Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:16]1[N:17]([CH2:24][C@:25]2([CH3:28])[CH2:27][O:26]2)[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[N:20]=1>CN(C=O)C>[CH3:27][C@@:25]1([CH2:28][O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[O:26][C:16]2=[N:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][N:17]2[CH2:24]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(OC(F)(F)F)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
4-Trifluoromethoxyphenol (1.1 g, 6.17 mmol) was dissolved in DMF (20 ml). To the solution, sodium hydride (260 mg, 6.45 mmol) was added at room temperature, and the solution was stirred for 15 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (1.22 g, 5.61 mmol) was added with cooling on ice-bath, and the solution was stirred for further 2 hours at 80° C. The reaction mixture was poured into ice-water, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and and then crystallized from methylene chloride-diisopropyl ether to afford (R)-2-methyl-6-nitro-2-(4-trifluoromethoxyphenoxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole (1.03 g, yield 51%) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[CH:7]([CH:9]=[CH2:10])=O>O1CCCC1>[CH:9]([CH:10]1[O:6][CH2:5][CH:2]([CH3:1])[CH2:3][O:4]1)=[CH2:7]
Reactant: C=CC=O
Reactant: CC(CO)CO
Solvent: C1CCOC1
Product: C=CC1OCC(C)CO1

Procedure:
This invention provides a process for producing tetrahydrofuran by (1) the condensation of 2-methyl-1,3-propanediol with acrolein to form 2-vinyl-5-methyl-1,3-dioxane; (2) the conversion of the 2-vinyl-5-methyl-1,3-dioxane under hydroformylation conditions to 3-(5'-methyl-1',3'-dioxane)propionaldehyde; and (3) hydrogenation of the propionaldehyde derivative under acidic conditions to yield tetrahydrofuran.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[NH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: N
Product: NS(=O)(=O)c1ccc(Br)c(F)c1
Reaction time: 16 h

Procedure:
According to general procedure A, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and ammonia (20 mL, ca. 7N in methanol) were stirred together for 16 hours. 4-bromo-3-fluorobenzenesulfonamide was provided after purification (0.23 g, 61%). HRMS: calcd for C6H5BrFNO2S, 252.92084; found (EI, M+), 252.9201. HPLC purity 100.0% at 210-370 nm, 7.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.[C:18]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=O)[CH3:19]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:18]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[CH:19]2
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)C1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Clc1ccc2[nH]c(C3CCNCC3)cc2c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A mixture of 0.60 gm (3.4 mMol) 4-chlorophenylhydrazine hydrochloride and 0.54 mL (6.7 mMol) pyridine in 20 mL ethanol were stirred at 60° C. for 15 minutes. To this mixture was then added 4-acetylpiperidine hydrochloride and the reaction mixture was stirred for 2 hours at 70° C. The reaction mixture was concentrated under reduced pressure and the residue was treated with polyphosphoric acid. This mixture was heated at 90-100° C. for 48 hours. The reaction mixture was quenched with a slurry of ice in 5N sodium hydroxide. The aqueous mixture was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a dichloromethane gradient containing 4-20% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.26 gm (36%) of the title compound as a tan solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[Li]CCCC.[CH2:12]([O:19][C@@H:20]1[C@@H:28]([CH:29]=[O:30])[O:27][C@H:26]2[C@H:22]([N:23]=[C:24]([N:31]([CH3:33])[CH3:32])[S:25]2)[C@H:21]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([O:19][C@@H:20]1[C@@H:28]([C@H:29]([CH:2]2[S:3][CH2:4][CH2:5][CH2:6][S:1]2)[OH:30])[O:27][C@H:26]2[C@H:22]([N:23]=[C:24]([N:31]([CH3:33])[CH3:32])[S:25]2)[C@H:21]1[O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](O)C3SCCCS3)O[C@@H]2S1
Reaction time: 1 h

