Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:12][CH:11]=2)=[N:6][CH:5]=1)[C:2]#N.SC[C@H]([C@@H](CS)O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClC1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[C:43]=1[F:52]>CO.CN(C=O)C>[C:20]([O:19][C:18]([NH:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7]2[S:8][C:4]([S:1][C:2]3[CH:47]=[CH:46][N:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[C:43]=3[F:52])=[CH:5][N:6]=2)=[N:15][CH:14]=1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1nccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(SC#N)s2)nc1
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1nccc(Sc2cnc(Nc3ccc(CNC(=O)OC(C)(C)C)cn3)s2)c1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Tert-butyl (6-(5-thiocyanatothiazol-2-ylamino)pyridin-3-yl)methylcarbamate (1.5 g, 4.13 mmol) was dissolved in methanol (30 mL) and treated with dithiothreitol (0.637 g, 4.13 mmol). The reaction was stirred at 23° C. for 1 hour. DMF (30 mL) was then added, followed by K3PO4 (0.351 g, 1.65 mmol) and methyl 4-chloro-3-fluoropicolinate (0.861 g, 4.53 mmol). The reaction was stirred at 23° C. for 1 hour, then methanol was evaporated. The title material was precipitated by adding water (˜200 mL), collected by filtration and dried under high vacuum to give the title material (1.875 g, 92%) as a solid. The compound was purified by silica gel chromatography (Biotage, dichloromethane/methanol) to give the title material as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.38 (9H, s) 3.91 (3H, s), 4.08 (2H, d, J=5.81 Hz), 7.09 (1H, d, J=8.34 Hz), 7.14 (1H, t, J=5.31 Hz), 7.41 (1H, t, J=5.94 Hz), 7.66 (1H, dd, J=8.46, 2.15 Hz), 7.82-7.85 (1H, m), 8.17 (1H, d, J=1.77 Hz), 8.33 (1H, d, J=5.05 Hz), 11.89 (1H, s). HPLC ret. time: 5.868 min. (Condition B).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][CH:20]([S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])=[O:23])[CH3:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:28]3[CH2:27][CH2:26][N:25]([S:22]([CH:20]([CH3:21])[CH3:19])(=[O:23])=[O:24])[CH2:30][CH2:29]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)S(=O)(=O)N1CCNCC1
Product: CC(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-(propane-2-sulfonyl)-piperazine using procedure C yielded 2-chloro-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:10][O:11][CH2:12][C:13]#N.C([O:17]CC)C>[Cl-].[Zn+2].[Cl-]>[CH3:10][O:11][CH2:12][C:13]([C:9]1[C:1]([OH:2])=[CH:3][C:4]([OH:5])=[CH:6][C:7]=1[OH:8])=[O:17]
Reactant: COCC#N
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Zn+2]
Product: COCC(=O)c1c(O)cc(O)cc1O
Reaction time: 5 h
Yield: 81 %

Procedure:
Phloroglucinol (35.1 g, 279 mmol) was dissolved into ethyl ether (500 mL) solution, followed by zinc chloride (8 g, 59 mmol) and 2-methoxy acetonitrile (18 g, 253 mmol) added in the solution under ice water bath condition. Dry HCl gas was bubbled into the reaction mixture, vigorously stirring for 5 hours, and precipitate was formed. The precipitate was filtered and collected, followed by dissolved into water and refluxed for 3 hours. After cooling, pink precipitate was collected, and desired white compound can be obtained after recrystallization with water. (45 g, yield 81%) 1HNMR (400 MHz, DMSO-d6): δ=12.14 (s, 2H), 10.41 (s, 1H), 5.79 (s, 2H), 4.56 (s, 2H), 3.32 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C@@H]3C[C@H](C)CC[C@H]3C(C)C)[C:6]3[CH2:21][CH:22]4[NH:26][CH:25]([C:5]=3[C:4]=2[C:3]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23]4.O.[OH-].[Li+]>O1CCCC1.CO.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:21][CH:22]4[NH:26][CH:25]([C:5]=3[C:4]=2[C:3]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23]4
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1n1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1c(Br)ccc2[nH]c3c(c12)C1CCC(C3)N1
Reaction time: 2.5 h
Yield: 92.1 %

