Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH:12]2[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: NC1CC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1nc(NC2CC2)c2occc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
2,4-Dichlorofuro[3,2-d]pyrimidine (30 g, 159 mmol, ArkPharm) was stirred in 1,4-dioxane (330 mL). TEA (26.5 mL, 190 mmol) and cyclopropylamine (12.2 mL, 175 mmol) were added and the mixture stirred at rt overnight. The mixture was diluted with EtOAc (500 mL) and washed with saturated aqueous NaHCO3 (400 mL). The aqueous layer was extracted with EtOAc (2×150 mL). The organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was suspended in water (400 mL) and allowed to stir at rt for about 1 h. The suspension was filtered and the solid was dried in a vacuum oven at about 70° C. overnight to give 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (31.9 g, 96%); LC/MS (Table 2, Method c) Rt=1.58 min.; MS m/z: 210 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.1 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 5.57-5.50 (m, 1H), 3.12-3.01 (m, 1H), 1.02-0.88 (m, 2H), 0.77-0.65 (m, 2H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[N:12][N:13]([C:15]3([CH2:26][C:27]#[N:28])[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH:14]=2)=[N:3][CH:2]=1.O.[ClH:30].C(O)(C)C>COC(C)(C)C.ClCCl>[ClH:30].[ClH:30].[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[N:12][N:13]([C:15]3([CH2:26][C:27]#[N:28])[CH2:18][NH:17][CH2:16]3)[CH:14]=2)=[N:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CNC1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added tert-butyl 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate (5, 15 g, 39.5 mmol), water (7.5 mL, 416 mmol) and dichloromethane (75 mL) at room temperature. The mixture was stirred at room temperature to generate a suspension. To the suspension was added a solution of 5 M hydrogen chloride (HCl) in isopropanol (55 mL, 275 mmol, 7.0 equiv) in 5 minutes. The resulting reaction mixture was then heated to gentle reflux and maintained at reflux for 3-4 hours. After the reaction was completed as monitored by HPLC, tert-butyl methyl ether (TBME, 45 mL) was added to the reaction suspension. The mixture was gradually cooled to room temperature, and stirred for an additional one hour. The solids were collected by filtration, washed with tert-butyl methyl ether (TBME, 45 mL) and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt (6, 13.6 g, 13.9 g theoretical, 98%) as an off-white to light yellow solid. For 6: 1H NMR (400 MHz, D2O) δ 8.96 (s, 1H), 8.81 (s, 1H), 8.49 (s, 1H), 7.78 (d, J=3.8 Hz, 1H), 7.09 (d, J=3.7 Hz, 1H), 4.93 (d, J=12.8 Hz, 2H), 4.74 (d, J=12.5 Hz, 2H), 3.74 (s, 2H) ppm; 13C NMR (101 MHz, D2O) δ 151.35, 143.75, 143.33, 141.33, 132.03, 131.97, 115.90, 114.54, 113.85, 103.18, 59.72, 54.45 (2C), 27.02 ppm; C14H15Cl2N7 (C14H13N7 for free base, MW 279.30), LCMS (EI) m/e 280 (M++H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C@H:10]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:11]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:34].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[C:1]([NH:8][CH2:9][C@H:10]1[O:16][C@H:13]([C:14]([OH:34])=[O:15])[C@@H:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:11]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NC[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1O[C@H](C(=O)O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
The product from step 5 was dissolved in dry DMF and cooled to 0° C. Pyridinium dichromate (PDC, 4 molar equiv) was added portion wise and the reaction mixture was stirred at room temperature for 12 h. It was then diluted with EtOAc, washed with saturated aqueous CuSO4, brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by silica gel column chromatography gave the required N-Boc-6-amino-2,5-anhydro-3,4-di-O-benzyl-6-deoxy-D-mannonic acid in 77% yield.
