Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[NH:10][C:11](=[O:19])[C:12]2[CH2:18][O:17][CH2:16][CH2:15][C:13]=2[N:14]=1.[F:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:7]([CH2:8][C:9]3[NH:10][C:11](=[O:19])[C:12]4[CH2:18][O:17][CH2:16][CH2:15][C:13]=4[N:14]=3)[CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:35])[CH2:31][CH2:32]2)=[O:26])=[CH:37][CH:38]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCc2cccs2)nc2c1COCC2
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)Cc2cccs2)CC1
Yield: 24.5 %

Procedure:
The title compound (296 mg) was prepared following the general procedure of Example from 2-((thiophen-2-ylmethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (710 mg, 2.3 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (720 mg, 2.7 mmol). 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.00 (d, J=8.8, 575 Hz, 2H), 7.38 (d, J=4.4 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 7.00 (s, 1H), 6.95 (s, 1H), 4.85 (s, 2H), 4.47 (s, 2H), 4.38 (s, 2H), 3.85 (t, J=5.7 Hz, 2H), 3.18-3.45 (m, 2H), 2.80-3.12 (m, 3H), 2.53 (t, J=5.4 Hz, 2H), 2.29 (t, J=10.7 Hz, 2H), 1.67-1.87 (m, 2H), 1.42-1.63 (m, 2H). HRMS calculated for C27H29FN4O4S 525.1972. found (ESI, [M+H]+), 525.1968. MS m/z 525.2 (M+1), retention time=3.08 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)cc2)cc1
Reaction time: 16 h
Yield: 134.9 %

Procedure:
To a solution of 4-methoxybenzenesulfonyl chloride (5.0 g, 24 mmol) and 4-methoxyaniline (3.0 g, 24 mmol) in dichloromethane (24 mL) at 0° C. was added triethylamine (3.4 mL, 24 mmol) over 10 minutes. The ice bath was removed, and the mixture was stirred for 16 hr. The mixture was diluted with dichloromethane (100 mL) and the combined solution was washed with water (50 mL) and brine (50 mL). The organic solution was dried over MgSO4, filtered, and evaporated, and the crude product was purified by silica gel chromatography (15-60% EtOAc/Hex). Product-containing fractions were pooled, evaporated, and dried under high vacuum to yield 9.5 g (79%) of the product as a tan-colored oil: 1H-NMR (DMSO-d6) δ 9.29 (s, 1H), 7.63 (d, 2H), 7.23-7.19 (m, 1H), 7.11-7.01 (m, 3H), 6.91-6.83 (m, 2H), 3.79 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:14])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[O:14])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a 3-necked round-bottomed flask was added AlCl3 (32 g, 0.24 mol.) followed by anhydrous toluene (250 mL). The flask was equipped with a reflux condenser and nitrogen inlet and the suspension was stirred at RT under a nitrogen atmosphere. To the stirred suspension was added methyl 4-{[4-(methyloxy)phenyl]carbonyl}benzoate (23) (16.0 g, 0.059 mol.) portionwise at RT under a nitrogen atmosphere. The reaction mixture was heated at 85° C. with stirring under a nitrogen atmosphere. After 2 h, the oil bath was removed and the reaction mixture was allowed to cool at RT. The reaction mixture was cooled in an ice-water bath and ice was added very slowly portionwise (Note: significant HCl evolved upon addition of ice to the reaction mixture.) followed by the slow addition of ice-water. The reaction mixture was partitioned between EtOAc and water. The organic phase washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as a red-brown solid. The crude product was triturated with hot hexanes and the brown solid was filtered to give 14.0 g (93%) of compound 24. 1H NMR (400 MHz, DMSO-d6): δ 3.88 (s, 3 H), 6.88 (d, J=8.6 Hz, 2 H), 7.65 (d, J=8.7 Hz, 2 H), 7.74 (d, J=8.2 Hz, 2 H), 8.07 (d, J=8.2 Hz, 2 H), 10.51 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[C:9]([O:10][CH3:12])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)ccc(O)c1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Cl)c(C=O)c1Cl
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Dissolve 2,6-dichloro-3-hydroxy-benzaldehyde (10.7 g, 56 mmol) in N,N-dimethylformamide (80 ml), add potassium carbonate (15 g, 112 mmol), cesium carbonate(18.3 g, 56 mmol), iodomethane (7 ml, 112 mmol) and stir over night at room temperature. Filter reaction mixture into water washing solids with DMF, extract filtrate with ethyl acetate wash with water, brine, dry over sodium sulfate, filter and concentrate to yield 10 g (87%) of 2,6-dichloro-3-methoxy-benzaldehyde.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([OH:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[F:34][C:35](I)([F:37])[F:36].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:34][C:35]([F:37])([F:36])[C:20]1[N:19]([C:28]2[N:27]=[CH:26][N:25]=[C:23]([OH:24])[C:22]=2[N:21]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:5]1[O:4][C:1](=[O:3])[CH3:2]
Reactant: FC(F)(F)I
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(C(F)(F)F)nc3c(O)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 7 %

