Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2](I)([F:7])[C:3]([F:6])([F:5])[F:4].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].Cl.O>C(Cl)Cl>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:13])([C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])[C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)I
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: OC(c1ccccc1Cl)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
74 g (0.3 mol) of phosphorous acid trisdiethylamide in 150 ml of CH2Cl2 were initially introduced into a round-bottomed flask with the exclusion of moisture. 74 g (0.3 mol) of pentafluoroethyl iodide and 26.4 g (0.15 mol) of o-chlorobenzoyl chloride were added at about -20° C. The mixture was warmed to 0° C. and stirred for about 8 hours at this temperature. 10 g of hydrogen chloride gas were then introduced, and the mixture was stirred for a further hour at 0° C. The reaction mixture was freed from solvent under reduced pressure and introduced into 3 times the volume of water. The organic phase was separated off, dried and distilled. 34.6 g (62%) of 3-(2-chlorophenyl)-1,1,1,2,2,4,4,5,5,5-decafluoropentan-3-ol of b.p. 66° C./2 mbar were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([OH:26])=O)[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[N:40](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([NH2:40])=[O:26])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.1 %

Procedure:
A mixture of (2-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (500 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (356 mg), 1-hydroxybenzotriazole ammonium salt (283 mg) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water, ethanol and diethyl ether. The obtained brown solid was recrystallized from ethanol to give the title compound (300 mg, yield 60%) as colorless crystals. melting point 134-135° C. MS 536 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].Br[CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:15])([F:17])[F:16]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Reactant: CCBr
Product: CCN1CCN(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(4-Chloro-3-trifluoromethyl-phenyl)-piperazine and bromo-ethane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 293 (M+, 6), 292 (30),277 (29), 57 (bp), 56 (41).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31](F)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:13]=1)=[O:6].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=2)[CH:13]=1)=[O:6]
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(F)c3)ccc2C)cc1
Reactant: C1COCCN1
Solvent: O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)ccc2C)cc1
Temperature: 100 °C

Procedure:
A mixture of N-[5-(3,5-difluorobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide (0.069 g) and morpholine (3 ml) was stirred and heated to 100° C. for 6 days. The mixture was cooled to ambient temperature and poured into water. The resultant solid was isolated, washed in turn with water and diethyl ether and dried under vacuum at 40° C. There was thus obtained the title compound (0.033 g); NMR Spectrum: (DMSOd6) 0.98 (t, 6H), 2.2 (s, 3H), 2.46-2.49 (m, 4H), 3.20-3.24 (m, 4H), 3.58 (s, 2H), 3.72-3.75 (m, 4H), 6.95 (d, 1H), 7.14 (d, 1H), 7.21 (d, 1H), 7.3 (s, 1H), 7.45 (s, 2H), 7.58 (d, 1H), 7.78 (s, 1H), 7.91 (d, 2H), 9.82 (s, 1H), 10.15 (s, 1H); Mass Spectrum: M+H+ 519.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C:5]2[C:14]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:16]=[C:17]([Cl:18])[C:4]=2[N:3]=1.[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=1[NH2:27].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:18][C:17]1[C:4]2[N:3]=[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:25]=3[Cl:24])[N:6]([CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C:5]=2[C:14]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CC(=O)OC(C)C)c12
Temperature: 100 °C
Reaction time: 15 h
Yield: 20.6 %

Procedure:
A mixture of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 10; 1.96 g, 5.49 mmol), 2,4-dichloroaniline (2.67 g, 16.5 mmol) and N-methyl-2-pyrrolidinone (1.5 mL) was stirred at 100° C. for 15 hr. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 3-15% ethyl acetate/n-hexane gradient mixture to give the title compound (546 mg, 1.13 mmol, 21%) as an oil.
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:20][NH:21][CH2:22][CH:23]2[CH2:28][O:27]C(C)(C)[O:25][CH:24]2[CH2:31][S:32][CH3:33])=[CH:11]1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.O.O.NN>[Pd]>[NH2:19][C:17]1[C:18]2[NH:10][CH:11]=[C:12]([CH2:20][NH:21][CH2:22][CH:23]([CH:24]([OH:25])[CH2:31][S:32][CH3:33])[CH2:28][OH:27])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CSCC1OC(C)(C)OCC1CNCc1cn(COCc2ccccc2)c2c(N)ncnc12
Agent: [Pd]
Agent: NN
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CSCC(O)C(CO)CNCc1c[nH]c2c(N)ncnc12
Yield: 62.4 %

