMILES: C[N:2](C)C=O.[CH3:6][O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:19])=[CH:12][CH:11]=1)=[O:9].C([O-])=O.[NH4+].C(OCC)(=O)C>O>[NH2:2][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:11][CH:12]=1)=[CH:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: CN(C)C=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dimethylformamide (123 l), 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (24.5 kg) and ammonium formate (21.0 kg) were charged in 2000-liter reactor at room temperature and heated, and a reaction was carried out at the inner temperature of 100 to 105° C. for 5 hours. After completion of the reaction, the mixture was cooled down to room temperature, ethyl acetate (613 l) and water (613 l) were added, the mixture was stirred, and an ethyl acetate layer was separated, and then washed with 10% sodium chloride solution (613 l) and with 20% sodium chloride solution (613 l). The ethyl acetate layer was concentrated in vacuo to 125 l and then diluted with n-heptane (625 l) at the inner temperature of 40 to 45° C. to separate crystals of 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene. The cyrstals were filtered at room temperature and washed with a mixture of n-heptane (104 l) and ethyl acetate (21 l). The crystals were dried overnight in vacuo and purified by suspending in a 70% aqueous acetone (158 l) to give 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (14.3 kg).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=3)[C:9](SC)=[C:8]2[CH3:23])=[CH:4][CH:3]=1.Cl[C:27]1C=CC=C(C(OO)=O)C=1.[S:37]([O-:40])(O)=[O:38].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=3)[C:9]([S:37]([CH3:27])(=[O:40])=[O:38])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc2c(c1)c(SC)c(C)n2Cc1ccc(F)cc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)c(S(C)(=O)=O)c(C)n2Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
A 300 mg portion of ethyl 1-(4-fluorobenzyl)-2-methyl-3-(methylthio)-1H-indole-5-carboxylate was dissolved in 3 ml of chloroform, and 483 mg of 3-chloroperbenzoic acid under ice-cooling was added, followed by stirring at the same temperature for 30 minutes and then at room temperature for 1 hour. A 10% sodium hydrogen sulfite aqueous solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated brine and then dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane:chloroform=0.2:1:1 to 0.3:1:1 to 0.4:1:1) to obtain 285 mg of ethyl 1-(4-fluorobenzyl)-2-methyl-3-(methylsulfonyl)-1H-indole-5-carboxylate as a pale green solid.
Reaction SMILES: O[C:2]1([CH2:26][O:27][CH2:28][CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:36])CC>ClCCl>[F:36][C:2]1([CH2:26][O:27][CH2:28][CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CCOCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOCC1(F)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 65 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-hydroxy-4-ethoxymethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with DAST (4.10 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 65% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:29](O)=[O:30])=[N:22][N:23]([CH2:25][CH:26]([F:28])[F:27])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH2:25][CH:26]([F:28])[F:27])[N:22]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1nn(CC(F)F)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3nn(CC(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound. MS (ISP): m/z=452.1 [M+H]+.