Procedure:
0.39 g (1.0 mmol) of 2′,3′,5′-tri-O-acetylinosine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 5.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l of dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethyl-2′,3′,5′-tri-O-acetylinosine (19F-NMR yield: 7.0%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 8-Trifluoromethyl-2′,3′,5′-tri-O-acetylinosine was obtained (0.018 g, yield: 4.0%) by column chromatography.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[CH3:13][C@H:14]1[CH2:23][NH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:32][O:31][CH2:30]4)[CH:28]=3)[CH:20]=2)[N:15]1[C:33](=[O:35])[CH3:34].C(N(CC)C(C)C)(C)C>ClCCCl>[C:33]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:32][O:31][CH2:30]4)[CH:28]=3)=[CH:18][CH:17]=2)[N:22]([C:7]([Cl:10])=[O:6])[CH2:23][C@@H:14]1[CH3:13])(=[O:35])[CH3:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2NC[C@@H]1C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Cl)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
Triphosgene (0.048 g, 0.16 mmol) was added slowly to a solution of (S)-1-(2-methyl-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.050 g, 0.16 mmol) and N,N-diisopropylethylamine (0.413 g, 3.20 mmol) in 1,2-dichloroethane (20 mL) at room temperature. The resulting solution was stirred for 1 hour at room temperature and then concentrated under vacuum. The crude product was purified via preparative thin layer chromatography (eluting with 1:1 petroleum ether:ethyl acetate) to afford (S)-4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride (0.040 g, 67%) as a yellow solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 7.92-7.80 (m, 3H), 7.41-7.38 (m, 1H), 7.26-7.23 (m, 1H), 5.55-5.45 (m, 1H), 5.13-5.08 (m, 5H), 4.58-4.53 (m, 1H), 3.33-3.20 (m, 1H), 2.23 (s, 3H), 1.10 (d, J=6.3 Hz, 3H). MS (ESI, pos. ion) m/z 375, 377 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][N:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH3:17])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1
Reactant: COC(=O)C1=C(O)c2ccccc2SN1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C1=C(OC)c2ccccc2SN1C
Yield: 61 %

Procedure:
This compound was prepared according to Zinnes et. al., J. Med. Chem., 1973, 16, 44-48. Thus, a solution of methyl 2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate (500 mg, 1.86 mmol) (Lombardino, et. al., J. Med. Chem., 1971, 14, 1171-1177, incorporated by reference herein in its entirety) in acetone (10 ml) was treated with anhydrous potassium carbonate (2.6 g, 18.6 mmol) and iodomethane (1.32 g, 9.29 mmol) and refluxed for 40 hours. The mixture was filtered and concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 285 mg (54%) of the title compound as a yellow viscous oil, used subsequently without need for further purification; NMR (CDCl3) δ 3.03 (s, 3H), 3.83 (s, 3H), 3.91 (s, 3H), 7.67-7.72 (m, 2H), 7.81-7.88 (m, 2H); MS: 284 m/z (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]2=[O:16].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:17]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=2[O:1][C:28]2[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[C:7]1=[O:16])[CH:18]([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)c2c(c1)C(=O)N(CC(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(CC(C)C)CC2
Temperature: 100 °C