Reaction SMILES: Cl[CH:2]([C:33]1[CH:38]=[C:37]([O:39][CH2:40][CH3:41])[CH:36]=[C:35]([O:42][CH:43]([CH3:45])[CH3:44])[C:34]=1[F:46])[C:3]1[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CCN(C(C)C)C(C)C.[NH2:56][C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[CH:63]=[N:62][CH:61]=[CH:60]2>CC#N.CCOC(C)=O>[CH2:40]([O:39][C:37]1[CH:36]=[C:35]([O:42][CH:43]([CH3:44])[CH3:45])[C:34]([F:46])=[C:33]([CH:2]([C:3]2[N:4]([C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:7]=2)[NH:56][C:57]2[CH:58]=[C:59]3[C:64](=[CH:65][CH:66]=2)[CH:63]=[N:62][CH:61]=[CH:60]3)[CH:38]=1)[CH3:41]
Reactant: Nc1ccc2cnccc2c1
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Cl)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc3cnccc3c2)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a mixture of Intermediate 25.2 (0.054 mmol) in 1 mL CH3CN at rt, were added DIEA (14 μL, 0.082 mmol) and 6-aminoisoquinoline (15.7 mg, 0.109 mmol). The mixture was stirred at rt for 2 h, then was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 22.5 mg of Intermediate 25.3 as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:39]([C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][C:35]=1[C:43]([F:46])([F:44])[F:45])(=[O:41])=[O:40]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(F)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-fluoro-2-(trifluoromethyl)benzenesulfonyl chloride (18 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 27 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-fluoro-2-(trifluoromethyl)benzenesulfonamide (percentage yield: 89%), was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][S:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:20]3=[O:33])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[O:35]C1C=CC(C2C=CC(S(NC(CC3OC3)C(OC)=O)(=O)=O)=CC=2)=CC=1.C([O-])(O)=O.[Na+].CCN(CC)CC.C(S)C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:35])[CH2:24][S:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]([OH:21])=[O:33])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CSCc4ccccc4)OC3=O)cc2)cc1
Agent: O=C([O-])O
Agent: SCc1ccccc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSCc3ccccc3)C(=O)O)cc2)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(benzylthio)methyl]-tetrahydrofuran: To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.5 g, 1.28 mmol) in benzene (3 mL), NaHCO3 (0.32 g, 3.84 mmol) and Et3N (0.23 mL, 1.6 mmol) at room temperature is added slowly benzyl mercaptan (0.62 mL, 4.99 mmol). The reaction mixture is heated at 70° C. for 3 h, and stirred two days at room temperature. The resulting mixture is diluted with water, and then the mixture is extracted three times with EtOAc. The combined EtOAc layer is washed with water, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with hexane/EtOAc (4:1) to give the desired product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].N1C=CC=CC=1C(O)=O>O1CCOCC1.[Cu]I>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)[C:9]([O:17][CH2:18][CH3:19])=[O:16])[CH3:15]
Reactant: Cc1ccc(I)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C)cn1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a stirred solution of 2-Iodo-5-methyl-pyridine (Preparation 272, 1 g, 4.57 mmol) and diethyl malonate (2.08 mL, 13.70 mmol) in anhydrous dioxane (12 mL) was added cesium carbonate (4.46 gm, 13.7 mmol) and the solution was degassed with argon for min. CuI (174 mg, 0.91 mmol) and picolinic acid (225 mg, 1.83 mmol) were added and the resultant mixture was heated in a sealed tube at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (25 mL) and extracted with EtOAc (3×25 ml). The combined organic layers were washed with water (2×10 mL) and brine (10 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of hexane:EtOAc 100:0 to 90:10) to afford the title compound as an oil in 23% yield, 300 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:18])(=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.[H-].[Na+].I[CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:18])(=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([O:16][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:9][CH:8]=3
Reactant: FC(F)(F)CI
Reactant: O=S1(=O)c2ccc(O)cc2Oc2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccc(F)cc2Oc2cc(OCC(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
Solid 3-fluoro-7-hydroxyphenoxathiin 10,10-dioxide (Example 64) (1.092 g, 4.10 mmoles) was added to an ice-bath cooled, stirred mixture of sodium hydride (60% dispersion in mineral oil) (Aldrich) (0.164 g, 4.10 mmole) in N,N-dimethylformamide (20 mL). After 10 minutes, within which effervescence ceased, 2-iodo-1,1,1-trifluoroethaane (4.993 g, 23.78 mmoles) was added and the solution was heated with stirring at 100° C. for 24 hours. The reaction was cooled and added in portions to 100 mL of vigorously stirred ice-water to give a solid, which was collected by suction filtration and washed with water. The solid which was two equal size spots on tlc (silica gel, ethyl acetate-hexanes:1-4) dissolved in dichloromethane (50 mL), absorbed on silica gel 60 and purified by flash column chromatography on silica gel 60. The column was eluted with ethyl acetate-hexanes:1-6 (1 L) and ethyl acetate-hexanes:1-3 (1 L), and the fractions that contained product (the higher Rf spot on tlc) were combined and spin evaporated in vacuo to give 0.731 g (51% yield) of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide as a white powder, m.p. 160-161° C.
