Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(O)[CH2:10][C@H:9]1[C:23](=[O:34])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:41])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([F:41])[CH2:10][C@H:9]1[C:23](=[O:34])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(C(C)(C)O[SiH2]C(C)(C)C)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@](F)(C(C)(C)O[SiH2]C(C)(C)C)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 1.5 h

Procedure:
To a solution of (2S,4S)-4-(tert-butyl-dimethyl-silanyloxymethyl)-2-(3-chloro-2-fluoro-benzyl carbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.35 mmol) in CH2Cl2 (10 mL) under N2 atmosphere at −78° C. was added DAST (92 μL, 0.7 mmol). The reaction mixture was then allowed to reach RT and further stirred for 1.5 h then poured into an aqueous saturated solution of NaHCO3 and extracted twice with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated to give the desired material which was used without further purification in the next step. TLC, Rf (c-hexane/EtOAc 1:1)=0.75; MS (LC/MS): 541.2/543.1 [M+Na]+, 463.1/465.1 [MH−tBu]+, 419.0/421.1 [MH−Boc]+; tR (HPLC conditions f): 2.81 min.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:30]=[C:29]3[C:25]([C:26](=[CH:11][C:8]4[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=4[CH3:13])[C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(CCC(=O)O)c2C)cc1
Yield: 58.7 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 120 mg 6-(4-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 118 mg (59%) of the title compound as a brown solid.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][C:20]=1[S:31](=[O:34])(=[O:33])[NH2:32]>O1CCCC1>[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[CH:9][NH:10]3)=[CH:6][CH:5]=2)=[O:24])=[CH:21][C:20]=1[S:31]([NH2:32])(=[O:34])=[O:33]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2ccc3cc[nH]c3c2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dispersion of potassium hydride in oil (33.15 mmol) is washed with hexanes under argon then tetrahydrofuran (310 mL) is added at 0° C. and the resulting suspension is treated by dropwise addition of 6.77 g of 6-bromoindole in tetrahydrofuran (61 mL). The reaction mixture is stirred at 0° C. for 15 min to give a yellow solution. A solution of 44.2 mL of tert-butyllithium (1.5 M in pentane) is added slowly at −78° C. while maintaining the temperature below −75° C. to produce a yellow suspension. After 15 min a solution of 3.08 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (61 mL) is added and the temperature is allowed to increase slowly to 0° C. The reaction mixture is quenched by addition of 62 mL of saturated aqueous ammonium chloride and extracted with ethyl ether. The organics were washed with water, dried over magnesium sulfate and concentrated to 9.65 g of a brown oil which is chromatographed on silica gel (1:1 hexanes/ethyl acetate) to give 2-chloro-5-(1H-indole-6-carbonyl)-benzenesulfonamide as a yellow foam. MS (m/z): 333 (M−1); Rf 0.37 (1:1 hexanes/ethyl acetate).
Reaction SMILES: O.C[O:3][C:4]([C:6]1[N:7]([CH3:34])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[N:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=4)[C:18]3=[O:31])[C:12]=2[CH2:32][OH:33])=[CH:9][CH:10]=1)=[O:5].[OH-].[Na+]>O1CCOCC1>[C:27]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:31])[N:17]([C:13]1[C:12]([CH2:32][OH:33])=[C:11]([C:8]3[N:7]([CH3:34])[C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=3)[CH:16]=[CH:15][CH:14]=1)[N:26]=[CH:25]2)([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(C(=O)O)ccc1-c1cccc(-n2ncc3cc(C(C)(C)C)ccc3c2=O)c1CO
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
Water (5 mL) was added to a solution of 5-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (150 mg, 0.337 mmol) in dioxane (5 mL). The mixture was stirred for 5 min and NaOH (40 mg) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was extracted with diethyl ether (5 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 5-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid (113 mg, yield 78%) as a yellow solid. LC-MS calcd for C25H25N3O4 (m/e) 431.18, obsd 885 [2M+23]+.
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([B:17]([OH:20])[OH:18])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COB(OC)OC
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)cc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 73.7 %

