Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:74]4[CH2:79][CH2:78][O:77][CH2:76][CH2:75]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C1COCCN1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N1CCOCC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol), PyBOP® (46 mg, 0.088 mmol), DIEA (28 μL, 0.16 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added morpholine (8.7 mg, 0.10 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalent of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of morpholine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-45_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-morpholinoethanone. (13 mg, 0.027 mmol, 17%)
Reaction SMILES: [Nb:1].[P:2](=[O:6])([OH:5])([OH:4])[OH:3].[O-2].[Nb+5].[O-2].[O-2].[O-2].[O-2].[Nb+5]>>[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Nb+5:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Nb+5:1].[Nb+5:1]
Reactant: O=P(O)(O)O
Reactant: [Nb]
Agent: [Nb+5]
Agent: [O-2]
Product: O=P([O-])([O-])[O-]
Temperature: 150 °C

Procedure:
A mixture is prepared containing niobic acid, Nb2O5.xH2O, (60.33 g; 0.211 moles; Niobium Products Company, AD-460) and 85% phosphoric acid (602.20 g; 5.22 moles). The mixture is heated to 150° C. with stirring. The niobium oxide dissolves to form a pink solution, and upon heating a precipitate forms. The precipitate is boiled in the phosphoric acid for about 2 hours. The boiled mixture is cooled to room temperature, and the liquid phase is decanted from the precipitate. The precipitate is washed by stirring with 500 ml of water, after which the aqueous mixture is filtered. The washing and filtering cycle is repeated five times. The filtered solid is dried at 110° C. under air for 21/2 days to yield a catalyst of niobium phosphate. The elemental analysis and X-ray diffraction pattern of the catalyst are consistent with the composition NbOPO4. The P/Nb mole ratio, as determined by neutron activation analysis and X-ray fluorescence, is 1.03.
Reaction SMILES: C(O)C.[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].[Br:24][C:25]1[CH:30]=[CH:29][C:28](I)=[C:27]([F:32])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC.O.C1C=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:18]2[CH:17]=[CH:16][C:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)=[CH:20][CH:19]=2)=[C:27]([F:32])[CH:26]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(B(O)O)cc2)CC1
Reactant: Fc1cc(Br)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: c1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(Br)cc3F)cc2)CC1

Procedure:
First, 150 ml of ethanol containing 17.84 g of 4-(trans-4-pentylcyclohexyl)phenylboronic acid dissolved therein, 150 ml of benzene containing 15.0 g of 4-bromo-2-fluoro-1-iodobenzene dissolved therein, 49.8 ml of a sodium carbonate aqueous solution with a concentration of 2.0 mol/l, and 1.44 g of tetrakis(triphenylphosphine)palladium(0) were put in an argon-replaced 500 ml flask, and stirred under reflux for 37 hours. After the reaction, water and ether were added to the reaction solution for extraction. The resultant ether layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:hexane) and recrystallized from hexane, to obtain 13.6 g (Y: 67.8%) of 4-bromo-2-fluoro-4′-(trans-4-pentylcyclohexyl)biphenyl. The purity of the resultant compound was 99.5% as measured by GC.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[NH3:17]>>[CH2:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:17])=[CH:8][CH:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1ccc(CC(Cl)C(=O)O)cc1
Reactant: N
Product: CCCCc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 40 °C
Reaction time: 96 h
Yield: 46 %

