Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](SC)=[N:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][OH:36]>>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[N:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[O:36][CH3:35])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSC(=Nc1cc(C)ccc1C)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Reactant: CO
Product: COC(=Nc1cc(C)ccc1C)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1

Procedure:
A solution of methyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-N-(2,5-dimethylphenyl)-1-piperidinecarboximidothioate (i.e. the product of Example 1, Step D) (0.10 g, 0.20 mmol) in methanol (5 mL) was heated in a Biotage® Creator XM microwave apparatus at 140° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using 1:1 ethyl acetate-hexanes as eluant to provide the title compound, a compound of the present invention, as a foamy white solid (19 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8][C:9]([O:11]C)=[O:10].[N:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[N+:15]=[N-:16].CO.C[O-].[Na+].[OH-].[Na+]>CO>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[C:8]([C:9]([OH:11])=[O:10])[N:16]=[N:15]1
Reactant: COCCCCC(=O)CC(=O)OC
Reactant: [N-]=[N+]=Nc1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCc1c(C(=O)O)nnn1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
A solution of methyl 7-methoxy-3-oxoheptanoate (2.0 g) in methanol (70 ml) was cooled to 0° C.-5° C., 1-azido-2-chlorobenzene (1.08 g) and 28% sodium methoxide methanol solution (2 g) were added and the mixture was stirred at 60° C. for 3 hr. Then, 1N sodium hydroxide (14 ml) was added, and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure and water (20 ml) was added to the residue. 1N Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate (50 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (1.26 g) as a powder.
Reaction SMILES: FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](OCC=C)CN2C(OC(C)(C)C)=O)OC(=O)N1.[F:32][C:33]1[CH:34]=[C:35]([CH:62]=[C:63]([F:65])[CH:64]=1)[CH2:36][C@H:37]1[C@@H:41]([C@H:42]2[CH2:47][CH2:46][CH2:45][CH2:44][N:43]2[CH:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:40]C(=O)[NH:38]1.FC1C=C(C=C(F)C=1)C[C@@H]([C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O)C(O)=O.C(=O)([O-])[O-].[K+].[K+].BrC(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[NH2:38][C@@H:37]([CH2:36][C:35]1[CH:62]=[C:63]([F:65])[CH:64]=[C:33]([F:32])[CH:34]=1)[C@@H:41]([C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][N:43]1[CH:48]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[OH:40]
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CCCCN2C(c2ccccc2)c2ccccc2)O1
Agent: BrC(c1ccccc1)c1ccccc1
Agent: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: C=CCO[C@@H]1C[C@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Solvent: CC#N
Product: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCCN1C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 50 %

Procedure:
Step I (7): Preparation of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-1-benzhydrylpiperidin-2-yl)oxazolidin-2-one. To a solution of (4S,5R)-4-(3,5-difluorobenzyl)-5-((R)-piperidin-2-yl)oxazolidin-2-one (Step I (6), 70 mg, 0.24 mmol) in acetonitrile (1.8 mL) were added potassium carbonate (50 mg, 0.36 mmol) and bromodiphenylmethane (90 mg, 0.36 mmol). The reaction mixture was then heated to 100° C. for 30 min using microwave heating. The solvent was removed and the crude mixture was purified by silica gel Flash Chromatography to give 60 mg of the title compound (50% yield): 1H NMR (CDCl3, 500 MHz) δ 1.28 (1H, brd s), 1.56-1.83 (4H, m), 1.94 (1H, m), 2.13 (1H, t, J=10 Hz), 2.67 (1H, m), 2.77 (1H, m), 2.88 (1H, m), 3.16 (1H, t, J=5 Hz), 3.81 (1H, m), 4.95 (1H, s), 5.10 (1H, s), 5.14 (1H, m), 6.54 (2H, m), 6.69 (1H, m), 7.18-7.27 (4H, m), 7.32-7.38 (4H, m), 7.42 (2H, d, J=10 Hz). MS (ESI) (M+Na)+ 485.12.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].Cl>C1C=CC=CC=1.[Zn]>[OH:15][C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1)([CH3:14])[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24]
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a refluxing mixture of 4′-cyclohexylacetophenone (25 g), I2 (5 mg) and Zn (17 g) in benzene (150 ml) was added ethylbromoacetate (20.7 ml) dropwise during 30 minutes. The mixture was refluxed for 2 h and then cooled to room temperature. It was acidified with 10% HCl (200 ml) an organic layer separated out. The organic phase was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography using SiO2 as adsorbent and hexane-ethylacetate mixture as eluant to give 28 g (80% yield) of ethyl 3-hydroxy-3-(4-cyclohexylphenyl)-butanoate (2b, formula 2, R=cyclohexyl) m.p. 45° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[CH2:4][NH2:5].[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[CH3:1][N:2]([CH3:17])[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[CH2:4][NH:5][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:22]2[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=2)[CH:26]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN(C)C(CN)c1nc(-c2ccccc2)cs1
Product: CN(C)C(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccccc2)cs1
Yield: 17 %