Procedure:
The product of Example 9.3 (17 mg, 0.036 mmol) was treated with TFA/water (9:1 v/v, 1 mL). After 5 min the mixture was evaporated in vacuo. The residue was redissolved in methanolic ammonia (7M, 4 mL) and Pd-black (17 mg, 0.16 mmol) was added, followed by hydrazine hydrate (250 μL, 5.1 mmol). After 15 min more Pd-black (22 mg, 0.21 mmol) was added and again after further 15 min (55 mg, 0.52 mmol) and also hydrazine hydrate (0.5 mL, 10.2 mmol). Shortly after the mixture was filtered through flux calcined diatomaceous earth and evaporated. The residue was dissolved in MeOH (2 mL) and treated with Amberlyst® A-26(OH) ion exchange resin (˜1 g) for 5 min, the solution was filtered and evaporated in vacuo which gave the product as an oil (7 mg, 62%). 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.48 (s, 1H), 3.97-3.80 (m, 2H), 3.79-3.61 (m, 2H), 3.16-3.05 (m, 1H), 2.85 (dd, J=6.0, 12.1, 1H), 2.79 (dd, J=6.7, 12.0 Hz, 1H), 2.66 (dd, J=4.8, 13.5 Hz, 1H), 2.56 (dd, J=8.0, 13.5 Hz, 1H), 2.11-1.88 (m, 4H). 13C NMR (CD3OD, referenced to the middle methanol peak at 49.0 ppm) δ 150.8, 146.5, 129.1, 114.6, 72.1, 62.1, 45.5, 43.9, 40.1, 16.3. HRMS: (M+H)+ calcd. for C13H22N5O2S: 312.1494. found: 312.1494.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4]([NH:12][CH2:13][C:14]([OH:16])=O)[N:3]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][CH3:31])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([N:30]([CH3:31])[C:14](=[O:16])[CH2:13][NH:12][C:4]2[N:5]=[C:6]([CH3:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[N:3]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(NCC(=O)O)nc(C)c1[N+](=O)[O-]
Reactant: CNC1CCN(Cc2ccccc2)CC1
Product: Cc1nc(NCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1[N+](=O)[O-]

Procedure:
The title compound was synthesized from Compound 11 and 1-benzyl-N-methylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(C)c(C)cc4nc3OC)CC2)c1
Yield: 75 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 75%). 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.39 (s, 3H), 3.21-3.29 (m, 4H), 3.75 (m, 4H), 3.79 (s, 3H), 4.11-4.13 (m, 3H), 6.06 (s, 1H), 6.12 (s, 2H), 7.52 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:25]=4[F:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(CS(C)(=O)=O)cc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cc4F)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-(2-fluoro-4-methanesulfonylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane following a procedure analogous to that described for Intermediate 10. LC (method 1): tR=1.61 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[N:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[C:31]([C:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=3)=[C:30]([NH2:38])[N:29]([CH3:39])[N:28]=2)[CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N=[C:44]=[O:45])C>N1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[C:31]4[C:32]5[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=5[C:44](=[O:45])[NH:38][C:30]=4[N:29]([CH3:39])[N:28]=3)[CH:22]=2)[C:9](=[O:40])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CCN=C=O
Reactant: COc1ccc(CN(Cc2cccc(-c3nn(C)c(N)c3C3=CCCCC3)c2)C(=O)OCc2ccccc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(CN(Cc2cccc(-c3nn(C)c4[nH]c(=O)c5c(c34)CCCC5)c2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
To a solution of EXAMPLE 56E (3.8 g, 7.1 mmol) in pyridine (100 mL) was added ethyl isocyanate (1.6 mL, 21 mmol) and the solution stirred at ambient temperature for 24 hours. The mixture was heated at reflux overnight, cooled, concentrated and the residue purified by flash chromatography on silica gel using ethyl acetate to give 3.4 g (85%) of the title compound. MS (DCI): m/z 563 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[C:13]3[CH2:19][NH:18][C:17]([CH3:21])([CH3:20])[C:14]=3[NH:15][N:16]=2)[N:6]=1)[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:31][C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[C:13]3[CH2:19][N:18]([C:32]([Cl:31])=[O:34])[C:17]([CH3:20])([CH3:21])[C:14]=3[NH:15][N:16]=2)[N:6]=1)[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOc1ccnc(Nc2n[nH]c3c2CNC3(C)C)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccnc(Nc2n[nH]c3c2CN(C(=O)Cl)C3(C)C)n1
Temperature: 22 °C