Procedure:
A mixture of methyl 5-hydroxy-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (250 mg, 0.90 mmol), 4-fluorophenyl methyl sulfone (236 mg, 1.35 mmol), Cs2CO3 (441 mg, 1.35 mmol) and Cul (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the ether (312 mg, 78%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.78 Hz, 6 H) 1.94-2.16 (m, 1 H) 2.94 (t, J=6.59 Hz, 2 H) 3.04-3.16 (m, 3 H) 3.41 (d, J=7.54 Hz, 2 H) 3.55 (t, J=6.59 Hz, 2 H) 3.87-4.01 (m, 3 H) 7.00-7.11 (m, 2 H) 7.80 (d, J=1.70 Hz, 1 H) 7.88-8.00 (m, 2 H) 8.66 (d, J=1.51 Hz, 1 H); MS (ESI, pos): 432.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH:37]([N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([CH:37]([CH3:39])[CH3:38])[CH3:50])=[O:49])[CH2:48][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)N(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-isopropyl-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 16c) in an analogous manner as described in example 25. LR-MS: 703.4 [(M+H)+]
Reaction SMILES: C([N:8]1[C:16]2[C:15]([S:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])=[N:14][C:13]([NH:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[N:12][C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[C:19]1([CH3:26])[CH:20]=[C:21]([CH3:25])[CH:22]=[C:23]([CH3:24])[C:18]=1[S:17][C:15]1[C:16]2[NH:8][CH:9]=[CH:10][C:11]=2[N:12]=[C:13]([NH:27][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[N:14]=1
Reactant: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Temperature: 160 °C
Yield: 66.6 %

Procedure:
To a suspension of 4-(5-benzyl-4-(mesitylthio)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (9.2 mg, 0.03 mmol) in 1,2-dichlorobenzene (1 mL) was added AlCl3 (26 mg, 0.3 mmol). The reaction mixture was heated at 160° C. for 1.5 h, which the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled and washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with Hexanes:Ethyl acetate (2.5:1) produced the product as a pink solid (7.7 mg, 20%).
Reaction SMILES: [Na:1].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].[C:44](Cl)(=[O:47])[CH2:45][CH3:46].O>N1C=CC=CC=1>[CH3:38][C:35]1[C:34]([O:39][C:44](=[O:47])[CH2:45][CH3:46])=[C:33]([C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[CH:37][CH:36]=1)[C:40]([OH:42])=[O:41].[Na:1]
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Reactant: CCC(=O)Cl
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Oc1c(C)ccc(CCC(C)C(O)C(C)C(=O)C(CC)C2OC(CC)(C3CCC(O)(CC)C(C)O3)CC2C)c1C(=O)O
Reaction time: 2 h

Procedure:
6.12 g. of the sodium salt of antibiotic X-537A was dissolved in pyridine (10 ml.) by warming slightly. The solution was cooled in an ice bath and treated with propionyl chloride, then allowed to stand at room temperature for 2 hours. The mixture was poured into water, extracted with ethyl acetate, and the organic phase washed in succession with 1N hydrochloric acid (several times) and sodium carbonate solution (twice). Evaporation of the ethyl acetate solution left a residue which was crystallized from methylene chloride/hexane to afford 3-methyl-2-propionyloxy-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo- 7[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}benzoic acid, sodium salt, m.p. 185°-186.5° [α]D25 -20.00° (C=1.00 in methanol).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[N:7][N:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=2)[C:5](=[O:19])[N:4]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[F:29].[I-].[Na+]>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:4]2[C:3](=[O:2])[CH:8]=[N:7][N:6]([C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)[C:5]2=[O:19])=[C:23]([F:29])[CH:24]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: COc1cnn(-c2cccc(NC(C)=O)c2)c(=O)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Nc1cccc(-n2ncc(=O)n(Cc3ccc(Cl)cc3F)c2=O)c1
Yield: 22.3 %

Procedure:
According to Scheme 6 Step 2: To a stirred solution of N-(3-(5-methoxy-3-oxo-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (40 mg, 0.15 mmol) in acetonitrile (3 mL) were added 1-(bromomethyl)-4-chloro-2-fluorobenzene (52 mg, 0.23 mmol) and sodium iodide (46 mg, 0.31 mmol). The mixture was heated irradiated at 160° C. under microwave irradiation. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water then with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 5 g column, CH2Cl2/MeOH 98/2 to afford the N-(3-(4-(4-chloro-2-fluorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 10(B) as a yellow solid (13 mg, 22%).
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[S:4]([CH2:7][CH:8]1[CH2:12][CH:11]([C:13]([NH:15][NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23](S(C4C=CC(C)=CC=4)(=O)=O)[C:20]3=[N:21][CH:22]=2)=O)[CH:10]([CH2:36][CH3:37])[CH2:9]1)(=[O:6])=[O:5])[CH3:2].O=S(Cl)Cl.CCO>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([N:3]([CH2:38][CH3:39])[S:4]([CH2:7][CH:8]1[CH2:12][CH:11]([C:13]2[N:18]3[C:19]4[CH:25]=[CH:24][NH:23][C:20]=4[N:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH:10]([CH2:36][CH3:37])[CH2:9]1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCC1CC(CS(=O)(=O)N(CC)CC)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CCC1CC(CS(=O)(=O)N(CC)CC)CC1c1nnc2cnc3[nH]ccc3n12
Temperature: 80 °C
Yield: 58.4 %