Procedure:
A solution of 1,3-dithiane (14.1 g, 117 mmol) in THF (100 mL) was treated with n-BuLi (44.9 mL, 112 mmol, 2.5M in hexane) at 0° C. for 1 hour, followed by the addition of a solution of the above aldehyde 95 in THF (20 mL) at −50° C. After kept additional 1 hour at 0° C., the reaction was quenched by saturated aqueous NH4Cl (150 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 20%-50% ethyl acetate in petroleum to afford the title compound as a yellow syrup (6.4 g, 62%, two epimers' ratio is 1:1 by 1H NMR); (ES, m/z) [M+H]+ 547.0; 1H NMR (300 MHz, CDCl3) δ 7.28-7.44 (m, 10H), 6.33 (d, J=6.6 Hz, 1H), 4.63-4.84 (m, 4H), 4.52-4.58 (m, 1H), 4.12-4.15 (m, 1H), 3.98-4.05 (m, 3H), 3.82-3.85 (m, 1H), 2.99 (s, 6H), 2.80-2.87 (m, 1H), 2.61-2.68 (m, 3H), 1.65-1.69 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[CH3:20]O>>[CH3:20][O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(O)CCCc1ccc(O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCCc1ccc(O)cc1
Yield: 99 %

Procedure:
The 4-(4-hydroxyphenyl)butanoic acid (1) (4.6 g) from the previous step was dissolved in methanol (60 mL), concentrated sulfuric acid (1 mL) was added, and refluxed by heating for two days. The reaction solution was poured into water, and extracted with ethyl acetate (200 mL). The organic layer was washed with water (50 mL), saturated aqueous solution of sodium hydrogen carbonate (50 mL) and saturated sodium chloride solution (50 mL). After drying on anhydrous sodium sulfate, filtration and vacuum concentration, the above-identified compound (4.9 g, yield 99%) was obtained.
Reaction SMILES: OC1C=C(C[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[OH:19])C=C(O)C=1.C[O:21][C:22]1[C:29]([CH3:30])=[C:28]([O:31]C)[CH:27]=[CH:26][C:23]=1[CH:24]=O>>[OH:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([OH:31])=[C:29]([CH3:30])[C:22]=1[OH:21]
Reactant: Oc1cc(O)cc(CCCc2ccc(O)cc2O)c1
Reactant: COc1ccc(C=O)c(OC)c1C
Product: Cc1c(O)ccc(CCCc2ccc(O)cc2O)c1O

Procedure:
Compound 32 was synthesized following a similar procedure as described for compound 30 using as starting materials 2,4-dibenzyloxyacetophenone and 2,4-dimethoxy-3-methylbenzaldehyde. 1H-NMR (MeOD, 500 MHz): δ 6.879 (d, 1H, J=8.5 Hz), 6.747 (d, 1H, J=8.0 Hz), 6.352 (d, 1H, J=1.5 Hz), 6.341 (d, 1H, J=4.0 Hz), 6.285 (dd, 1H, J=8.0 Hz & 2.5 Hz), 2.567 (dd, 4H, J=8.0 & 7.5 Hz), 2.133 (s, 3H), 1.786-1.817 (m, 2H). 13C-NMR (MeOD, 125 MHz): δ 155.486 (C), 155.316 (C), 153.428 (C), 152.906 (C), 130.295 (CH), 126.523 (CH), 120.933 (C), 120.518 (C), 111.556 (C), 106.788 (CH), 106.377 (CH), 102.283 (CH), 30.767 (CH2), 29.649 (CH2), 29.127 (CH2), 7.833 (CH3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[I-].[Na+].Cl.[OH-:26].[Na+]>CS(C)=O.O>[CH3:16][C:15]1[C:3]2[C:2](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[NH:5][C:4]=2[N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:14]=1
Reactant: [OH-]
Reactant: Cc1cccc2nc3c(c(C)nn3-c3ccccn3)c(Cl)c12
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc2[nH]c3c(c(C)nn3-c3ccccn3)c(=O)c12
Temperature: 100 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of 4-chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.65 g, 5.34 mmol), sodium iodide (0.96 g, 6.41 mmol) and conc. hydrochloric acid (1 mL) in dimethylsulfoxide (20 mL) was heated and stirred at 100° C. for 2 hours. The solution was allowed to cool to room temperature, and the residue was poured into water. The solution was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with 10% methanol/chloroform. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate:hexane=90:10) to give the title compound (1.13 g, 73% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=1)[CH:8]=[CH:7]2.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1.C(N(CC)CC)C>O1CCCC1>[O:33]=[C:31]1[NH:30][C:29](=[O:34])[CH:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:19]3[N:18]([CH3:37])[C:17]4[CH:38]=[C:13]([O:12][C:9]5[CH:10]=[C:11]6[C:6]([CH:5]=[CH:4][CH:3]=[C:2]6[NH:1][S:45]([C:42]6[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=6)(=[O:47])=[O:46])=[CH:7][CH:8]=5)[CH:14]=[CH:15][C:16]=4[N:20]=3)=[CH:36][CH:35]=2)[S:32]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(N)c4c3)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2cccc3ccc(Oc4ccc5nc(COc6ccc(CC7SC(=O)NC7=O)cc6)n(C)c5c4)cc23)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 27 %

