Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:8]=1)C.[Li+].[OH-]>C1COCC1.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:9]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[N:8]=[C:7]([CH2:6][CH:5]([C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[C:4]([OH:33])=[O:3])[CH:11]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Br)cc2)cc1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
3-[5-(4-Bromo-phenyl)-1-β-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid. To a solution of 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (100 mg, 0.2 mmol) was added LiOH (14 mg, 0.6 mmol, 3 equiv) in 2:1 THF/H2O (1 mL). After 3 h at 45° C., the mixture was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the title compound (66 mg, 79%). HPLC: Rt=4.25 (Method A). MS (ESI): mass calculated for C26H23BrN2O2, 474.09; m/z found, 475/477 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.40 (d, J=8.5 Hz, 2H), 7.22 (d, J=7.6 Hz, 2H), 7.19-7.05 (m, 7H), 7.01 (d, J=8.5 Hz, 2H), 6.23 (s, 1H), 4.10 (dd, J=9.6, 5.5 Hz, 1H), 3.53 (dd, J=14.8, 9.6 Hz, 1H), 3.13 (dd, J=14.8, 5.5 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH2:52]([N:59]=[C:60]=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:60]([NH:59][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:61])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: O=C=NCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)NCc3ccccc3)cc2)C1=O

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and benzyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.38 (s, 6H), 1.82 (m, 1H), 2.15-2.55 (m, 3H), 4.14 (s, 2H), 4.24 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.05-7.42 (m, 22H). FAB-MS: calculated for C44H45N5O5 723; found 724 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.BrC(C(C1C=CC(Br)=CC=1)=O)C(OCC)=O.[C:40]([N:47]1[CH2:54][CH2:53][CH2:52][C@H:48]1[C:49]([OH:51])=[O:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CCN(C(C)C)C(C)C>C(Cl)Cl.C(#N)C>[N:47]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:54][CH2:53][CH2:52][CH:48]1[C:49]([O:51][C@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:15])=[O:50]
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)C(Br)C(=O)c1ccc(Br)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](OC(=O)C1CCCN1C(=O)OC(C)(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 18 h

Procedure:
The ethyl 3-(4-bromophenyl)-3-oxopropanoate (15 g, 55 mmol) was dissolved in CH2Cl2 (600 mL) and freshly recrystallized NBS (9.8 g, 55 mmol) was added and the solution stirred 18 hr. The reaction mixture was washed with NaHCO3 solution, brine, and dried (MgSO4), filtered, and concentrated to give a residue which was not purified. Ethyl 2-bromo-3-(4-bromophenyl)-3-oxopropanoate (16.5 g, 48 mmol) and N-Boc-L-proline (10 g, 48 mmol) were taken up in acetonitrile (450 mL) and Hunig's base (16 mL, 95 mmol) was added and the solution stirred 18 hr. The solvent was removed by rotary evaporation and the residue taken up in ethyl acetate, washed with 0.1 N HCl, and brine. 1H NMR (300 MHz, DMSO-d6) δ 7.95 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 6.68-6.65 (m, 1H), 4.39-4.30 (m, 1H), 4.21-4.12 (m, 2H), 2.27-2.21 (m, 1H), 2.0-1.95 (m, 1H), 1.90-1.76 (m, 2H), 1.39 (s, 2H), 1.31 (s, 9H), 1.11 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7]3)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Reactant: O=C=Nc1ccccc1
Product: Cc1cc(NC(=O)Nc2ccccc2)c2[nH]c(-c3ccccn3)cc2c1