Procedure:
t-BuLi (1.7 M in pentatne, 63 mL, 106 mmol, 2.1 equiv) was added dropwise to a cold (−78° C.) solution of 3,5-dimethoxy-bromobenzene (11 g, 50.7 mmol) in THF (400 mL), under an argon atmosphere. The yellow mixture si stirred for 45 min at −78° C. Trimethyl borate (20 mL, 179 mmol, 3.5 equiv) was then added. The colorless reaction mixture was allowed to warm to 0° C., quenched by addition of a saturated solution of NH4Cl (5 mL), and concentrated. The residue was diluted with EtOAc/NH4Cl (saturated aqueous solution), and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was triturated in Et2O to provide 6.8 g of the title compound as a white solid: ESI-MS: 183.1 [M+H]+; tR=2.70 min (System 1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.O>[S:13]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2cccnc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cccnc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
To a solution of compound 147-B (0.508 g, 2.63 mmol) in a mixture of MeOH (15 mL) and H2O (3 mL) was added 3N NaOH (1.9 mL, 5.66 mmol) and the reaction mixture was stirred at ambient temperature for 5 h. The solvent was evaporated under reduced pressure, the residue dissolved in H2O, and acidified with 1N HCl. The precipitate was filtered, washed with H2O, and dried under vacuum to afford compound 147-C as a white solid (0.366 g, 78%). MS: m/z 180.0 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C:21]=2[CH:20]=1)(=[O:18])=[O:17])([CH3:3])[CH3:2].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:35].[Na+].[Na+].C(O)(=O)C>O>[CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[S:16]([C:19]1[C:20](=[O:35])[C:21]2[C:29](=[CH:30][CH:31]=1)[C:28]1[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:22]=2)(=[O:18])=[O:17])([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3c(c2)Cc2ccccc2-3)c(C(C)C)c1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)C2=CC=C3C(=Cc4ccccc43)C2=O)c(C(C)C)c1
Yield: 40.3 %

Procedure:
A portion of the 2-(2,4,6-triisopropylphenylsulfonyl)fluorene just described (8.67 g, 20.0 mmol) was placed in a 1 liter flask (equipped with a magnetic stirrer and reflux condenser) along with 17.9 g (60.0 mmol, 3.0 eq) of sodium dichromate dihydrate and 500 ml of glacial acetic acid. The mixture was refluxed for 15 hours, cooled, and poured into 2.0 liters of water. The solids were collected by filtration and washed with additional water (2×1.0 liter). The crude product was dried and purified by chromatography. A total of 3.60 g (8.06 mmol, 40.3%) of pure 2-(2,4,6-triisopropylphenylsulfonyl)fluorenone was obtained in this manner. Its structure was confirmed by IR, NMR, and ultraviolet-visible (UV-VIS) spectroscopy, FDMS, and combustion analysis.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[N:18][C:17](O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>O>[Cl:3][C:17]1[N:18]=[N:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2ccc(O)nn2)cc1
Solvent: O
Product: COc1ccc(-c2ccc(Cl)nn2)cc1
Yield: 40 %