Reaction SMILES: [C:1]([N:9]1[C@H:13]([C:14]([O:16]COC)=[O:15])[CH2:12][S:11](=[O:21])(=[O:20])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[C:1]([N:9]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][S:11](=[O:20])(=[O:21])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOC(=O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
31.3 g of methoxymethyl (4R)-3-benzoyl-1,1-dioxothiazolidine-4-carboxylate (prepared as described in Preparation 11) were dissolved in 200 ml of a 1:1 by volume mixture of trifluoroacetic acid and water, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated by evaporation under reduced pressure to leave crystals. These crystals were washed with 150 ml of water and then recrystallized from ethyl acetate to give 21.6 g (80.3%) of the title compound in the form of colorless needles melting at 175°-176° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Br)([Br:18])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Br)Br
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCc1cccc(Oc2ccccc2)c1
Yield: 81.3 %

Procedure:
A solution of 3-phenoxybenzyl alcohol (36.0 grams, 0.18 mole) in toluene (95 ml) was added dropwise during a thirty minute period to a stirred solution of thionyl bromide (50 grams, 0.24 mole), pyridine (0.5 gram) and toluene (175 ml) while maintaining the temperature below 30° C. After the addition was complete,the reaction mixture was heated at 50°-60° C. for two hours. Upon cooling, the reaction mixture was concentrated under reduced pressure leaving a residue. This residue was dissolved in toluene (200 ml) and washed with water (10×100 ml) until a neutral pH was obtained. The dried (magnesium sulfate) toluene layer was concentrated under reduced pressure leaving a residue. This residue was distilled yielding 38.5 grams of 3-phenoxybenzyl bromide, b.p. 120°-144° C./0.05 mmHg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[O:20][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][N:17]=2)[CH:5]=[CH:4][N:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:2]2[CH:7]=[C:6]([CH2:8][S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[O:20][C:19]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[N:18][N:17]=3)[CH:5]=[CH:4][N:3]=2)[CH2:30][CH2:29]1
Reactant: Fc1cc(CSc2ccccc2-c2nnc(Nc3ccccc3)o2)ccn1
Reactant: NC1CC1
Product: c1ccc(Nc2nnc(-c3ccccc3SCc3ccnc(NC4CC4)c3)o2)cc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To 5-(2-(2-fluoropyridin-4-yl) methylthiophenyl)-N-phenyl-1,3,4-oxadiazol-2-amine (80 mg, 0.19 mmol; Compound 1-(48)) was added cyclopropylamine (200 μL) at room temperature and then the mixture was stirred at 150° C. for 2 hours. The reaction solution was concentrated under a reduced pressure and the residue was purified with a silica gel column chromatography (hexane/ethyl acetate) and to give 5.0 mg (6%) of the titled compound as a colorless solid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl.CN(C)C1C=CN=CC=1.O>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:12](=[O:14])[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cccc(F)c1
Temperature: 25 °C

Procedure:
Thionyl chloride (0.38 ml, 5.0 mmole) was added to an ice water cooled solution of 4-Biphenylacetic acid (0.2 g, 0.9 mmole) in 5 ml dichloromethane, solution allowed to warm to room temperature then heated under reflux for 1 hr, the solvent and excess thionyl chloride was evaporated under vacuum, the oil formed was redissolved in 5 ml dichloromethane followed by addition of 4-Dimethylaminopyridine (0.12 gm, 1.0 mmole) and 3-Fluoroaniline (0.11 gm, 1.0 mmole), stirred at room temperature over night, then the reaction mixture was diluted with 10 ml dichloromethane and 20 ml water, the organic layer washed with 1 N HCl, saturated NaHCO3 solution, and saturated NaCl solution, dried using Na2SO4 and evaporated dryness (0.2 gm, 72%), H1-NMR INOVA-500 (CDCl3) δ 3.805 (s, 2H), 6.815 (t, J=8.5 Hz, 1H), 7.068(d, J=8.0 Hz, 1H), 7.218-7.284(m, 2H), 7.380-7.499(m, 6H) 7.620-7.664(m, 4H). MS (m/z) 306.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[CH3:18][C:19]1([CH3:28])[S:23][C:22](=[O:24])[NH:21][CH:20]1[C:25]([OH:27])=O.[N+]([O-])(O)=O.[N+:33]([O:36][CH2:37][CH2:38][NH2:39])([O-:35])=[O:34]>O1CCCC1>[N+:33]([O:36][CH2:37][CH2:38][NH:39][C:25]([CH:20]1[C:19]([CH3:18])([CH3:28])[S:23][C:22](=[O:24])[NH:21]1)=[O:27])([O-:35])=[O:34]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC1(C)SC(=O)NC1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Product: CC1(C)SC(=O)NC1C(=O)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.3 %