Procedure:
This compound was synthesized from N,N-dimethyl-1-(4-phenylthiazol-2-yl)ethane-1,2-diamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (16 mg, yield 17%). 1H NMR (400 MHz, CDCl3) δ 8.57-8.56 (t, J=1.5 Hz, 1H), 8.26-8.23 (dt, J=7.8 Hz, 1.4 Hz, 1H), 8.07-8.05 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.91-7.87 (m, 3H), 7.63-7.59 (t, J=7.8 Hz, 1H), 7.51 (s, 1H), 7.42-7.38 (m, 2H), 7.36-7.31 (m, 1H), 4.35-4.29 (ddd, J=13.2 Hz, 6.6 Hz, 5.5 Hz, 1H), 4.15-4.12 (m, 1H), 3.85-3.78 (ddd, J=13.0 Hz, 8.3 Hz, 4.6 Hz, 1H), 2.51 (s, 6H). MS (ESI) m/z: Calculated for C23H20F3N5O2S: 487.13. found: 488.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)C#N)=[C:6]2[C:5](=[O:24])[N:4]([CH3:25])[C:3]1=[O:26])[CH2:12][CH2:11][CH2:10][C:9]3=[O:23].BrC1C=CC=C([F:34])C=1>>[F:34][C:17]1[CH:16]=[C:15]([C:14]2[N:13]3[C:8]([C:9](=[O:23])[CH2:10][CH2:11][CH2:12]3)=[C:7]3[N:2]([CH3:1])[C:3](=[O:26])[N:4]([CH3:25])[C:5](=[O:24])[C:6]=23)[CH:22]=[CH:21][CH:20]=1
Reactant: Fc1cccc(Br)c1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(=O)CCC3
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(=O)CCC3

Procedure:
The title compound was prepared analogously to 3-(1,3-dimethyl-2,4,10-trioxo-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile (Example 9 steps 1-7) by replacing 3-bromobenzonitrile (step 3) with 1-bromo-3-fluorobenzene (commercially available).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=CC(O)=C[CH:4]=1)=C.C(C1C=CC(O)=CC=1)C.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:3]([C:22]1[CH:23]=[CH:24][C:19]([OH:25])=[CH:20][CH:21]=1)([CH3:8])([CH3:4])[CH3:1]
Reactant: Oc1ccccc1
Reactant: C=Cc1ccc(O)cc1
Agent: CCc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(O)cc1
Reaction time: 5 h

Procedure:
This toluene solution was fed into the second extraction tower at a point 3/4 from the top of the tower so that the rate of feed of all phenols was 0.0422 mol./hr., and otherwise, the total reflux operation was performed in the same way as in the case of the first extraction tower described above. The second extraction tower and a reflux zone attached to the tower had quite the same structure as the first extraction tower and the reflux zone atached thereto. After completion of the total reflux operation, the extracting operation was carried out for 5 hours while maintaining the reflux ratio at 52.4. As a result, 1.06 liters of a toluene solution containing 0.199 mol of purified p-vinylphenol of 99.4 mol% p-vinylphenol, 0.39 mol% p-ethylphenol, 0.20 mol% phenol and 0.01 mol% p-tert.-butylphenol was obtained from the top of the second extraction tower.
Reaction SMILES: [F:1][C:2]1[N:3]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.C1(C)C=CC(S([N:40]=[N+:41]=[N-:42])(=O)=O)=CC=1.Cl[Si](C)(C)C>C1COCC1.C1(C)C=CC=CC=1>[N:40]([C:5]1[N:6]=[C:2]([F:1])[N:3]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1)=[N+:41]=[N-:42]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-1-triphenylmethylimidazole in THF was treated with t-butyllithium at -70° for 2 hours. A solution of toluene-p-sulphonyl azide in toluene was added, followed after 10 minutes by chlorotrimethylsilane, and the mixture allowed to come to 0°. Work-up and chromatography on magnesium silicate gave 4-azido-2-fluoro-1-triphenylmethylimidazole. This was dissolved in ether and treated with triphenylphosphine at 25°, to precipitate 2-fluoro-1-triphenylmethyl-4-(triphenylphosphimino)imidazole. A solution of this compound in EtOAc was treated for 10 minutes at 25° with propionyl chloride. Aqueous work-up, followed by magnesium silicate chromatography gave 2-fluoro-4-propionylamino-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.05 (t, 3H); 2.2 (q, 2H); 6.95 (s, 1H); 7.05-7.4 (m, 15H); 9.05 (s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[CH:11]=1>ClCCCl>[C:5]([C:16]1[CH:17]=[CH:18][C:19]2[O:20][C:21]3[C:12](=[CH:11][C:10]([Br:9])=[CH:23][CH:22]=3)[S:13][C:14]=2[CH:15]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Brc1ccc2c(c1)Sc1ccccc1O2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)Sc1cc(Br)ccc1O2
Reaction time: 0.17 h
Yield: 12 %