Procedure:
A mixture of 5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g), p-toluenesulfonyl chloride (0.30 g), triethylamine (0.16 g) and anhydrous tetrahydrofuran (8 ml) was stirred at 50° C. for 5 hours and then at 70° C. for 2 hours. The reaction mixture was concentrated. To the residue was added water and the precipitate was washed with water and tetrahydrofuran to afford the title compound (0.14 g, mp 137-144° C.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@@H:13]([NH2:15])[CH2:12]1.[Cl:16][C:17]1[C:18]([C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])=[N:19][CH:20]=[CH:21][N:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:12][C@H:13]([NH:15][C:24](=[O:25])[C:23]([C:18]2[C:17]([Cl:16])=[N:22][CH:21]=[CH:20][N:19]=2)([CH3:28])[CH3:27])[CH2:14]1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Reactant: N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a round bottomed flask was added cis-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (Intermediate 32, 0.3010 g, 1.030 mmol), 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (Intermediate 29, 0.248 g, 1.236 mmol), HATU (0.509 g, 1.339 mmol, GenScript Corp), and triethylamine (0.573 ml, 4.12 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (2.060 ml) to stir at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic extract was washed with water, saturated NaHCO3, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product (592.4 mg) was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.3181 g, 0.791 mmol, 77% yield). LCMS showed product peak at 1.536 min (m+1=401.9). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (s, 4 H) 1.88-2.03 (m, 1 H) 2.60-2.69 (m, 1 H) 3.87-4.03 (m, 1 H) 6.97-7.07 (m, 1 H) 7.18-7.26 (m, 1 H) 7.39 (d, J=7.43 Hz, 1 H) 7.63-7.71 (m, 1 H) 7.76 (d, J=6.65 Hz, 1 H) 8.27 (d, J=6.26 Hz, 1 H) 8.45 (d, J=2.54 Hz, 1 H) 8.68 (d, J=2.54 Hz, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])(=[O:30])=[O:29])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3F)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and the 2-fluoro-benzenesulfonyl chloride (92 mg, 0.63 mmol) was dissolved in pyridine (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide (113 mg, yield: 44%) as yellow solid. MS (ESI+APCI) M+1=445.1.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].CS[C:8]1[S:12][CH:11]=[CH:10][S+:9]=1.[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[S:9]1[CH:10]=[CH:11][S:12][C:8]1=[N+:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CSc1scc[s+]1
Reactant: CCCCNCCCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCCC[N+](CCCC)=c1sccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 10 ml of tetrahydrofuran, 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was suspended, and 0.75 ml of dibutylamine was dropwise added over a period of 5 minutes. The mixture was stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of acetone-ethyl ether, and cooled to -70° C. in a cooling medium, whereupon crystals precipitated. The crystals were collected by decantation under cooled condition, and purified by liquid chromatography (column: Senshu pack, Senshu ODS-5301, mobile phase: methanol/water=50/50), whereby 0.20 g (yield: 75%) of N-(1,3-dithiol-2-ylidene)-N,N-di(n-butyl)ammonium perchlorate was obtained as oily substance. (Compound No. 23)
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[F:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:35][NH2:36]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[F:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:35][NH2:36])(=[O:3])[NH2:2]
Reactant: NN
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 28C (497 mg, 1 mmol) in 1,4-dioxane (10 mL) was added hydrazine hydrate (0.3 mL). After stirring at ambient temperature for about 4 hours, the mixture was concentrated. The residue was washed with hexane and dried under vacuum to give the title compound, which was used in the next step without further purification. MS: 493 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.O>C(Cl)Cl.CCOCC>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:8]2[CH2:9][CH:10]3[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]3)[CH2:7]2)=[O:21])=[CH:18][CH:17]=1
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)N1CC2CC(CN(C(=O)c3ccc(Cl)cc3)C2)C1
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A 25-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with a N2 inlet, a 10-mL addition funnel and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) in CH2Cl2 (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise a solution of 4-chlorobenzoyl chloride (0.69 g, 3.92 mmol) in CH2Cl2 (5 mL) over 15 min. Stirring of the mixture was continued for an additional 3 h under N2. An aqueous mixture, formed upon addition of H2O (30 mL), was extracted (CH2Cl2, 4×25 mL). Combined extracts were dried (Na2SO4, 2 h), filtered, and concentrated to give a viscous yellow oil. Chromatography of the oil was performed by adding an ether solution of the oil to a neutral alumina column (69 g, 1.7 cm×30 cm) and then using 60:40 hexanes/ethyl acetate as eluant. Fractions (Rf =0.41) were saved and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 0.86 g (80.4%) of off-white solid (33); mp 97°-98° C. IR (KBr) cm-1 3085, 3070 (Ar C--H), 2965, 2935, 2865, 2800, 2770 (C--H), 1630 (C=O); 1H NMR (DCCl3) δ0.95 (d, 3 H, CH3, J=6.5 Hz), 1.05 (d, 3 H, CH3, J=6.4 Hz), 1.63-1.75 [m, 3 H, H(5) and H(9)], 1.97 [bs, 1 H, H(1)], 2.41 [bd, 1 H, H(4)ax, J=10.6 Hz], 2.50 [bd, 1 H, H(6)ax, J=11.2 H], 2.59 [heptet, 1 H, CH(CH3 )2, J=6.5 Hz], 2.71 [bd, 1 H, H(6)eq, J=11.0 Hz], 3.03-3.06 [m, 2 H, H(2)ax and H(4)eq ], 3.31 [bd, 1 H, H(8)ax, J=12.8 Hz], 3.71 [bd, 1 H, H(8)eq, 13.1 Hz], 4.77 [bd, 1 H, H(2)eq, J=13.2 Hz], 7.27-7.37 (m, 4 H, Ar--H); 13C NMR (DCCl3) ppm 16.37, 19.35 (CH3), 29.07 [C(1)], 29.80 [C(5)], 32.29 [C(9)], 46.68 [C(2)], 52.22 [C(4)], 52.56 [C(8)], 54.38 [CH(CH3)2 ], 54.79 [C(6)], 128.35, 128.51, 134.67, 136.11 (Ar--C), 169.03 (C=O). Anal. Calcd. for C17H23ClN2O: C, 66.55; H, 7.56. Found: C, 66.45; H, 7.71.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>N1C=CC=CC=1>[C:33]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18](=[O:19])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(=O)C(C)(C)C)cc2n1Cc1ccccc1
Yield: 7.5 %