Procedure:
7-Amino-5-methyl-2-(pyridin-2-yl)-1H-indole prepared in Step A of Example 1 and phenylisocyanate were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](I)=[CH:28][N:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: Nc1ncc(I)cn1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 g, 1.0 mmol) and commercially available 2-amino-5-iodopyrimidine (287 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (52 mg, 12%). MS (ISP) 431.3 [(M+H)+]; mp 242-243° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:15])([F:14])[CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([F:14])([F:15])[CH2:11][CH2:12][O:13][S:23]([CH3:22])(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC(F)(F)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyloxy-2,2-difluoro-4-hydroxybutane (50 g, 0.231 moles) and dry pyridine (100 mL) in dichloromethane cooled in an ice bath, methanesulfonyl chloride (26.52 g, 0.232 moles) in dichloromethane (100 mL) is slowly added. After stirring at room temperature overnight, the mixture is washed with 2N HCl (2×1 L) and twice with water. Drying and subsequent evaporation of the solvent yields 1-benzyloxy-2,2-difluoro-4-methanesulfonyloxybutane as a yellow oil: 63.44 g (93%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2].CC([O:16][C:17]([CH3:19])=[O:18])=O.OS(O)(=O)=O.[CH3:25][C:26]([OH:28])=[O:27]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:16][C:17](=[O:18])[CH3:19])[O:28][C:26](=[O:27])[CH3:25])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc([N+](=O)[O-])ccc1C
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: COc1cc([N+](=O)[O-])ccc1C(OC(C)=O)OC(C)=O
Temperature: 8 °C
Yield: 51 %

Procedure:
To a 5 L three necked round bottom flask equipped with a mechanical stirrer was added 4-nitro-2-methoxytoluene (150.0 g, 0.8973 mol), HOAc (900 mL) and Ac2O (900 mL). The mixture was stirred and cooled to 8° C. with an acetone/ice bath. Concentrated H2SO4 (136 mL) was carefully added while keeping the pot temperature <190 C. After cooling to 0° C., CrO3 (252.6 g, 2.526 mol, 2.815 equiv.) was added portion-wise over 1 hour while maintaining the reaction temperature between 0-10° C. After the addition, the mixture was stirred at 0° C. for 30 minutes at which time the reaction was complete. The reaction mixture was then carefully poured into ice (1.5 kg) with stirring to give a slurry. The remaining black gummy residue was rinsed with HOAc (3×100 mL), and the washes were added to the slurry. After stirring for 10 minutes, the slurry was filtered. The cake was washed with water (3×400 mL) and suction dried for 17 hours to give 4-nitro-2-methoxy-(a,a-bisacetoxy)toluene (1A, 129.0 g, 51%). 1H NMR (CDCl3) d 8.02 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), (d, 8.4 Hz, 1H), 3.98 (s, 3H), 2.16 (s, 6H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([OH:29])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Na+].[H][H].Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44]>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([O:29][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCOC(=O)CCCCCCCCBr
Reactant: CCCCCc1ccc(-c2ccc(CC(O)C3CCC(CCC)CC3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOC(=O)CCCCCCCCOC(Cc1ccc(-c2ccc(CCCCC)cc2)cc1)C1CCC(CCC)CC1
Reaction time: 3 h

Procedure:
0.1 mol of 1-(4-propylcyclohexyl)-2-(4'-pentylbiphenyl-4-yl)-ethanol is stirred with 0.1 mol of sodium hydride in 350 ml of toluene at room temperature until evolution of hydrogen is complete. 0.1 mol of allyl 9-bromopelargonate (obtained from allyl bromide and 9-bromopelargonic acid in dimethylformamide using potassium carbonate) is then added, and the mixture is kept at 60° C. for 3 hours. After cooling, the mixture is washed with water and dried over sodium sulfate, and the solvent is removed under reduced pressure to give allyl 9-(1-(4-propylcyclohexyl)-2-(4'-pentylbiphenyl-4-yl)-ethoxy)-pelargonate.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:33]>O1CCOCC1.O>[CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[C:8]([OH:9])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)Sc1ccc([C@@H](CC2CCCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Sc1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Temperature: 110 °C
Yield: 87 %