Procedure:
To a suspension of aluminum chloride (1.2 g, 9 mmol) in 1,2-dichloro ethane (20 mL) at room temperature there was added acetyl chloride (0.57 mL, 628 mg, 8 mmol) and the mixture stirred for 10 minutes. There was added 2-bromophenoxathiin (J.A.C.S. 1936, 58, 717) (1.8 g, 6.4 mmol) and the mixture was stirred for 18 hours. After quenching with ice water, the organic portion was collected and the aqueous portion extracted with methylene chloride. The combined organic fractions, after washing 3 times with water and drying over MgSO4, were evaporated to a residue which on crystallization from methanol, followed by column chromatography on silica gel, eluting with a 1:5 mixture of ethyl acetate-hexane, gave the title product as a white solid (247 mg), m.p.: 143°-145° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([CH3:73])[C:68]=2[CH3:74])[C:56]=1[CH3:75].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:74][C:68]1[C:69]([CH3:73])=[CH:70][CH:71]=[CH:72][C:67]=1[C:57]1[C:56]([CH3:75])=[C:55]([NH:47][C:46]2[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[N:42][CH:43]=[C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[CH:45]=2)[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=1
Reactant: Cc1cccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1C
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1C

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.022 g, 0.045 mmol), 2,5-dimorpholinopyridin-3-amine (0.090 g, 0.34 mmol), 4-chloro-2-(2,3-dimethylphenyl)-5,7-difluoro-3-methylquinoline (0.090 g, 0.28 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.068 g, 0.71 mmol) in toluene (2.8 mL) at 120° C. for 1 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 2-(2,3-dimethylphenyl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.71-7.68 (1H, br d, J=10.0 Hz), 7.63 (2H, m), 7.22-7.28 (2H, m), 6.98-7.11 (2H, m), 6.26 (1H, d, J=2.3 Hz), 3.93 (4H, m), 3.80 (4H, app t, J=4.2 Hz), 3.35 (4H, br. s), 3.01 (4H, app t, J=4.2 Hz), 2.37 (3H, s), 2.07 (3H, s), 1.94 (3H, s). Mass Spectrum (ESI) m/e=546.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:23][CH2:24][CH2:25][OH:26])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]([C:14](=[O:16])[CH3:15])=[N:13][N:7]3[C:6]=2[CH:27]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:14]([C:12]1[C:11]([CH2:23][CH2:24][CH:25]=[O:26])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][C:6]=3[N:7]2[N:13]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCCO)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCC=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
1-[8-Chloro-3-(3-hydroxypropyl)-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl]ethanone (4-4; a racemic mixture, 15 mg, 39 μmol) was dissolved in anhydrous CH2Cl2 (2 mL) and was treated with Dess-Martin periodinane (25 mg, 58 μmol) and the resulting cloudy yellow solution was stirred 1.5 h. Upon completion, the cloudy solution was treated with 1 mL sat. sodium thiosulfate/NaHCO3 solution (1:1) and stirred 30 min. The mixture was extracted with EtOAc (3×5 mL), and the combined organics were dried (MgSO4), filtered and concentrated. The crude residue 3-(2-acetyl-8-chloro-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-3-yl)propanal (4-5; a racemic mixture) was carried directly into the next transformation.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2.[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[C:24]([CH:36]=O)[NH:23][C:22]=1[CH3:38])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[C:24]([CH:36]=[C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[CH:14][C:6]=3[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[NH:10][C:9]2=[O:15])[NH:23][C:22]=1[CH3:38])=[O:20])[CH3:17]
Reactant: O=C1Cc2c(cccc2-c2nccs2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4nccs4)c32)c1CCCN1CCN(C)CC1