Procedure:
α-Chloro-β-p-butylphenylpropionic acid 3 (128 g, 0.534 moles) was suspended in 800 mL 30% aqueous ammonia. The reaction was stirred for 4 days at 40° C. in a tightly stoppered flask. After cooling to room temperature, the precipitate was removed by filtration through a coarse glass frit. The solid was washed thoroughly with ethanol followed by diethyl ether. The solid was dried under vacuum yielding 54.3 g (0.245 moles, 46% yield) of p-butylphenylalanine as a white solid. The solid was recrystallized from 2N HCl to give a white solid, mp 218°-223° C.
Reaction SMILES: F[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([NH2:22])(C)(C)C.O>O1CCOCC1>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:3]([N+:15]([O-:17])=[O:16])=[C:2]([NH2:22])[CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1-c1ncccn1
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(F)cc(-c2ncccn2)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of 2-(3,5-difluoro-2-nitro-phenyl)-pyrimidine (1.5 g, 6.32 mmoles) in dioxane (10 mL) was added tBuNH2 (6.6 mL, 63.24 mmoles) at room temperature. The mixture was heated to 100° C. in a sealed tube for 10 hours. The mixture was then cooled to room temperature, poured into water, and the solids stirred for 1 hour. The mixture was filtered, solids washed with water until filtrate was clear. The crude product was then diluted in MeOH, 6N HCl added, and the resulting mixture heated at reflux for 3 hours. The reaction was cooled to room temperature and poured into ice. The resulting heterogeneous mixture was warmed to room temperature, filtered, solids washed with water until filtrate ran clear, and dried in vacuo to afford the title compound (1.33 g, 90%) as an orange powder. 1H NMR (dmso-d6, 500 MHz): 8.87 (d, 2H); 7.52 (dd, 1H); 7.08 (dd, 1H); 6.86 (dd, 1H); 6.60 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br.O>CN(C)C=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH2:35][CH:37]1[CH2:38][O:39]1)[N:19]=[CH:18][CH:17]=[C:16]2[O:15][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 345) (146 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution, potassium carbonate (162 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (98 mg, yield 59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([OH:14])=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)C(C)C(=O)Nc1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)C(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Prepared according to procedure B using ethyl 3-(3,5-difluorophenylamino)-2-methyl-3-oxopropanoate (11.4 g, 44.3 mmol) (described herein) in THF (40 mL), and sodium hydroxide (1.22 g, 53.2 mmol) in water (10 mL). The reaction was stirred at rt for 2 h, affording 3-(3,5-difluorophenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=230 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH2:27][CH2:28][CH2:29][CH:30]=1)CCC.[F-].[K+]>CN(C)C=O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:26]1[CH2:27][CH2:28][CH2:29][CH:30]=[C:25]1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1cnc(C2=CCCCO2)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
A solution of 2-amino-5-bromopyrazine (100 mg, 0.58 mmol) in N,N-dimethylformamide (6 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.01 mmol), N,N-diisopropylethylamine (250 μL, 1.43 mmol), lithium chloride (85 mg, 2.01 mmol), and 5,6-dihydro-2-(tributylstannyl)-4H-pyran (214 mg, 0.58 mmol). The resulting reaction mixture was heated at 120° C. for 4 h. After such time, the reaction was cooled to 25° C., treated with a saturated aqueous potassium fluoride solution (10 mL), and stirred at 25° C. overnight for 16 h. The solution was then diluted with methylene chloride (25 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 1/1 to 1/3 hexanes/ethyl acetate) afforded 5-(5,6-dihydro-4H-pyran-2-yl)-pyrazin-2-ylamine (25 mg, 25%) as a foam: EI-HRMS m/e calcd for C9H11N3O (M+) 177.0902, found 177.0906.
Reaction SMILES: CI.[CH2:3](OC1C=CC(CCl)=CC=1)C1C=CC=CC=1.[C:19]1([S:25]([CH:27]2[C:32](=[O:33])[NH:31][CH2:30][CH2:29][N:28]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25]([C:27]2([CH3:3])[C:32](=[O:33])[NH:31][CH2:30][CH2:29][N:28]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1S(=O)c1ccccc1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1(C)S(=O)c1ccccc1

Procedure:
When in the procedure of Example 3a, methyl iodide is substituted for p-benzyloxybenzyl chloride and 27b is substituted for 2, the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].CN(P(N(C)C)(N(C)C)=O)C.[CH2:21]=[O:22]>C1(C)C=CC=CC=1.C([Mg]Br)C>[OH:22][C:21]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH:3]=[O:9]
Reactant: Cc1ccc(O)c(C)c1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cc(C)c(O)c(C=O)c1
Yield: 58.4 %

Procedure:
To a solution of 2,4-dimethylphenol (24.9 g, 204 mmole) in anhydrous toluene (75 mL) at 0° C. was added HMPA (35 mL) and then a solution of ethylmagnesium bromide (61 mL-3 M in ethyl ether, 0.183 mmole), keeping the temperature <10° C. Then paraformaldehyde (13 g, 0.43 mole) was added and the cooling was removed. The ethyl ether was removed by distillation and the mixture was refluxed. The mixture was quenched with 10% HCl and EtOAc was added. The EtOAc solution was washed twice with H2O, twice with aqueous NH4Cl, dried over Na2SO4 and concentrated in vacuo. Purification by silica chromatography (98:2 hexanes:EtOAc) gave 17.9 g (59% yield) of the product as a yellow oil: ESHRMS m/z 147.0619 (M−H, C9H9O2, Calc'd 147.0603).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[O:31]=[C:24]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 18 h
Yield: 7.4 %