Procedure:
A solution of (R)-3-cyclopentyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-2-(4-isopropylsulfanyl-phenyl)-N-methyl-propionamide (830 mg, 1.89 mmol) in dioxane (10 mL) was treated with a 9 N aqueous sulfuric acid solution (6.0 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (100 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL). The organics were concentrated and then the residue dissolved in acetonitrile and silica gel (4 g) was added and it was concentrated in vacuo and then purified on Biotage Flash chromatography system (40S column, silica gel, 60% ethyl acetate/hexanes) to afford (R)-3-cyclopentyl-2-(4-isopropylsulfanyl-phenyl)-propionic acid (479 mg, 87%) as a yellow viscous oil: [α]28589=−52.3° (c=0.22, methanol); ES-HRMS m/e calcd for C17H24O2S (M+Na)+ 315.1389, observed 315.1388; 1H NMR JT (300 MHz, DMSO-d6) δ 1.07 (m, 2H, CH2), 1.22 (d, J=6.6 Hz, 6H, 2×CH3), 1.37-1.78 (m, 8H, 4×CH2), 1.94 (m, 1H, CH), 3.45 (m, 1H, SCH), 3.49 (d, J=7.5 Hz, 1H, ArCHCO), 7.25 (d, J=8.4 Hz, 2H, Ar), 7.32 (d, J=8.4 Hz, 2H, Ar), 12.35 (br, 1H, CO2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A mixture of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid (1.28 kg, 4.44 mol), diethylamine (461 mL, 4.44 mol), HOBT (600 g, 4.44 mol), DIPEA (1.547 L, 8.88 mol) in anhydrous DCM (8 L) was cooled to 0° C. EDCI (851.2 g, 4.44 mol) was added to the reaction mixture and it was stirred at 0° C. for 30 minutes and then at RT overnight. The reaction mixture was sequentially washed with aqueous NaHCO3, brine and water before being dried over MgSO4. Filtration and concentrated under reduced pressure provided a residue that was purified by silica gel chromatography (5-20% EtOAc in hexane) to provide 950 g of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide.
Reaction SMILES: [OH:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C>ClCCl>[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33]([O:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(COC(=O)[C@@H](O)C(C)C)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@@H](OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)C(C)C)cc1

Procedure:
4-Methoxybenzyl 2-hydroxy-3-methyl-(S)-(+)-butyrate was acylated with N-benzyloxycarbonyl-L-valine by the method described in Example A-I-1, step b. The title compound (5.74 g) was obtained after silica gel column chromatography (0, 1, 1.5% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.70.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.B1([C:33]2[CH:38]=[N:37][CH:36]=[CH:35][C:34]=2[C:39]#[N:40])OCC(C)(C)CO1.C(=O)([O-])[O-:42].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:7]=[C:2]([C:33]3[CH:38]=[N:37][CH:36]=[CH:35][C:34]=3[C:39]([NH2:40])=[O:42])[CH:3]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:5]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CC1(C)COB(c2cnccc2C#N)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cnccc2C(N)=O)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 16.6 %