Procedure:
To a solution of the product from step E (8.51 g, 15.23 mmol) in tetrahydrofuran (102 mL) and MeOH (51 mL) was added a solution of lithium hydroxide monohydrate (1.92 g, 45.69 mmol) in water (25 mL) at ambient temperature. The mixture was stirred vigorously for 2.5 h, quenched with aqueous saturated NH4Cl solution (75 mL), and extracted with ethyl acetate (2×200 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate, 70:30) to afford (+)-tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (5.29 g, 92%) as a white solid: [α]D=+142.4° (c 0.33, MeOH); 1H NMR (CDCl3, 300 MHz) δ 7.93 (s, 1H), 7.61 (d, J=0.9 Hz, 1H), 7.11-7.23 (dd, J=16.8, 8.4 Hz, 2H), 5.14 (s, 1H), 4.65 (s, 1H), 3.28-3.57 (m, 1H), 2.47 (d, J=16.2 Hz, 1H), 2.10-2.38 (m, 2H), 1.88-1.98 (m, 1H), 1.54-1.70 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[NH2:9].C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30]>C(Cl)Cl>[OH:30][C:29]1[C:28](=[O:32])[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[CH:7][CH:6]=[C:5]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=1)[CH:4]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(O)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Yield: 46.2 %

Procedure:
A solution of N3-methyl-4′-(trifluoromethoxy)biphenyl-3,4-diamine (1 g) in methylene chloride (35 ml) was cooled in an ice bath, and triethylamine (1.5 ml) was added, followed by dropwise addition of oxalyl chloride (670 mg). After 1 hour the solvent was removed under reduced pressure, and the residue was crystallized from methanol, to provide 3-hydroxy-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one (550 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][O:27][CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][CH:35]=2)[CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:41]([CH2:40][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:30]4[CH2:31][CH2:32][CH:28]([O:27][CH3:26])[CH2:29]4)=[CH:39][CH:38]=3)[CH3:42])=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CNCc1ccc(CN2CCC(OC)C2)cc1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc(CN4CCC(OC)C4)cc3)o2)c(C)c1
Reaction time: 2 h

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 1-{4-[(3-methoxypyrrolidin-1-yl)methyl]phenyl}-N-methylmethanamine (45 mg, 0.19 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3. The fraction collected was dissolved in DCM (5 mL) and shaken with PL-MIA resin for 2 h, and the beads were filtered and washed with DCM (10 mL). The combined filtrates were concentrated in vacuo and the residue purified using prep method D to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:10])=O)=[CH:4][C:3]1=[O:11].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:10])=[CH:4][C:3]1=[O:11]
Reactant: Cn1ccc(C(N)=O)cc1=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cn1ccc(C#N)cc1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a cold solution of 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (7.2 g, 47.3 mmol, Journal of Organic Chemistry, 1959, 24, 196) in DCM (70 mL) was added TEA (13.19 mL, 95 mmol) and TFAA (8.02 mL, 56.8 mmol) at about 0° C. The reaction mixture was stirred for about 2 h at about 0° C. The reaction mixture was filtered and the filtrate was diluted with DCM (100 mL). The organic layer was washed successively with water (2×70 mL) and brine (1×70 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 1-methyl-2-oxo-1,2-dihydropyridine-4-carbonitrile as a white solid 3.3 g, (52.0%), 1H NMR (400 MHz, DMSO) δ: 7.94-7.92 (d, J=7.2 Hz, 1H), 7.00 (s, 1H), 6.53-6.50 (dd, J=2 Hz, 1 Hz), 3.45 (s, 3H), LC/MS (Table 1, Method d) Rt=0.77 min.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13](C(N=[N+]=[N-])=O)=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.[OH-].[Na+].C[N:30](C=O)C>>[NH2:30][C:13]1[N:12]=[CH:11][C:10]([O:22][CH3:23])=[C:9]2[C:14]=1[CH2:15][CH2:16][N:7]([CH2:6][C:5]1[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]2=[O:24]
Reactant: CN(C)C=O
Reactant: COc1cnc(C(=O)N=[N+]=[N-])c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Agent: [Na+]
Agent: [OH-]
Product: COc1cnc(N)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.33 h