Procedure:
With cooling with ice, 50 ml of phosphorus oxychloride was added to 10.00 g (49.5 mmol) of the obtained 6-(4-methoxyphenyl)-pyridazin-3-ol, and the reaction liquid was stirred under reflux for 6 hours. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.41 g (yield: 40%) of 3-chloro-6-(4-methoxyphenyl)-pyridazine as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([O:21][CH3:22])[CH:4]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:24][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([O:21][CH3:22])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C(Oc1ccc(CO)cc1OC)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(Oc1ccc(CBr)cc1OC)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
To a cooled (0° C.) solution of 0.490 g (1.62 mmol) of the product of Step A dissolved in 8 mL of CH2Cl2 was added 0.673 g (2.03 mmol) of carbon tetrabromide and 0.531 g (2.03 mmol) of triphenylphosphine. The reaction mixture was stirred for 1.5 hours and was allowed to slowly warm to room temperature. The reaction mixture was then concentrated in vacuo, and purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.478 g (81%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]1=[O:13].Cl[CH2:16][CH2:17][S:18][CH3:19]>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:16][CH2:17][S:18][CH3:19])[C:3]1=[O:13]
Reactant: CC1(C)C(=O)NC(=O)c2ccccc21
Reactant: CSCCCl
Solvent: CN(C)C=O
Product: CSCCN1C(=O)c2ccccc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
11.4 gm of potassium tert.butylate were added to a solution of 18 gm of 4,4-dimethyl-2H,4H-isoquinoline-1,3-dione in 70 ml of dimethylformamide, and the mixture was stirred for 5 minutes at room temperature. 11.1 gm of 1-chloro-2-methylmercapto-ethane were then added, and the mixture was heated at 80° C. for 2 hours. After distilling off the dimethylformamide in vacuo, the residue was taken up in chloroform and water. The organic phase was separated and evaporated, and the residue was purified on a silicagel column (eluant: chloroform), yielding 23.1 gm (87.7% of theory) of an oily product which was identified to be the compound of the formula ##STR6##
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32]I>>[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C@:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=2[CH:10]=1
Reactant: FC(F)(F)Cc1ccc(OCCCI)c(Cl)c1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Product: CC[C@@]1(C(=O)O)Cc2cc(OCCCOc3ccc(CC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the chiral phenol prepared in Example 10, Step 2 and the iodide prepared in Step 2.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[C:6](=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:8])[CH3:7].[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:6]([CH:1]1[CH2:3][CH2:2]1)([CH3:7])[CH3:8])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:14]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: Br[Mg]C1CC1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
Step A To a suspension of CuI (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at −50° C. was added cyclopropylmagnesium bromide (0.5 M, 160 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to −50° C., a tetrahydrofuran solution (50 mL) of diethyl isopropylidenemalonate (Aldrich) (4 g, 20 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4Cl solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20, 1:10) to give 2-(1-cyclopropyl-1-methyl-ethyl)-malonic acid diethyl ester as a colorless oil (4.3 g, 89%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]4[CH:30]=[C:29]([F:31])[C:28]([OH:32])=[C:27]([Cl:33])[CH:26]=4)[N:23]=3)[N:18]=[CH:17][C:16]=2[C:34](=[O:36])[CH3:35])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:57].Cl>>[ClH:33].[ClH:57].[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]4[CH:30]=[C:29]([F:31])[C:28]([OH:32])=[C:27]([Cl:33])[CH:26]=4)[N:23]=3)[N:18]=[CH:17][C:16]=2[C:34](=[O:36])[CH3:35])[CH2:10][CH2:9]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1NC1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure IV-2, tert-butyl(4-{[3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl]amino}cyclohexyl)carbamate (0.20 mmol) was reacted with TFA (2 mL) followed by formation of the dihydrochloride salt to afford the desired product (45 mg, 45% over two steps) as a white solid: 1H NMR (500 MHz, D2O) δ 8.99 (s, 1H), 8.13 (d, J=9.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.40-7.34 (m, 2H), 4.91-4.94 (m, 1H), 3.35-3.28 (m, 1H), 2.72 (s, 3H), 2.30-2.22 (m, 2H), 2.21-2.14 (m, 2H), 1.75-1.68 (m, 2H), 1.56-1.48 (m, 2H); ESI MS m/z 429 [M+H]+; HPLC>99% (AUC), tR=9.10 min.
Reaction SMILES: [C@@H]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[Cl:20]C1C=C(C=CC=1)C(OO)=O.C1(C)C=CC=CC=1>CC(N(C)C)=O.Cl>[Cl:20][C:11]1[NH:12][C:13]2[C:19](=[N:18][CH:17]=[N:16][C:14]=2[NH2:15])[N:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2nc(Cl)[nH]c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.9 %

Procedure:
To a solution of adenosine (2.67 g, 10 mmol) in DMA/HCl (0.5M, 45 mL) was added m-chloroperoxybenzoic acid (MCPBA, 3.22 g, 16 mmol 87%) and stirred at room temperature for 2.5 h. An additional portion of MCPBA (0.9 g, 5 mmol) was added and stirring continued for another 1 h. Toluene (50 mL) was added to the reaction mixture and the solvents evaporated at 60° C. under vacuo to dryness. The residue was dissolved in water (50 mL) and extracted with ether (3×50 mL). The pH of the aqueous phase was adjusted to 5 with 2N NaOH and then diluted with EtOH (100 mL). The solution was stored in the refrigerator overnight. The light yellow solid that separated was collected, washed with cold EtOH (2×25 mL) and dried to give 1.44 g (85.2%) of 1: mp 305°-310° C. (dec.) [Lit. mp>300° C. (dec.)]: IR (KBr): 630 (C-C1), 3100-3300 (NH2) cm-1 : UV: λmax (pH 1) 262 nm (ε 8,700): λmax (pH 7) 268 nm (ε 7,900): λmax (pH 11) 269 nm (ε 8,300): 1H NMR (Me2SO-d6): δ 7.48 (br s, 2, NH2), 8.10 (s, 1, C2H) and 13.60 (br s, 1, N9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[S:13])[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]([NH:15][NH2:16])=[S:13])[CH3:2]
Reactant: CCc1cc(OC)ccc1N=C=S
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1cc(OC)ccc1NC(=S)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of 2-ethyl-1-isothiocyanato-4-methoxybenzene (4.9 g, 25 mmol) in ethanol (22 mL), was added slowly, hydrazine hydrate (1.3 g, 28 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and diluted with ethyl acetate (250 mL) and washed with water (2×50 mL), followed by brine (2×50 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification by flash column chromatography using 0-40% ethyl acetate/hexanes as eluent provided the title compound as a white solid (4.9 g, 86%): mp 113-115° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.89 (s, 1H), 7.20-7.19 (m, 1H), 6.77-6.71 (m, 2H), 4.71 (bs, 2H), 3.74 (s, 3H), 2.52-2.47 (m, 2H), 1.13-1.08 (m, 3H); ESIMS m/z 224 ([M−H]−).
Reaction SMILES: COC[O:4][C:5]1[C:17]([CH2:18][CH2:19][CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=[CH:14][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][S:11][CH2:10]1)=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:4][C:5]1[C:17]([CH2:18][CH2:19][CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=[CH:14][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][S:11][CH2:10]1)=[O:8]
Reactant: CCCc1c(OC)ccc(C(=O)N2CCSC2)c1OCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCCc1c(OC)ccc(C(=O)N2CCSC2)c1O
Temperature: 60 °C
Reaction time: 23 h
Yield: 93.8 %