Procedure:
150 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 235 mg of 4-cyanopyridine-3-boronic acid neopentyl glycol ester, 184 mg of sodium carbonate and 25 mg of tetrakis(triphenylphosphine)palladium were added in turn to a degassed mixed solution of 3.5 ml of 1,4-dioxane and 1.5 ml of water, and the mixture was stirred at 100° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained powder was washed with ethyl acetate, and filtered and dried under reduced pressure to obtain 31 mg of (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinamide as white powder.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C@H:24]2[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]2[O:26][C:27](=[O:29])[CH3:28])[C@@H:16]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:15][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[C:52]1([C:64](Cl)=[O:65])[CH:57]=[C:56]([C:58](Cl)=[O:59])[CH:55]=[C:54]([C:61](Cl)=[O:62])[CH:53]=1.[OH2:67]>N1C=CC=CC=1CC#N>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C@H:24]2[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]2[O:26][C:27](=[O:29])[CH3:28])[C@@H:16]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:15][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:64]([C:52]2[CH:57]=[C:56]([C:58]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([S:7][C@@H:6]4[O:15][C@H:16]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[C@@H:17]([O:23][C@H:24]5[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]5[O:26][C:27](=[O:29])[CH3:28])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:5]4[O:67][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=3)=[O:59])[CH:55]=[C:54]([C:61]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([S:7][C@@H:6]4[O:15][C@H:16]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[C@@H:17]([O:23][C@H:24]5[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]5[O:26][C:27](=[O:29])[CH3:28])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:5]4[O:4][C:1](=[O:3])[CH3:2])=[CH:9][CH:10]=3)=[O:62])[CH:53]=2)=[O:65])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(N)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: N#CCc1ccccn1
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(NC(=O)c3cc(C(=O)Nc4ccc(S[C@@H]5O[C@H](COC(C)=O)[C@@H](O[C@H]6O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]6OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)cc4)cc(C(=O)Nc4ccc(S[C@@H]5O[C@H](COC(C)=O)[C@@H](O[C@H]6O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]6OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)cc4)c3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 24 h

Procedure:
To a solution of 2.5 g of 4-aminophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 25 ml of pyridineacetonitrile (1:1) was added 300 mg of 1,3,5-benzenetricarboxylic acid chloride. The resulting solution was kept at ambient temperature, protected from moisture for 24 hours, then poured into 250 ml of water. The solution was extracted several times with chloroform. The combined extracts were washed with 0.5 N hydrochloric acid and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness giving 2.7 g of the desired intermediate as a foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=3[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[C:14]([O:19][C:20](=[O:22])[CH3:21])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(-n2ccc3c(O)cccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc2c1ccn2-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In 8 mL of methylene chloride, 387 mg (1.52 mmol) of 1-(4-nitrophenyl)-1H-indole-4-ol was dissolved, and 0.186 mL (2.00 mmol) of acetic anhydride and 0.318 mL (2.28 mmol) of triethylamine were added thereto and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was partitioned between methylene chloride (50 mL) and a saturated ammonium chloride aqueous solution (20 mL) and washed with a saturated sodium chloride solution, and the organic layer was dried and then concentrated under reduced pressure to obtain acetic acid 1-(4-nitrophenyl)-1H-indol-4-yl ester. The product was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:41]1([S:47](Cl)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:41]1([S:47]([CH:2]([NH2:1])[C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]3[O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:5][CH:4]=2)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CN)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(N)S(=O)(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of 47 mg (0.105 mmol) of tert-butyl (3RS,4RS)-4-(4-aminomethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 2 ml of methylene chloride was treated with 18 μl (1 2.7 mg, 0.1 26 mmol, 1.2 eq.) of triethylamine and cooled to 0° C. 15 μl (20.4 mg, 0.116 mmol, 1.1 eq.) of benzenesulphonyl chloride were added dropwise, the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. There were obtained 47 mg of crude tert-butyl (3RS,4RS)-4-[4-(phenylsulphonyl-amino-methyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, which was used in the following step without further purification and characterization.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([OH:10])[C:8]#[CH:9]>C[O-].[Na+]>[CH2:7]([O:10][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[C:8]#[CH:9]
Reactant: C=CC(=O)OC
Reactant: C#CCO
Agent: C[O-]
Agent: [Na+]
Product: C#CCOCCC(=O)OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
25.8 g of methyl acrylate were added dropwise to a mixture of 16.8 g of propargyl alcohol and 0.1 g of sodium methoxide maintained at 55°-60° C. The mixture was then heated at 80° C. for 4 hours, after which it was left to stand overnight. The mixture was then poured into ice-water and extracted with ethyl acetate. The extract was dried and then purified by distillation to give 25.8 g of methyl β-propargyloxypropionate, boiling at 80°-83° C./10 mmHg.