Procedure:
4-Thiazol-2-yl-1,3-dihydroindol-2-one (54 mg, 0.25 mmol) was condensed with 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (88 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]([N+:11]([O-:13])=[O:12])([CH3:10])[CH2:6][CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O>[CH3:21][S:22]([O:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:10])([N+:11]([O-:13])=[O:12])[CH3:4])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCCO)[N+](=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Anhydrous DCM (200 mL) was added via canula to a flask containing 4-methyl-4-nitropentanol (12.0 g, 81.8 mmol) under a nitrogen atmosphere. The solution was cooled in an ice bath for 15 minutes and triethylamine (17.1 mL, 1.5 equiv, 123 mmol) was added followed by the addition of methanesulfonyl chloride (8.23 mL, 1.3 equiv, 106 mmol) via syringe over one min. The mixture was stirred for 1 h at 0° C. Then water (100 mL) was added and the layers were separated. The organic layer was washed with 1 M HCl (100 mL), saturated NaHCO3 solution (100 mL) and brine (100 ml). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a liquid which crystallized upon addition of a mixture of 20% EA in hexanes (50 mL). The solid was filtered and dried under high vacuum to give a white solid (14.3 g, 78%). 1H NMR (CDCl3, 400 MHz): δ 1.61 (s, 6H), 1.73-1.77 (m, 2H), 2.02-206 (m, 2H), 3.02 (s, 3H), 4.23 (t, 2H). LRMS (ESI+) for C7H15NO5S (225.1); Found: 226 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:18]([Cl:17])[CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(3,4-dichlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,4-dichlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: Oc1ccccc1F
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1ccccc1F
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 2-fluorophenol (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted 3 times with EtOAc to yield 2.5 g of less pure compound.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:6]1[CH:7]=[C:8]([N:13]2[C:17]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=3)=[CH:16][C:15]([C:27]([O:29]CC)=[O:28])=[N:14]2)[CH:9]=[CH:10][C:11]=1[F:12])#[N:5].Cl>C1COCC1>[C:4]([C:6]1[CH:7]=[C:8]([N:13]2[C:17]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=3)=[CH:16][C:15]([C:27]([OH:29])=[O:28])=[N:14]2)[CH:9]=[CH:10][C:11]=1[F:12])#[N:5]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)n(-c2ccc(F)c(C#N)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.0 ml of water and 570 mg (23.8 mmol) of lithium hydroxide are added to 900 mg (1.78 mmol) of the carboxylic ester of Example 132A with 75% purity in 30.0 ml of THF. The mixture is stirred at RT for 5 h and a 1N aqueous hydrogen chloride solution is subsequently added to the reaction solution. The mixture is extracted with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 527 mg (86% of theory) of the title compound are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH2:13])([O-:3])=[O:2].N1C=CC=CC=1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[CH3:20][N:21]([CH3:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)=[O:26]
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=O)Nc2n[nH]c3ccc([N+](=O)[O-])cc23)c1
Temperature: 25 °C

Procedure:
To a solution of 5-nitro-1H-indazol-3-ylamine in pyridine (Ryan Scientific, 0.150 g, 0.838 mmol) cooled to about 0° C. in an ice bath, was added 3-dimethylamino-benzoyl chloride (0.154 g, 0.838 mmol). The reaction mixture was stirred as it warmed to ambient temperature. After about 1 hour it was poured into crushed ice, then extracted with EtOAc (10 mL). The organic solvent portion was washed with a 1M aqueous HCl solution, then concentrated and dried under reduced pressure. The residue was further purified via preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 35 cm; 5-100% acetonitrile/0.1 M ammonium acetate over 20 min, 100% acetonitrile hold 10 minutes, 21 mL/min) to obtain 3-dimethylamino-N-(5-nitro-1H-indazol-3-yl)-benzamide as a white solid (0.002 g, 0.006 mmol); RP-HPLC (Table 1, Method e) Rt 1.95 min; m/z: (M+H)+ 326.4.
Reaction SMILES: [CH2:1]([CH:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].IC[CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26]>>[F:29][C:24]([F:30])([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][CH2:15][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: FC(F)(F)C(F)(F)CCCI
Reactant: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Product: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(7-octenyl)malonate prepared in Example 5 and the 1-iodo-4,4,5,5,5-pentafluoropentane prepared in Example 1, the same procedure as shown in Example 5 was repeated to give ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate.