Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][NH2:37].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:29])([F:27])[F:28])[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:37][CH2:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)=[O:20])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccccn1)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.4 %

Procedure:
To the solution of 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoic acid (0.3 g) and 2-picolylamine (0.07 g) in DMF was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g) and 1-hydroxybenzotriazole monohydrate (0.01 g), and the mixture was stirred for 6 hour at room temperature. The reaction solution was poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent, was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 4-[3(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitro-N-(pyridine-2-ylmethyl)benzamide (0.19 g). 1H-NMR (CDCl3) δ: 2.54-2.65 (1H, m), 2.89-2.97 (1H, m), 3.51-3.67 (2H, m), 3.83 (1H, d), 4.13 (1H, d), 4.74 (2H, d), 6.75 (1H, dd), 7.08 (1H, d), 7.15-7.23 (2H, m), 7.28 (2H, br s), 7.37 (1H, d), 7.41 (1H, t), 7.49 (1H, d), 7.70 (1H, td), 8.52 (1H, d).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[S:9](=O)(=[O:12])([OH:11])[OH:10].C(C(CCCC)C([O-])=O)C.[K+:24]>C(OCC)(=O)C>[K+:24].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:9]([O-:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 77.9 %

Procedure:
Hydroquinone (10 g, 0.09 mol) was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. Temperature was slowly raised to 50-60° C. then stirred for 3-8 h. The reaction mass was then cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (18.2 g, 0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 16 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=2.[O:13]1CCOCC1.[Se](=O)=O>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: Cc1c(Br)cnc2ncccc12
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Product: O=Cc1c(Br)cnc2ncccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-4-methyl-[1,8]-naphthyridine (1.5 g, 6.7 mmol), dioxane (16 mL) and water (0.6 mL) was treated with selenium dioxide (3.0 g, 27 mmol) and stirred at 80° C. for 1 h. The mixture was cooled to RT, diluted with satd. aq. NaHCO3, extracted 3× with EtOAc, and the combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum. Filtration through a pad of silica gel eluting with EtOAc gave 0.70 g of the title compound as a yellow solid. 1H NMR (CDCl3) δ 10.62 (s, 1H), 9.32 (s, 1H), 9.28 (d, 1H), 1.18 (d, 1H), 7.66 (dd, 1H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:9][N:8]([CH3:10])[C:7](=[NH:11])[N:6]1[CH3:12].[CH3:13][NH:14][CH3:15].C[OH:17]>>[OH2:17].[ClH:2].[ClH:1].[NH:11]=[C:7]1[N:6]([CH3:12])[CH:5]([CH2:4][CH2:3][N:14]([CH3:15])[CH3:13])[CH2:9][N:8]1[CH3:10]
Reactant: CN1CC(CCCl)N(C)C1=N
Reactant: CNC
Reactant: CO
Agent: Cl
Product: CN(C)CCC1CN(C)C(=N)N1C
Product: O
Yield: 26 %

Procedure:
To 10.0 g (0.047 mole) of 4-(2-chloroethyl)-2-imino-1,3-dimethylimidazolidine hydrochloride was added 6.8 g (0.15 mole) of dimethylamine in 175 ml of methanol. The mixture was heated in a steel bomb at 100° C. for 15 hours. After concentrating in vacuo, the residue was partitioned between a dilute sodium carbonate solution and chloroform. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and treated with ethereal HCl. The hydrochloride was recrystallized from ethanol twice, and weighed 3.2 g (26% yield); m.p. 210°-212° C.
Reaction SMILES: [O:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([C:23]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]([C:23]([C:13]45[CH2:22][CH:17]6[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]6)[CH2:20]4)[CH2:14]5)=[O:24])[CH2:11][CH2:12][O:1][CH2:2][CH2:3]3)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C1COCCNCCOCCN1
Product: O=C(N1CCOCCN(C(=O)C23CC4CC(CC(C4)C2)C3)CCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 2 from 1,7-dioxa-4,10-diazacyclododecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH2:17][CH3:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.Cl.O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH2:17][CH3:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(CC)c2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 91.6 %

Procedure:
Employing ethyl 1-cyclopropyl-6,7,8-trifluoro-5-ethyl-1,4-dihydro-4 -oxoquinoline-3-carboxylate (5 g), conc. hydrochloric acid (11 ml), water (4.4 ml) and acetic acid (44 ml), the procedure of Reference Example 23 is repeated to give 1-cyclopropyl-6,7,8-trifluoro-5-ethyl-1,4-dihydro-4 -oxoquinoline-3-carboxylic acid (4.2 g), as white powder, m.p. 197°-198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:10][C:11]([C@H:13]1[NH:17][CH2:16][CH2:15][S:14]1)=[O:12].[CH:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:10][C:11]([C@H:13]1[N:17]([C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([CH:35]=[O:36])[CH:38]=2)[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1cccc(C(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (Int 4, 208 mg, 0.389 mmol), 3-formylbenzoic acid (87 mg, 0.583 mmol), EDC (149 mg, 0.777 mmol), and DMAP (57.0 mg, 0.466 mmol) were dissolved in DMF (2 ml). The reaction was stirred at RT for 8 hours to achieve completion. The reaction mixture was diluted with HCl 1N, and the precipitate was filtered, washed with HCl 1N, dissolved in DCM and extracted with HCl 1N, Na2CO3 sat and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-formylbenzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (108 mg, 0.162 mmol, 41.6% yield). The compound was used in the next step without any further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:32][O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])[C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25]Cl)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1.CN(C)C=O.[CH3:45][N:46]([CH2:48][C:49]1[CH2:54][C:53](=[O:55])[C:52]([OH:56])=[CH:51][N:50]=1)[CH3:47]>C(OCC)(=O)C>[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:32][O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])[C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:46]([CH3:47])([CH3:45])[CH2:48][C:49]4[NH:50][CH:51]=[C:52]([OH:56])[C:53](=[O:55])[CH:54]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CN(C)CC1=NC=C(O)C(=O)C1
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1nsc(N)n1)C(=O)O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.2 %

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (1.0 g) in-N,N-dimethylformamide (10 ml) was added 2-(N,N-dimethylamino) methyl-5-hydroxy-4-pyridone (.1.09 g). After being stirred for 5 hours at ambient temperature, the mixture was poured into ethyl acetate (150 ml). The resulting precipitate was collected by filtration, washed with ethyl acetate and dried under reduced pressure. The precipitate was suspended in water (50 ml) at pH 2.0 and stirred for 30 minutes. After removal of insoluble material, the aqueous solution was subjected to column chromatography on Diaion HP-20. The column was washed with water and the elution was carried out with 30% aqueous methanol. The fractions containing desired product was combined and methanol was evaporated in vacuo. The resulting aqueous layer was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (0.30 g) as a powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:27])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:32]=[N+:33]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)(=[O:19])=[O:20])=[CH:16][CH:17]=2)=[N:10][C:9]([Br:27])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(S(=O)(=O)N3CCOCC3)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cc(Br)nc(-c2ccc(S(=O)(=O)N3CCOCC3)cc2)c1N=[N+]=[N-]