Procedure:
To a −78° C. solution of N-(4-ethoxypyrimidin-2-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine hydrochloride (0.300 g, 1.09 mmol) in CH2Cl2 (15 mL) and diisopropylethylamine (0.952 mL, 5.47 mmol) was added triphosgene (0.227 g, 0.766 mmol) in CH2Cl2 (5 mL) dropwise over 10 min. The reaction was quenched with H2O (10 mL), warmed to 22° C., and made pH 8-9 with NaHCO3. The aqueous layer was extracted with CH2Cl2 (2×30 mL) and the combined organic layers washed with brine (1×30 mL), dried over MgSO4, and concentrated to give the desired product M1(i) as a brown solid (0.35 g, 95%). Mass Spectrum: Calcd for C14H18ClN6O2 (M+H): 337. Found: 337.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH2:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH2:28][CH2:29][CH3:30].[O-]CC.[Na+]>>[CH2:27]([NH:31][C:32]1[N:34]=[C:11]([C:10]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:8][N:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=23)[CH:12]=[CH:13][N:33]=1)[CH2:28][CH2:29][CH3:30]
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: CCCCNC(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Yield: 59 %

Procedure:
In a similar manner as described in Example 34 from 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.50 g, 1.7 mmol), N-butylguanidine sulfate and sodium ethoxide (0.81 mL, 21 wt % in ethanol, 2.2 mmol) at room temperature was obtained N-butyl-4-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (0.39 g, 59%) as a fluffy pale yellow solid. 1H NMR (CDCl3): δ 8.40 (d, 1 H), 8.07 (d, 1 H), 7.65 (m, 2 H), 7.29 (m, 1 H), 7.15 (t, 2 H), 7.06 (d, 1 H), 6.32 (d, 1 H), 5.16 (bs, 1H), 3.49 (q, 2 H), 1.71–1.41 (m, 4 H), 0.99 (t, 3 H); 19F NMR (CDCl3) δ −112.77; MS m/z 396 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=O)[CH2:10][CH3:11])=[CH:4][C:3]=1[CH3:13].[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].[B][B][B][B][B][B][B][B][B][B]>CO>[Br:14][C:15]1[CH:16]=[C:17]([NH:18][CH:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[C:3]([CH3:13])[CH:4]=2)[CH2:10][CH3:11])[CH:19]=[CH:20][CH:21]=1
Reactant: CCC(=O)c1cc(C)c(Cl)c(C)c1
Reactant: Nc1cccc(Br)c1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCC(Nc1cccc(Br)c1)c1cc(C)c(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ketone INT 17 (910 mg, 4.63 mmol) and 3-bromoaniline (0.504 mL, 4.63 mmol) in MeOH (25 mL) was added decaborane (283 mg, 2.313 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[CH2:9]([O:16][C@@H:17]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][C:19](OC)=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([O:16][C@@H:17]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][C:19](=[O:20])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCC[C@@H](CC(=O)OC)OCc1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[C@@H](CC(=O)CC(=O)OC(C)(C)C)OCc1ccccc1
Temperature: -50 °C
Reaction time: 0.75 h
Yield: 59.4 %

Procedure:
A solution of 48.7 g of t-butyl acetate in 50 ml of dried THF was then added dropwise to the solution from a dropping funnel at the same temperature over 30 minutes, followed by stirring for 45 minutes. The resulting reaction mixture was further cooled to -50° C., and a solution of 45.4 g of methyl (S)-3-benzyloxyheptanoate in 50 ml of dried THF was added thereto over 30 minutes, followed by stirring for 2 hours while maintaining at that temperature. The reaction mixture was poured into a saturated ammonium chloride aqueous solution and extracted with diethyl ether. The extract was washed with a sodium chloride aqueous solution, and the solvent was removed by distillation under reduced pressure to obtain 67 g of a crude product, which was then purified by silica gel column chromatography to obtain 36 g (53.3%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].IC.[C:31](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:31])[CH:17]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccccc2Cl)cc1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(2-chloro-phenyl)-3-(4-methanesulfonyl-phenyl)-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=430.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)(=[O:13])=[O:12])[CH:3]=1.[CH3:24][O:25][C:26]1[N:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(OCC)(=O)C.O>C(=O)([O-])[O-].[K+].[K+].O1CCCC1.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>[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[N:22]=[CH:21][CH:20]=[CH:19]4)(=[O:13])=[O:12])[CH:3]=2)=[CH:28][N:27]=1
Reactant: O=S(=O)(c1cccc2cccnc12)n1cc(Br)c2cccnc21
Reactant: COc1nccc(B(O)O)n1
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: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(-c2cn(S(=O)(=O)c3cccc4cccnc34)c3ncccc23)cn1
Temperature: 120 °C
Yield: 5.6 %

