Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:7])[C:5]#[CH:6].Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].Cl>O1CCCC1>[CH3:3][CH:4]([O:7][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]#[CH:6]
Reactant: COC(=O)CBr
Reactant: C#CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(C)OCC(=O)OC
Reaction time: 0.58 h

Procedure:
A mechanically stirred suspension of sodium hydride (60% dispersion in mineral oil, 10 g, 0.25 mol) in tetrahydrofuran (160 mL) at 0° C. under nitrogen was treated with a solution of (±)-3-butyn-2-ol (21 g, 0.30 mol) in tetrahydrofuran (35 mL) over 30 minutes, stirred for 35 minutes, treated with a solution of methyl bromoacetate in tetrahydrofuran (50 mL) over 10 minutes, stirred for 30 minutes at 0° C., stirred at ambient temperature for 16 hours and treated with 2M HCl (150 mL). The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (2×, 100 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, concentrated and distilled under vacuum to provide the title compound (20 g).
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[P:18](Cl)([O:35][C:36]1[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][C:39]([CH3:46])=[CH:38][C:37]=1[C:47]([CH3:50])([CH3:49])[CH3:48])[O:19][C:20]1[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]([CH3:30])=[CH:22][C:21]=1[C:31]([CH3:34])([CH3:33])[CH3:32].Cl>O1CCCC1.C(#N)C>[P:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:9]2[CH:14]=[CH:13][C:12]([O:15][P:18]([O:35][C:36]3[C:37]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:38][C:39]([CH3:46])=[CH:40][C:41]=3[C:42]([CH3:45])([CH3:44])[CH3:43])[O:19][C:20]3[C:21]([C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:22][C:23]([CH3:30])=[CH:24][C:25]=3[C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:11][CH:10]=2)=[CH:3][CH:4]=1)([O:35][C:36]1[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][C:39]([CH3:46])=[CH:38][C:37]=1[C:47]([CH3:50])([CH3:49])[CH3:48])[O:19][C:20]1[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]([CH3:30])=[CH:22][C:21]=1[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Reactant: Cc1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)c(OP(Oc2ccc(Sc3ccc(OP(Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 0.65 gram of 4,4'-thiobisphenol (0.003 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-thiobisphenol solution under nitrogen, 0.14 gram (0.006 mol) of sodium hydride, as a 50 weight percent dispersion in mineral oil was added to the 4,4'-thiobisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,6-di-t-butyl-4-methylphenyl) phosphorochloridite (3.0 grams, 0.006 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,6-di-t-butyl-4 -methylphenyl) 4,4'-thiobisphenyl diphosphite was 1.19 grams. The molecular weight, FD/MS was 1154. NMR data obtained was, (CDCl3): 1.44 (S, 72H), 2.24 (S, 12H), 6.06 (d, J=8.4, 4H), 6.85 (d, J=8.4, 4H), 7.30 (S, 8H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH3:39])=[O:38])[C:30]=2[CH:31]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 33.3 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (70.1 mg, 0.12 mmol) in dichloromethane (1 mL) was added ethanesulfonyl chloride (32 mg, 0.24 mmol). Triethylamine (50 mg, 0.50 mmol) was added and the resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 26.4 mg (33%) of the title compound as off white solid. MS (ES) m/e 661.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH:11]=[C:10]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=5)[NH:9][C:8]4=[O:18])[CH2:5][CH2:6]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c(-c2ccccn2)cn1C1CCNCC1
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(n3cc(-c4ccccn4)[nH]c3=O)CC2)C1=O
Yield: 37 %

Procedure:
Title compound was prepared from 1-(piperidin-4-yl)-4-(pyridine-2-yl)-1H-imidazol-2(3H)-one in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 37% yield. MS m/e (M+H)+=590.2. 1H NMR (500 MHz, DMSO-D6): δ=13.54 (s, 1H), 10.69 (d, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 7.74 (s, 1H), 7.54 (d, J=8.24, 1H), 7.33 (d, J=4.88, 1H), 7.25 (s, 1H), 7.15 (dd, J1=6.71, J2=5.19, 1H), 5.37 (d, J=17.09, 1H), 4.63 (d, J=15.87, 1H), 4.50 (s, 1H), 4.12 (m, 2H), 3.87 (m, 1H), 3.56 (dd, J1=28.69, J2=13.43, 1H), 3.18 (t, J=$$ 13.73, 1H), 3.10 (d, J=14.65, 1H), 3.01 (m, 2H), 2.88 (t, J=15.26, 1H), 2.66 (m, 1H), 2.35 (d, J=14.95, 1H), 1.84 (m, 3H), 1.57 (m, 1H), 0.73 (d, J=16.17, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[O:16][C@@H:15]([CH2:18][N:19]=[N+]=[N-])[CH2:14][CH2:13]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[O:16][C@@H:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2cccc(-c3ccccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CCc2cccc(-c3ccccc3Cl)c2O1
Reaction time: 72 h