Procedure:
To a solution of sodium azide (0.24 g, 3.69 mmol) in water (2.5 mL) was added 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl chloride (1.17 g, 3.36 mmol) in acetone (15 mL). After 20 minutes, the product mixture was concentrated under vacuum to provide 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl azide. The crude azide (1.19 g, 3.35 mmol) in DMF (20 mL) was heated to 110° C. After 20 minutes, the product mixture was cooled for 10 minutes, then 1N NaOH (3.3 mL) was added. After 20 minutes, the mixture was concentrated under vacuum, re-dissolved in toluene and CHCl3 and evaporated. The residue was partitioned between CHCl3 and saturated sodium bicarbonate. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C([O:45][C:46](=[O:57])[NH:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=1)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@@H:9]([C:28]([NH:56][C:53]3[CH:52]=[CH:51][C:50]([CH2:49][CH2:48][NH:47][C:46](=[O:57])[OH:45])=[CH:55][CH:54]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCNC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h

Procedure:
To a solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (51.1 mg, 0.11 mmol) in dichloromethane (3 mL) were added DIPEA (71.2 mg, 0.55 mmol), [2-(4-AMINO-PHENYL)-ETHYL]-CARBAMIC ACID TERT-BUTYL ESTER (52.3 mg., 0.22 mmol, Chem-Impex) and HATU (77.8 mg, 0.20 mmol) (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 mins, the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral [2-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-ethyl]-carbamic acid tent-butyl ester (40.6 mg., 54.2%) as a white lyophilized solid. HRMS (ES+) m/z Calcd C36H40Cl2F2N4O3+H [(M+H): 685.2519. Found: 685.2517.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)([O-])=O>C(OCC)(=O)C.O.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])=[N:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc2[nH]c(-c3ccccc3O)nc2c1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To 2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (90 mg, 0.35 mmol) in ethyl acetate/water/acetic acid 1:1:0.01 v/v/v (10 mL) was added palladium on carbon (15 mg). The reaction vessel was purged three times with nitrogen, followed by three times with hydrogen, and then left stirring under hydrogen for 2 h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite®, which was washed with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 2:1 v/v to afford 60 mg (76%) of the title compound (LCMS RT=5.39 min, MH+ 226.1)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][N:12]1[CH:21]=[C:20]([CH:22]=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]3[CH:25]=[C:26]([CH:33]=[C:34]([F:37])[C:35]=3[CH3:36])[C:27]([NH:29][CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH:18]=2)[C:13]1=[O:38])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:41][Mg]Cl>>[Si:1]([O:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][N:12]1[CH:21]=[C:20]([CH:22]([OH:23])[CH3:41])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]3[CH:25]=[C:26]([CH:33]=[C:34]([F:37])[C:35]=3[CH3:36])[C:27]([NH:29][CH:30]3[CH2:31][CH2:32]3)=[O:28])[CH:18]=2)[C:13]1=[O:38])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(C=O)c2c1
Reactant: C[Mg]Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(C(C)O)c2c1

Procedure:
3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-formyl-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 26f, 1.10 g) was reacted with methylmagnesium chloride (3 M in THF) (1.62 mL) by the method of Example 38a to afford the subtitle compound (1.10 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.N1CCOCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 176.2 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (7.9 ml) is added to the bottle, and morpholine (7.9 ml) is added thereto at the temperature. The above mixture is reacted at the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (11.2 g). The yield is about 65.4%.
Reaction SMILES: N([C@@H]1[C@@H:11]([OH:12])[C@H:10](O)[C@@H:9]([CH2:14]O)[O:8][C@H]1SC)=[N+]=[N-].C([O:19][C:20](=[O:22])[CH3:21])(=O)C>N1C=CC=CC=1>[CH3:14][C:9]([CH2:10][C:11]([CH2:21][C:20]([OH:19])=[O:22])=[O:12])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CS[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N=[N+]=[N-]
Solvent: c1ccncc1
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h