Procedure:
The N-(2-methoxymethoxy-3-n-propyl-4-methoxybenzoyl)thiazolidine (9.0 g) was dissolved in a solution of methanol (100 ml)-water (20 ml). To the solution was added p-toluenesulfonic acid (2 spoonfuls in spatula) and the mixture was agitated at 60° C. for 23 hours. The reaction mixture was concentrated in evacuated atomosphere to about one fourth of the original volume. Saturated aqueous solution of sodium bicarbonate was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere. The residue was subjected to column chromatography using silica gel, and there was obtained N-(2-hydroxy-3-n-propyl-4-methoxybenzoyl)thiazolidine (7.3 g) from fractions eluted with n-hexane-ethyl acetate (5:1).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8][O:7][N:6]=1)[NH2:4].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)NCCCNc1nonc1C(N)=NO
Product: CS(=O)(=O)NCCCNc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Yield: 10 %

Procedure:
The title compound was prepared according to the procedure of Example 4, step E, using N′-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide [made according to Example 4, steps A through D] and 3-chloro-4-fluoroaniline [Aldrich, product #228583] as the starting materials in 10% yield. LCMS for C13H17ClFN6O4S (M+H)+: m/z=407.1. 1H NMR (400 MHz, CD3OD): δ 7.06 (t, J=8.9 Hz, 1H), 6.98 (m, 1H), 6.80 (m, 1H), 3.73 (m, 2H), 3.28 (m, 2H), 2.94 (s, 3H), 1.28 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:23][CH2:24]2)[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:47]
Reactant: Cc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Reactant: Nc1cnn(C2CC2)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C4CC4)c3N3CC[C@H](N)[C@@H](F)CC3)c(N)s2)c1
Yield: 55 %

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-cyclopropyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxylic acid gave 277 as a yellow solid (228 mg, 55% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.07 (dd, J=7.3, 2.3 Hz, 1H), 7.48 (s, 1H), 7.24-7.19 (m, 1H), 7.11 (dd, J=11.4, 8.4 Hz, 1H), 4.49 (dtd, J=48.3, 8.8, 3.8 Hz, 1H), 3.56-3.48 (m, 1H), 3.47-3.34 (m, 4H), 3.23-3.13 (m, 1H), 2.41 (s, 3H), 2.35-2.21 (m, 1H), 2.19-2.06 (m, 1H), 2.01-1.91 (m, 1H), 1.84-1.72 (m, 1H), 1.19-1.10 (m, 2H), 1.11-1.04 (m, 2H). LCMS (ES+) m/z 488 (M+1)
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10](Cl)[N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH2:3][CH3:4])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1>>[CH:1]([NH:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][C:20]=2[CH3:27])[N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1nc(SC)nc(Cl)c1C=O
Reactant: Cc1cc(F)ccc1B(O)O
Product: CCC(C)Nc1nc(SC)nc(-c2ccc(F)cc2C)c1C=O

Procedure:
Prepared as described above in Example 11 starting from 4-sec-butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-sec-butylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 1.02 (m, 3H), 1.30 (m, 3H), 1.70 (m, 2H), 2.28 (m, 3H), 2.59 (s, 3H), 4.37 (m, 1H), 6.98 (m, 2H), 7.20 (m, 1H), 9.04 (br s, 1H), 9.50 (s, 1H). LC MS (m/e)=334 (MH+).