Procedure:
1.38 ml of triethylamine and 0.37 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 360 mg of 5,5-dimethyl-2-oxothiazolidine-4-carboxylic acid and 417 mg of N-(2-nitrooxyethyl)amine nitrate in 50 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 4 hours, after which the solvent was removed by distillation under reduced pressure. The residue was mixed with ethyl acetate, and the resulting mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residual pale yellow oil was purified by column chromatography through silica gel, using a 50:1 by volume mixture of methylene chloride and methanol as the eluent. The crystals thus obtained were recrystallized from diethyl ether, to give 180 mg of the title compound as colorless crystals, melting at 98°-100° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[F:45][C:46]([F:52])([F:51])[S:47](Cl)(=[O:49])=[O:48]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([S:47]([C:46]([F:52])([F:51])[F:45])(=[O:49])=[O:48])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(S(=O)(=O)C(F)(F)F)C3)cc1
Reaction time: 8 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0473 g, 0.115 mmol) in dry N,N-Dimethylformamide (0.60 mL, 7.7 mmol) was added N,N-Diisopropylethylamine (0.0636 mL, 0.365 mmol) followed by Trifluoromethanesulfonyl chloride (0.01940 mL, 0.1822 mmol). The reaction mixture was stirred for overnight. The reaction mixture was concentrated and was chromatographed through silica gel (4 g, 0-100% EtOAc in heptane followed by 10% MeOH in dichloromethane). The trifluoromethanesulfonamide was isolated and purified by HPLC. (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-7-(trifluoromethylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (xi): 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.16 (d, J=8.7, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.68-4.52 (m, 2H), 4.01 (s, 1H), 3.82 (dd, J=26.3, 11.2, 3H), 3.69 (t, J=12.6, 3H), 3.54 (t, J=11.1, 1H), 3.49-3.38 (m, 1H), 3.18-3.06 (m, 2H), 2.87 (s, 1H), 2.75 (d, J=16.4, 1H), 1.80 (dd, J=11.3, 6.9, 2H), 1.06 (t, J=7.2, 3H), 0.83 (t, J=7.4, 3H). LC/MS-m/z+543.2 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:27]([OH:28])[C@@H:26]([CH2:29][OH:30])[O:25][C@H:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:10]1[O:31][C@H:32]1[O:61][C@H:60]([CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C@@H:51]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C@H:42]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:33]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:71]([O-])(=[O:74])(=[O:73])[CH3:72]>>[CH2:1]([O:8][C@H:9]1[C@H:27]([OH:28])[C@@H:26]([CH2:29][O:30][S:71]([CH3:72])(=[O:74])=[O:73])[O:25][C@H:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:10]1[O:31][C@H:32]1[O:61][C@H:60]([CH2:62][O:63][CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[C@@H:51]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C@H:42]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C@H:33]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CS(=O)(=O)[O-]
Product: COC(=O)CCCCCCCCO[C@H]1O[C@H](COS(C)(=O)=O)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 79.1 %

Procedure:
Compound 38 (450 mg, 0.47 mmol) was converted into its 6-O-methane sulfonyl derivative exactly as described for the preparation of 10 to provide 39 (385 mg, 79.1%) as a syrup after chromatography on silica gel using (hexane:ethyl acetate; 2:1) as eluant; ›α!D +36.1° (c 0.95, chloroform). 1H-n.m.r. (CDCl3): δ 4.99(d, 1H, J1',2' 3.8 Hz, H-1'), 4.96(d, 1H, J1,2 3.8 Hz, H-1), 3.58(s, 3H, OCH3), 2.93(s, 3H, CH3SO2), 2.39(d, 1H, J 3.2 Hz, OH, D2O exchangeable), 2.21(t, 2H, J 7.5 Hz, CH2COO).