Procedure:
To a stirred solution, under N2 atmosphere, of 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) (10.0 g, 38 mmol), and triethylamine (15.35 g, 150 mmol) in methylene chloride (100 mL) was added ethyl 3-chloro-3-oxopropionate (6.32 g, 42 mmol). The reaction was stirred for 18 hours. The reaction mixture was concentrated down in vaco and purified by flash silica gel chromatography eluting with 1:1 ethyl acetate / hexanes to give an orange solid (0.86 g, 7%); 1H NMR (300 MHz, CDCl3) δ 1.32 (t, J=7.2 Hz, 3H), 2.55 (t, J=6 Hz, 4H), 3.46 (s, 2H), 3.56 (t, J=6 Hz, 4H), 4.22 (q, J=7.2 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 9.09 (s, 1H); MS (ES) m/z: 305.3 (MH+, 100%).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:40])=[C:24]([NH:26][C:27](=[O:39])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4([C:37]#[N:38])[CH2:36][CH2:35]4)[CH:29]=3)[CH:25]=1)[N:13]=2>N1C=CC=CC=1>[C:37]([C:34]1([C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([NH:26][C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=2[CH3:40])[O:19][C:14]2[N:13]=[C:12]3[S:11][C:10]([NH:9][C:6]([C:4]4[N:3]=[CH:2][O:1][CH:5]=4)=[O:7])=[N:18][C:17]3=[CH:16][CH:15]=2)=[O:39])[CH2:36][CH2:35]1)#[N:38]
Reactant: O=C(Cl)c1cocn1
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
1,3-Oxazole-4-carbonyl chloride synthesized above was suspended in pyridine (2.0 mL) at 0° C., N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl)-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.452 mmol) produced in Example C29(iv) was added, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, 1% aqueous citric acid solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate/hexane to give the title compound (125 mg, 77%) as a colorless powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:32][C:29]([CH3:30])([CH3:31])[C:28](=[O:33])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]([C:9]2[CH:8]=[C:7]3[C:12]([CH:13]=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[CH:6]3)=[CH:11][CH:10]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:34]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2ccc(C(=O)OC)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2ccc(C(=O)O)cc2c1
Temperature: 55 °C
Yield: 89.6 %

Procedure:
Treat 7-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carboxylic acid methyl ester (1.1 g, 2.4 mmol) in THF (15 mL) and MeOH (30 mL) with 2N NaOH (6.0 mL, 12.0 mmol) and heat to 55° C. for 16 h. Then concentrate the reaction mixture and dilute the residue with CH2CL2 and water (50 mL each). Acidify the mixture to pH 1 using 1N HCl. Discard the aqueous layer and wash the organic layer with brine. Dry the organic layer over Na2SO4, filter and concentrate the filtrate. Purify by silica gel radial chromatography (2:98 MeOH:CH2CL2 to 10:90 MeOH:CH2CL2) to give the title compound as a yellow solid (0.96 g, 90%). MS (ES) m/e 447 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[S:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2)(=[O:14])=[O:13].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:12]([C:15]1[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]3)(=[O:13])=[O:14])[CH2:6][CH2:5]2
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: Fc1ccc2c(c1)CCN2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)N3CCc4cc(F)ccc43)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of 5-fluoroindoline from above, 5-chlorosulfonyl-2-oxindole (6.1 g, 1.2 equivalent) and pyridine (7.1 mL) in dichloromethane (40 mL) was stirred at room temperature overnight. The reaction was concentrated and the residue was recrystallized from methanol to give 5 g (68% yield) of 5-(5-fluoro-2,3-dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one as a pink-colored solid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.75 (br s, 1H, NH), 7.60 (m, 2H), 7.60 (dd, 1H), 7.02 (m, 2H), 6.90 (d, 1H), 3.89 (t, 2H, CH2), 3.52 (s, 2H, CH2), 2.87 (t, 2H, CH2). MS 331 [M+−1].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1(/[CH:13]=[CH:14]/[C:15]2[CH:16]=[C:17]([CH:21]([OH:25])[CH2:22][C:23]#[N:24])[CH:18]=[N:19][CH:20]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.N.CO.C(Cl)Cl>>[NH2:24][CH2:23][CH2:22][CH:21]([C:17]1[CH:18]=[N:19][CH:20]=[C:15](/[CH:14]=[CH:13]/[CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:16]=1)[OH:25]
Reactant: N#CCC(O)c1cncc(/C=C/C2CCCCC2)c1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: NCCC(O)c1cncc(/C=C/C2CCCCC2)c1