Procedure:
To a solution of {[(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}azide (0.14 g, 0.47 mmol) in tetrahydrofuran (7.8 mL) and water (0.8 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.36 g, 1.08 mmol) and the mixture gently shaken for 3 days. The brown suspension was then filtered through celite, the filter cake washed with diethyl ether (10 mL) and the combined filtrates dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. The crude product was purified by reverse phase HPLC using a solvent gradient of 5 to 95% acetonitrile in water containing 0.1% trifluoroacetic acid. The fractions containing product were concentrated under reduced pressure to remove acetonitrile and the aqueous phase basified by the addition of sodium carbonate and then extracted with ethyl acetate (100 mL). The separated organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford {[(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amine as a yellow syrup. The product was dissolved in diethyl ether (1 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.25 mL, 0.25 mmol) was added followed by 2-propanol (2 drops). The resulting white precipitate was filtered and the solid product triturated with diethyl ether (3×3 mL) to afford 36 mg (25%) of {[(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amine hydrochloride as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11](=[O:16])[N:10]1[C:17]1[CH:32]=[CH:31][C:20]2[N:21](C(OC(C)(C)C)=O)[CH:22]=[N:23][C:19]=2[CH:18]=1.[F:33][C:34]([F:38])([F:37])[CH2:35]I>>[F:33][C:34]([F:38])([F:37])[CH2:35][O:15][C:12]1[C:11](=[O:16])[N:10]([C:17]2[CH:32]=[CH:31][C:20]3[NH:21][CH:22]=[N:23][C:19]=3[CH:18]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[C:13]=1[CH3:14]
Reactant: FC(F)(F)CI
Reactant: CC1=C(O)C(=O)N(c2ccc3c(c2)ncn3C(=O)OC(C)(C)C)C1c1cccc(F)c1F
Product: CC1=C(OCC(F)(F)F)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cccc(F)c1F

Procedure:
The compound was synthesized starting from tert-butyl 5-(2-(2,3-difluorophenyl)-4-hydroxy-3-methyl-5-oxo-2H-pyrrol-1(5H)-yl)-1H-benzo[d]imidazole-1-carboxylate (0.441 g, 1 mmol), trifluoroiodoethane (0.15 ml, 1.5 mmol) and P1-tBu (1.38 ml, 1.5 mmol) according to the method described above and was further purified by semi-preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][NH:12][C:11]([C:10]1[NH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:14]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:13]2)=[O:26])[CH3:23]
Reactant: CCN(CC)CCN1C(=O)CN=C(c2ccc(Cl)cc2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1[nH]c(-c2ccc(Cl)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 11.1 g. of 5-(p-chlorophenyl)-1-[2-(diethylamino)ethyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 100 ml. of dimethylformamide is treated under an atmosphere of argon at room temperature with 0.035 mol. of sodium hydride (1.55 g. of a 55% dispersion in mineral oil). The mixture is first warmed to 60° C. over a period of about 30 minutes, then stirred at this temperature for 1 hour and thereafter at 70° C. for 1 hour. After cooling, 4 ml. of water are added dropwise and the mixture is then poured on to 800 ml. of ice-water. After the addition of 30 g. of sodium chloride, the precipitated product is extracted with methylene chloride. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. The oily residue obtained crystallizes upon trituration with hexane. Recrystallization from ethyl acetate yields 3-(p-chlorophenyl)isoindole-1-carboxylic acid [2-(diethylamino)ethyl]amide in the form of felt-like greenish crystals having a melting point of 145°-147° C.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[CH3:20])[C:13]([C:4]1[C:3](=[O:23])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][CH:5]=1)=[O:22]
Reactant: COC(=O)C(=CNc1ccccc1)C(=O)c1ccc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Yield: 80.7 %