Procedure:
In a microwave reaction tube, 8-(3-bromo-pyrrolo[2,3-b]pyridine-1-sulfonyl)-quinoline (44, 68 mg, 0.18 mmol), 2-methoxy-pyrimidine-4-boronic acid (67.4 mg, 0.438 mmol), and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.0088 mmol) were mixed in 1.0 M of potassium carbonate (0.52 mL) and tetrahydrofuran (0.84 mL). The resulting mixture was heated at 120° C. in a CEM Discover microwave unit for 10 minutes. Ethyl acetate and water were added and two layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulfate. The product was concentrated under reduced pressure and the resultant crude material was purified by column chromatography (80-90% ethyl acetate in hexane) to yield the desired product as a white solid (43, 0.005 g, 0.01 mmol). MS(ESI) [M+H+]+=417.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:23][OH:24])[NH:5][C:6]([O:8][CH2:9][CH:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[C:35]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2>C(#N)C>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:23][O:24][C:35]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:5][C:6]([O:8][CH2:9][CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7]
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.17 g (0.5 mmol) Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester, 0.043 g (0.6 mmol) potassium carbonate and 0.083 g (0.5 mmol) potassium iodide in acetonitrile (2 mL) was added 0.16 g (0.5 mmol) of 9-bromo-9-phenyl-9H-fluorene (Aldrich), and the mixture stirred at 40° C. for 2 h. Filtration and removal of the solvent under vacuo gave the crude Nα -(9-fluorenylmethoxycarbonyl)-O-(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester which was subjected to the Fmoc deprotection in Step 2 without further purification.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>O.O1CCOCC1>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][O:12][C@@H:11]1[C@@H:13]([CH2:14][OH:15])[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([F:3])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: ClCc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3Cl)[C@@H](CO)O2)cc1F
Temperature: 30 °C
Reaction time: 72 h
Yield: 23 %

Procedure:
A 3.75 g quantity of potassium hydroxide was dissolved in a mixture of 150 ml of water and 40 ml of dioxane. To the solution were added 1.00 g of 2'-deoxy-5-fluorouridine and 10 ml of 2-chlorobenzyl chloride, and the resulting mixture was stirred at 30° C. for 3 days. After the reaction, the same subsequent procedure as in Examples 4 and 5 was carried out, and the residue was placed on a silica gel column and eluted with 2% methanol-chloroform, thereby producing 0.34 g of the title compound in a yield of 23%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:21][CH2:20][CH2:19][O:18][C:5]2=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]([OH:17])=[O:16].CC([O-])=O.[Na+]>C(OCC)(=O)C.[Pd]>[CH2:11]([N:9]1[C:10]2[C:6](=[C:5]3[O:18][CH2:19][CH2:20][O:21][C:4]3=[CH:3][CH:2]=2)[C:7]([CH2:14][C:15]([OH:17])=[O:16])=[CH:8]1)[CH2:12][CH3:13]
Reactant: CCCn1cc(CC(=O)O)c2c3c(cc(Br)c21)OCCO3
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCn1cc(CC(=O)O)c2c3c(ccc21)OCCO3
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
A mixture of 40-4 (0.16 g, 0.45 mmol), NaOAc (0.9 g, 0.74 mmol) and 10% Pd/C (0.2 g) in ethyl acetate (20 mL) was stirred under H2 at room temperature for 12 h. The solid was filtered off and the filtrate was concentrated to obtain the desired product 40-5 (0.12 g, 97%) as a yellow solid, which was used in the next step without further purification. LCMS: calc 275.0 found 276.0 [MH]+.