Procedure:
To a mixture of N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methanesulfonamide (0.730 g, 1.27 mmol) and TEA (0.529 mL, 3.80 mmol) in 1,4-dioxane (12.7 mL) was added SOCl2 (0.185 mL, 2.53 mmol). The reaction mixture was heated at about 80° C. for about 2 h. The reaction mixture was cooled to ambient temperature and partitioned between saturated aqueous NaHCO3 (30 mL) and DCM (30 mL). The aqueous layer was washed with DCM (2×30 mL). The organic layers were combined, concd under reduced pressure, and purified by silica gel (80 g) chromatography eluting with a gradient of 0-60% MeOH in DCM to give a brown solid. The resulting solid was suspended in Na2CO3 (2 M aqueous, 2 mL), EtOH (2 mL) and 1,4-dioxane (2 mL). The reaction mixture was heated at about 60° C. for about 16 h. The reaction mixture was cooled to ambient temperature and purified by RP-HPLC (Table 1, Method d) to afford N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (0.300 g, 58%) as a tan solid: LC/MS (Table 1, Method b) Rt=1.89 min; MS m/z: 405 (M+H)+. The solid was further purified by using General Procedure AA to give N,N-diethyl-1-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=11.8 min, or =negative) (0.021 g, 7%) [Example #1.1]; N,N-diethyl-1-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methane-sulfonamide (Table 2, Method 27, Rt=11.1 min, or =positive) (0.018 g, 6%) [Example #1.2]; N,N-diethyl-1-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentyl)methanesulfonamide (Table 2, Method 27, Rt=10.7 min, or =positive) (0.018 g, 6%) [Example #1.3]; N,N-diethyl-1-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 28, Rt=20.1 min, or =negative) (0.031 g, 11%) [Example #1.4]; N,N-diethyl-1-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=12.8 min, or =positive) (0.002 g, 1%) [Example #1.5]; and N,N-diethyl-1-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=12.8 min, or =positive) (0.001 g, 1%) [Example #1.6].
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]([S:17][C:18]2[C:26]([C:27]3[CH:28]=[N:29]O[CH:31]=3)=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:32])([CH3:3])[CH3:2].O1C=C(B2OC(C)(C)C(C)(C)O2)[CH:35]=N1.CC(NCCCN1C(SC2C=C3OCOC3=CC=2I)=NC2C(N)=NC=NC1=2)C.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[NH:29]1[CH:35]=[CH:31][C:27]([C:26]2[C:18]([S:17][C:16]3[N:8]([CH2:7][CH2:6][CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])[C:9]4[C:14]([N:15]=3)=[C:13]([NH2:32])[N:12]=[CH:11][N:10]=4)=[CH:19][C:20]3[O:24][CH2:23][O:22][C:21]=3[CH:25]=2)=[CH:28]1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2-c2cnoc2)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2cc[nH]c2)OCO3)nc2c(N)ncnc21
Temperature: 60 °C
Yield: 28 %

Procedure:
9-(3-(isopropylamino)propyl)-8-(6-(isoxazol-4-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine [DZ3-49]. 4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 60° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was attempted to be purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 4:7:2:1) to give 7.4 mg (28%) of an inseparable mixture of DZ3-49 and DZ3-39 in a ratio of approximately 71:29, respectively, as determined by HPLC. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.66 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.18 (s, 1H), 7.01 (s, 1H), 6.13 (s, 2H), 4.37 (t, J=7.0 Hz, 2H), 3.27 (septet, J=7.1 Hz, 1H), 2.89 (t, J=7.1 Hz, 2H), 2.22 (m, 2H), 1.38 (d, J=6.5 Hz, 6H); MS (ESI) m/z [M+H]+ 454.1; HPLC: method ARt=5.67 (DZ3-39, 29%) and 5.87 (DZ3-49, 71%); method B Rt=4.58 (DZ3-39, 34%) and 5.57 (DZ3-49, 66%).