Procedure:
2-(3,4-dimethyl-benzoyl)-3-phenylamino-acrylic acid methyl ester 2a(7.00 g, 22.6 mmol) (prepared as described by Silin, O. V.; et al. Heterocycles, 2004, 63, 1883-90) was heated at 260° C. in 150 mL of diphenyl ether for 6 h, then cooled down and 100 mL of hexane was added to the reaction solution. The mixture was filtered and the solid was washed with hexane to give 5.06 g of 3-(3,4-Dimethyl-benzoyl)-1H-quinolin-4-one 3a as off-white crystals: LC-MSD, m/z for C18H15NO2 [M+H]+=278.4; HPLC retention time: 1.7 min.
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].C([Mg]Cl)(C)C.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[C:30]([F:32])[CH:31]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[F:25][C:26]1[CH:27]=[C:28]([C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:6])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(F)c1
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a −15° C. solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (1.96 g, 7.36 mmol) in THF (9.4 mL) was added i-propyl magnesium chloride (3.6 mL of a 2M solution in Et2O, 7.2 mmol). The reaction was stirred at −15° C. for 15 minutes and then 3,5-difluorophenylmagnesium bromide (29.44 mL of a 0.5 M solution in THF, 14.72 mmol) was added. The reaction was warmed to room temperature and stirred for 24 hours. The reaction was then poured into saturated NH4Cl (100 mL) and extracted with EtOAc (3×100 mL). The organic extracts were washed with water and brine (100 mL each), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (15% EtOAc/hexanes) afforded benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. Rf=0.34 (15% EtOAc/hexanes). LCMS=342.3 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-(trifluoromethyl)benzene sulfonyl chloride (8 uL, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 16 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3-(trifluoromethyl)benzenesulfonamide (percentage yield: 54%), was obtained.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:24][OH:25])[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:50][O:51][C:52](=[O:60])[C:53]1[CH:58]=[CH:57][CH:56]=[C:55](O)[CH:54]=1>O1CCCC1>[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH2:24][O:25][C:55]3[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=3)[C:52]([O:51][CH3:50])=[O:60])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COc1ccc(CO)cc1OC1CCCC1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2ccc(OC)c(OC3CCCC3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropylazodicarboxylate (1.2 ml, 5.99 mmol, 1.2 eq)was added to a mixture of (1.10 g,4.99 mmol, 1.0 eq) 3-cyclopentyloxy-4-methoxybenzyl alcohol, (1.44 g, 5.49 mmol, 1.1 eq) triphenylphosphine, and (0.75 g, 4.99 mmol, 1.0 eq) methyl-3-hydroxy-benzoate in 30 ml of anhydrous tetrahydrofuran. After stirring for 18 hours at room temperature the reaction mixture was concentrated in vacuo and chromatographed on a silica gel column, eluting with 10%, then 15% ethyl acetate-hexane to yield 897 mg, 50%, of a clear oil. High Resolution Mass Spectra: Calc'd 356.1624. Found: 356.1600.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[C:11]([O:13][CH3:14])=[O:12].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:14][O:13][C:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])=[O:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1c(C(F)(F)F)noc1N
Product: COC(=O)c1c(C(F)(F)F)noc1NS(=O)(=O)c1ccccc1
Yield: 85 %

Procedure:
N-(4-Methoxycarbonyl-3-trifluoromethyl-5-isoxazolyl)benzenesulfonamide was prepared as described in Example 25 from 5-amino-4-methoxycarbonyl-3-trifluoromethylisoxazole and benzenesulfonyl chloride in 85% yield. The crude product was purified by recrystallization from methanol/water to give a solid, m.p. 100°-101° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]1([CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[CH3:24])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[C:9]1([CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:20][CH:19]2[CH3:24])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccco1
Reactant: CC1CNCCN1CCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1CN(C(=O)c2ccco2)CCN1CCCc1ccccc1