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-(morpholinosulfonyl)phenyl)-isonicotinate (0.988 g, 2.17 mmol) was dissolved in TFA (11 mL) and the yellow solution was cooled in an ice bath. Powdered sodium nitrite (0.299 g, 4.33 mmol) was added with stirring to give a dark red mixture with gas evolution. After 20 min, powdered sodium azide (1.41 g, 21.7 mmol) was added over 5 min followed by Et2O (11 mL). A thick precipitate formed and, after 30 min, water was added and the mixture was extracted with EtOAc. The organic phase was washed with water (3×), brine (1×), saturated aqueous Na2CO3 solution (so that the aqueous phase was basic), and brine. After drying the solvent with sodium sulfate, the solvent was removed and silica gel chromatography (step gradient elution with DCM containing 0 to 10% EtOAc) afforded methyl 3-azido-6-bromo-2-(4-(morpholinosulfonyl)phenyl)isonicotinate (918 mg, 1.90 mmol, 88% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.93-7.96 (2H, m), 7.87 (1H, s), 7.85 (2H, d, J=8.24 Hz), 4.03 (3H, s), 3.73-3.77 (4H, m), 3.03-3.07 (4H, m).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C@@H:5]1[C:17]2[N:16]([C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH3:19])[C:15]3[C:10](=[CH:11][C:12]([F:34])=[CH:13][C:14]=3[S:30]([CH3:33])(=[O:32])=[O:31])[C:9]=2[CH2:8][CH2:7][CH2:6]1.C1COCC1.CO.[Li+].[OH-]>CC(O)=O>[F:34][C:12]1[CH:11]=[C:10]2[C:15](=[C:14]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:13]=1)[N:16]([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=1)[CH3:19])[C:17]1[C@@H:5]([CH2:4][C:3]([OH:35])=[O:2])[CH2:6][CH2:7][CH2:8][C:9]2=1
Reactant: COC(=O)C[C@H]1CCCc2c1n([C@@H](C)c1ccc(C(F)(F)F)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)n1c2c(c3cc(F)cc(S(C)(=O)=O)c31)CCC[C@@H]2CC(=O)O

Procedure:
To a solution of the above ester (1 eq) in a 3.5/1 mixture of THF/MeOH (0.25M) at 0° C. was slowly added aqueous LiOH 1N (1 eq) and the mixture was stirred at 0° C. for 16 h or until almost complete hydrolysis of the ester; under these conditions, the other minor diastereomer has a much slower rate of hydrolysis. AcOH was added and the solvent was removed in vacuo. The residue was taken up in EtOAc/H2O and the organic layer was washed with brine, dried over Na2SO4 filtered and concentrated. To remove the unreacted methyl ester, the residue was filtered through a pad of silica gel eluting first with 10% EtOAc/toluene and then with 60% EtOAc/toluene containing 1% of AcOH. The residue was swished in 30% EtOAc/hexane and dried under high vacuum at 50° C. for 16 hr to give the desired title compound as a white solid with de and ee >95% (checked by chiral HPLC). MS (−APCI) m/z 496.0 (M−H)−. [α]D=−181° in MeOH.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:39]([O:46][P:47]([CH2:56][C@H:57]([OH:60])[CH2:58][NH2:59])([CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH2:39]([O:46][P:47]([CH2:56][C@H:57]([OH:60])[CH2:58][NH:59][C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])([CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:48])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
To a solution of N-Boc-L-valine (1.798 g, 7.15 mmol) and HOBT, (1.257 g, 9.30 mmol) in DMF (10 mL) under N2 was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.440 g, 7.51 mmol). The resulting clear solution was stirred at room temperature for 5 min and then a solution of ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (2.589 g, 7.15 mmol) in DMF (15 mL) was added via cannula. Triethylamine (2.0 mL, 14.3 mmol) was added dropwise to the reaction mixture and the resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (75 mL) and was washed with saturated NaHCO3, half saturated brine and then brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography using 0-5% MeOH/CH2Cl2 as the eluent to yield the title diastereomeric compound (2.254 g, 4.296 mmol). 1H NMR (CD3OD, 300 MHz): δ 7.43-7.30 (m, 5H), 5.03 (m, 2H), 4.07 (m, 1H), 3.83-3.80 (m, 1H), 3.34-3.23 (m, 2H), 2.07-1.94 (m, 3H), 1.91-1.75 (m, 5H), 1.69-1.60 (m, 3H), 1.43 (s, 9H), 1.28-1.17 (m, 3H), 1.07-1.00 (m, 2H), 0.94 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H). 31P NMR (CD3OD, 300 MHz): δ 61.20, 60.48. LCMS m/z: [M+H]+=525.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:3]=1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[NH2:29].O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[NH:29][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:3]=1