Procedure:
To methyl 2-azido-2-deoxy-1-thio-β-D-glucopyranoside. (10 g, 42.50 mmol) in pyridine (50 mL) at 0° C. was added acetic anhydride (20 g) and the reaction stirred for 1 hour. The reaction mixture was evaporated to dryness and the residue extracted to give the title triacetate (15.23 g, quantitative), Rf=0.7 (CHCl3/Petroleum ethers, 1:1).
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].[C:40](=[O:43])([O-])[O-].[Na+].[Na+].C([O:49][CH2:50][CH3:51])(=O)C>CN(C=O)C>[C:40]1(=[O:43])[N:1]([CH2:2][CH2:34][CH2:35][NH:1][C@H:2]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3][N:4]2[C:9](=[O:10])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]3[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=3[F:32])[C:5]2=[O:33])[C:50](=[O:49])[C:51]2=[CH:20][CH:7]=[CH:8][CH:11]=[C:12]12
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Reactant: CCOC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](NCCCN3C(=O)c4ccccc4C3=O)c3ccccc3)c2=O)c1F
Temperature: 80 °C
Yield: 67 %

Procedure:
To a solution of compound 6d (4.0 g, 7.2 mmol) in anhydrous DMF (8 mL) was added sodium carbonate (0.76 g, 7.2 mmol) and N-(3-bromopropyl)phthalimde (2.4 g, 9.0 mmol). The reaction mixture was heated to 80° C. under nitrogen for 4 hr. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane, 50% ethyl acetate in hexane and then ethyl acetate to yield 6e as a pale yellow solid (3.6 g, 4.9 mmol, 67%). MS (CI) m/z 743.1 (M+H+), tR=2.539 min. (method 4). 1H NMR (CDCl3): δ 1.62–1.70 (m, 2H), 2.26 (s, 1.5H), 2.27 (s, 1.5H), 2.29–2.33 (m, 1H), 2.40–2.48 (m, 1H), 3.51 (s, 1.5H), 3.52 (s, 1.5H), 3.54–3.74 (m, 2H), 3.90 (s, 1.5H), 3.91 (s, 1.5H), 3.93–4.26 (m, 3H), 5.60 (brs, 2H), 6.80–6.89 (m, 1H), 6.99 (dd, 1H), 7.11–7.36 (m, 8H), 7.42–7.49 (m, 1H), 7.71–7.75 (m, 2H), 7.84–7.89 (m, 1H), 7.95 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[C:10]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CCN)ccc1O
Reactant: O=C(O)C(O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CCNC(=O)C(O)c2ccc(Cl)c(Cl)c2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (3,4-dichloro-phenyl)-hydroxy-acetic acid (3 g), 4-(2-amino-ethyl)-2-methoxy-phenol hydrochloride (2.7 g) and ethyl-diisopropyl-amine (7 ml) in dimethylformamide (60 ml) is added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (6 g) in one portion. The mixture is stirred at room temperature for 3 hours. Then water (400 ml) is added. The mixture is extracted with ethyl acetate (2×400 ml) and washed with brine (2×200 ml). The organic layers are collected, dried with MgSO4 and evaporated. 2-(3,4-dichloro-phenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-acetamide is obtained which is purified by flash column chromatography on silica gel (ethyl acetate/hexane 2:1); the product is an oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[C:15]([CH3:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH3:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([CH3:34])[CH:28]=1>CN(C)C=O>[ClH:1].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[C:15]([CH3:22])[CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH3:23])[C:9]3[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[C:29]([CH3:34])[CH:28]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1cccc2c(N3CCc4cccc(C)c4C3C)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4cccc(C)c4C3C)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 21 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 2.50 g of the compound (7.06 mM) prepared in Example 14 and 15 ml of dimethyl-formamide, 1.21 ml of 4-fluoro-2-methylaniline(14.9 mM) was added, 0.70 g of the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 500 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (6 g, 21.65 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (7.25 g, 21.65 mmol) [prepared according to the procedure of Preparation 6], N,N-diisopropyl ethylamine (5.67 ml, 32.5 mmol) and Pybrop (15.08 g, 32.5 mmol) in Dichloromethane (DCM) (150 ml). After stirring at RT for 12 h, the reaction solution was washed with H2O (2×100 mL) and the organic layer was dried Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with [EtOAc/hexanes, 1:1] to give the product [9.0 g, 74%] as a white solid: LCMS (ES) m/z 558 (M+H)+.