Procedure:
2-Furoyl chloride (1.5 g) was added dropwise with stirring to a solution of 1-(3-phenylpropyl)-2-methylpiperazine [b.p. 138° - 140°C (8 mmHg)] (2.2 g) and CHCl3 (100 ml).
Reaction SMILES: [CH3:1][C:2]1([CH3:69])[O:7][CH2:6][C:5]([C:9]([O:11][CH2:12][C:13]([CH2:56][O:57][C:58]([C:60]2([CH3:68])[CH2:65][O:64][C:63]([CH3:67])([CH3:66])[O:62][CH2:61]2)=[O:59])([CH3:55])[C:14]([O:16][CH2:17][C:18]([CH2:23][O:24][C:25](=[O:54])[C:26]([CH2:41][O:42][C:43]([C:45]2([CH3:53])[CH2:50][O:49][C:48]([CH3:52])([CH3:51])[O:47][CH2:46]2)=[O:44])([CH2:28][O:29][C:30]([C:32]2([CH3:40])[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34][CH2:33]2)=[O:31])[CH3:27])([CH3:22])[C:19]([OH:21])=[O:20])=[O:15])=[O:10])([CH3:8])[CH2:4][O:3]1.[N+:70]([C:73]1[CH:74]=[C:75]([CH:91]=[C:92]([N+:94]([O-:96])=[O:95])[CH:93]=1)[C:76]([O:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89]Br)=[O:77])([O-:72])=[O:71]>>[CH3:66][C:63]1([CH3:67])[O:64][CH2:65][C:60]([C:58]([O:57][CH2:56][C:13]([CH2:12][O:11][C:9]([C:5]2([CH3:8])[CH2:6][O:7][C:2]([CH3:69])([CH3:1])[O:3][CH2:4]2)=[O:10])([CH3:55])[C:14]([O:16][CH2:17][C:18]([CH2:23][O:24][C:25](=[O:54])[C:26]([CH2:28][O:29][C:30]([C:32]2([CH3:40])[CH2:33][O:34][C:35]([CH3:38])([CH3:39])[O:36][CH2:37]2)=[O:31])([CH2:41][O:42][C:43]([C:45]2([CH3:53])[CH2:50][O:49][C:48]([CH3:51])([CH3:52])[O:47][CH2:46]2)=[O:44])[CH3:27])([CH3:22])[C:19]([O:21][CH2:89][CH2:88][CH2:87][CH2:86][CH2:85][CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH2:79][O:78][C:76](=[O:77])[C:75]2[CH:74]=[C:73]([N+:70]([O-:72])=[O:71])[CH:93]=[C:92]([N+:94]([O-:96])=[O:95])[CH:91]=2)=[O:20])=[O:15])=[O:59])([CH3:68])[CH2:61][O:62]1
Reactant: CC1(C)OCC(C)(C(=O)OCC(C)(COC(=O)C2(C)COC(C)(C)OC2)C(=O)OCC(C)(COC(=O)C(C)(COC(=O)C2(C)COC(C)(C)OC2)COC(=O)C2(C)COC(C)(C)OC2)C(=O)O)CO1
Reactant: O=C(OCCCCCCCCCCCBr)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: CC1(C)OCC(C)(C(=O)OCC(C)(COC(=O)C2(C)COC(C)(C)OC2)C(=O)OCC(C)(COC(=O)C(C)(COC(=O)C2(C)COC(C)(C)OC2)COC(=O)C2(C)COC(C)(C)OC2)C(=O)OCCCCCCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CO1

Procedure:
Preparation can be carried out analogously to Example 1 using 10.19 g (9.81 mmol) 2,2-bis[({2,2-bis[({(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl}oxy)methyl]propanoyl}oxy)methyl]propanoic acid, 1.494 g (9.81 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(l,5-5) (DBU) and 4.81 g (10.79 mmol) 11-bromoundecyl 3,5-dinitrobenzoate, to yield 11-[(3,5-dinitrobenzoyl)oxy]undecyl 2,2-bis[({2,2-bis[({(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl}oxy)methyl]propanoyl}oxy)methyl]propanoate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[C:6]=1[CH2:13]Br)(=[O:4])=[O:3].[CH3:15][CH:16]([CH3:18])[O-:17].[Na+]>C(O)(C)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[C:6]=1[CH2:13][O:17][CH:16]([CH3:18])[CH3:15])(=[O:4])=[O:3]
Reactant: CC(C)[O-]
Reactant: CS(=O)(=O)c1ccc(Br)c(Cl)c1CBr
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OCc1c(S(C)(=O)=O)ccc(Br)c1Cl
Reaction time: 8 h
Yield: 315.7 %

Procedure:
To a suspension comprising 20.0 g of 4-bromo-2-bromomethyl-3-chlorophenyl methyl sulfone and 200 ml of isopropanol, 100 ml of an isopropanol solution of sodium isopropoxide (prepared from 1.4 g of metal sodium) was added at room temperature, and the mixture was stirred overnight. The post treatment was conducted in the same manner as in Example 1-3-(2) to obtain 18.4 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:22])[CH:19]([CH3:21])[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]#[N:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]([CH:19]([CH3:21])[CH3:20])[CH3:22])=[N:16][C:15]3[C:10]([N:9]=2)=[CH:11][CH:12]=[C:13]([C:23]2[N:25]=[N:26][NH:27][N:24]=2)[CH:14]=3)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)N(C)c1nc2cc(C#N)ccc2nc1-c1ccc(F)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N(C)c1nc2cc(-c3nn[nH]n3)ccc2nc1-c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 35.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile (150 mg, 0.47 mmol) in DMSO (10.0 mL) and water (10.0 mL) was added NaN3 (90 mg, 1.38 mmol) and ZnBr2 (51.9 mg, 0.23 mmol), and the resulting mixture was stirred for 48 h at 130° C. in an oil bath. The reaction mixture was cooled down to room temperature, diluted with water (150 mL), extracted with dichloromethane (4×40 mL), and the organic layers combined, dried over magnesium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (2% dichloromethane in methanol) to afford 3-(4-fluorophenyl)-N-isopropyl-N-methyl-7-(2H-tetrazol-5-yl)quinoxalin-2-amine as a light yellow solid (60 mg, 35.0%).