Reactant: Nc1n[nH]c2ccc(F)cc12
Reactant: Cc1cc(Cl)nc(-c2ccccc2C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2n[nH]c3ccc(F)cc23)nc(-c2ccccc2C(F)(F)F)n1
Temperature: 165 °C
Yield: 56.5 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (0.10 g, 0.37 mmol) and 5-fluoro-1H-indazole-3-ylamine (0.072 g, 0.48 mmol) was heated neat at 160-170° C. for 8 hours. The resulting residue was cooled to ambient temperature then dissolved in N-methyl-pyrrolidinone (2 mL). This mixture was poured into water (20 mL) and sodium bicarbonate (5 mL) was added and the resulting mixture filtered, washing with water. Purification by preparative HPLC provided the title compound (0.081 g, 43% yield) as a tan solid. 1H-NMR (500 MHz, DMSO-d6) δ 12.8 (br s, 1H), 10.6 (br s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.77 (m, 4H), 7.62 (br s, 1H), 7.50 (m, 1H), 7.29 (m, 1H), 2.44 (s, 3H) ppm; LC-MS 388.05 (M+H); Rt (Method A) 2.900 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]#N)[N:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[OH-:20].[Na+].[OH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:22])=[O:20])[N:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: O
Reactant: Cn1c(CC#N)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCO
Product: Cn1c(CC(=O)O)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.3 g. (0.015 mole) of 4-chloro-5- (p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile and 1.2 g. (0.030 mole) of sodium hydroxide in 11 ml. of deionized water and 20 ml. of 95% ethanol is stirred and refluxed for seven hours and is then stirred at ambient temperature for about 18 hours. The precipitate which results when this reaction mixture is poured into 500 ml. of dilute hydrochloric acid is filtered off, washed with water, and recrystallized once from acetonitrile and once from diethyl ether in a Soxhlet extractor to give 4-chloro-5-(p-chlorobenzoyl)-1- methylpyrrole-2-acetic acid as a buff solid; m.p. 203°-204° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([N+]([O-])=O)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]([OH:41])=[O:40].Cl>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([O:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][CH:33]=[C:34]3[C:39]([OH:41])=[O:40])[CH:3]=1
Reactant: O=C(O)c1cccc2c(O)cccc12
Reactant: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])cc(Cl)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc4c(C(=O)O)cccc34)cc(Cl)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of 6-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.22 mmol) in DMSO (4 mL) were added K2CO3 (507 mg, 3.67 mmol) and 5-hydroxy-1-naphthoic acid (230 mg, 1.22 mmol). The reaction mixture was stirred for overnight at 100° C. after which, It was cooled to room temperature. To the reaction mixture was added 1N HCl solution to reach pH=5. The produced solid was filtered and dried nitrogen gas flow. The title compound (380 mg, 66% yield) was used next reaction without further purification. MS m/z: 469 [M+1].
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.[SH:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:31][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[S:25][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1
Reactant: Cn1ccnc1S
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1SCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (193 mg, 0.61 mmol) and 2-mercapto-1-methylimidazole (80 mg, 0.7 mmol) in dry DMF (2 mL) was treated with K2CO3 (97 mg, 0.7 mmol). The mixture was stirred at rt for 2 h, and then it was poured into ice-water. The mixture were extracted with EtOAc and the extract was washed with water and brine, dried over anhydrous MgSO4, and evaporated to yield the crude product, which was crystallized from EtOAc-hexane to give the title compound as colorless rods (142 mg); mp 155-160° C.; 1H NMR (CDCl3) 7.36 (s, 1H), 7.27 (s, 1H), 7.17 (d, J=7.7, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 6.95 (d, J=7.7, 1H), 6.91 (s, 13H), 6.14 (s, 2H), 6.07 (s, 2H), 4.53 (s, 2H), 3,51 (s, 3H). Anal. calcd. for C21H16N4O4S: C, 59.99; H 3.84; N 13.33. Found: C, 59.78; H 3.82; N 13.20.