Procedure:
LiAlH4 reduction of (E)-3-(5-(2-cyclohexylvinyl)pyridin-3-yl)-3-hydroxypropanenitrile following the method used in Example 3 gave after flash chromatography purification (10%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 10 as a light yellow oil. Yield (0.5 g, 59%); 1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=2.0 Hz, 1H), 8.33 (d, J=1.5 Hz, 1H), 7.85 (t, J=2.0 Hz, 1H), 6.40-6.38 (m, 2H), 4.84-4.76 (m, 1H), 2.86-2.78 (m, 2H), 2.24-2.08 (m, 1H), 1.98-1.66 (m, 7H), 1.44-1.28 (m, 5H); RP-HPLC tR=6.23 min; ESI-MS m/z 261.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[F:13][C:14]1[C:24]([NH2:25])=[CH:23][C:17]2[NH:18][C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1.C(N(CC)CC)C.O>C(Cl)Cl>[F:13][C:14]1[C:24]([NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:23][C:17]2[NH:18][C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cc2c(cc1F)OCC(=O)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1COc2cc(F)c(NC(=O)c3ccccc3[N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 2-nitro-benzoyl chloride (2.04 g, 90% purity, 10 mmol) in CH2Cl2 (20 mL) was added dropwise into a mixture of 7-fluoro-6-amino-2H-1,4-benzoxazin-3-(4H)-one (1.78 g, 10 mmol) and triethylamine (1.1 g, 11 mmol) in CH2Cl2 (20 mL) over 10 min with ice-water bath cooling. The reaction mixture was then stirred at room temperature overnight. The mixture was poured into water and the resulting precipitate was collected by suction-filtration and washed with hexane and then water to give 7-fluoro-6-(2-nitrobenzoyl)amino-2H-1,4-benzoxazin-3-(4H)-one, 2.9 g (yield: 92%) as a solid: mp >248° C.
Reaction SMILES: Cl[Si](C)(C)C.[I-].[K+].[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([CH:19]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[C:29]([F:36])[CH:28]=3)[CH2:20][C@@H:21]3[NH:25][C:24](=[O:26])[CH2:23][CH2:22]3)=[N:15][C:16]=2[O:17]C)[CH2:10][CH2:9]1.O>C(#N)C>[CH:8]1([C:11]2[C:16](=[O:17])[NH:15][C:14]([CH:19]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[C:29]([F:36])[CH:28]=3)[CH2:20][C@H:21]3[CH2:22][CH2:23][C:24](=[O:26])[NH:25]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1
Reactant: CCOc1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(OC)n2)cc1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(=O)[nH]2)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (0.17 mL) and potassium iodide (370 mg) were added to a solution of (5R)-5-[2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(4-ethoxy-3-fluorophenyl)ethyl]pyrrolidin-2-one (222 mg) in acetonitrile (4.4 mL) at room temperature, and then the mixture was stirred at 50° C. for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. One diastereomer (A) of the title compound was obtained as a white solid (71 mg, 33% (two steps)) by separating the residue by preparative HPLC (CHIRALPAK IB (20 mm i.d.×250 mm L, Daicel Chemical Industries, LTD.), 40° C., flow rate: 10 mL/min, ethanol:hexane=40:60) and concentrating the fraction eluted with a retention time of 13 minutes. The fraction eluted with a retention time of 28 minutes was concentrated to give the other diastereomer (B) of the title compound as a white solid (71 mg, 33% (two steps)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])[CH3:13])=[O:4].[C:16]([CH:18]1[CH2:20][CH2:19]1)#[CH:17]>C(N(CC)CC)C.C1COCC1.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.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]#[C:16][CH:18]2[CH2:20][CH2:19]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])[CH3:13])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N=CN(C)C
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC2CC2)cc1N=CN(C)C
Reaction time: 1 h

Procedure:
Firstly bis(triphenylphosphine)palladium(II) chloride (602 mg) and then copper(I) iodide (164 mg) were added to a mixture of 5-bromo-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester (1 g), ethynylcyclopropane (463 mg) in triethylamine (9.5 mL) and THF (4.5 mL). After one hour, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 276.36 (C14H16N2O2S) was obtained in this way; MS (ESI): 277 (M+H+).