Procedure:
Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 18 mg, 0.041 mol) in pyridine (1 ml) was reacted with pivaloyl chloride (5.1 μl, 0.41 mmol) to yield the title compound (16 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]=[CH:16][NH:17][C:18](=O)[C:19]=3[N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:24])=O.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[Cl:24][C:18]1[C:19]2[N:20]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:12]=[CH:13][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: COc1ccc(-c2ccc3nc[nH]c(=O)c3n2)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1OC
Yield: 76.9 %

Procedure:
To a suspension of 6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (150 mg, 0.53 mmol) in toluene (30 ml) was added phosphorus oxychloride (148 μl, 1.59 mmol) and 2,6-lutidine (185 μl, 1.59 mmol). The reaction mixture was refluxed overnight until a black solution was obtained. After evaporation to dryness, the residue was redissolved in ethyl acetate and extracted with a saturated sodium bicarbonate solution. The combined organic layers were evaporated in vacuo. The residue was purified by silica gel column chromatography, the mobile phase being an ethyl acetate/hexane mixture, in a ratio gradually ranging from 2:8 to 3:7, resulting in the pure title compound (123 mg, yield 77%) which was characterised by its mass spectrum as follows: MS (m/z): 302, 304 ([M+H]+, 100).
Reaction SMILES: C(O[C:4](=[O:15])[CH:5]([CH3:14])[C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])C.C(OC(O[CH2:22][CH3:23])=C)C.[CH3:24][NH2:25].O>C(OCC)C.C[O-].[Na+]>[CH2:11]([O:10][C:8]([C:7]1[C:6]([OH:13])=[C:5]([CH3:14])[C:4](=[O:15])[N:25]([CH3:24])[C:22]=1[CH3:23])=[O:9])[CH3:12]
Reactant: CN
Reactant: CCOC(=O)CC(=O)C(C)C(=O)OCC
Reactant: C=C(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c(O)c(C)c(=O)n(C)c1C
Temperature: 85 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
A mixture of 2-methyl-3-oxo-pentanedioic acid diethyl ester (10.0 g, 46.3 mmol), 1,1-diethoxy-ethene (12.8 mL, 92.5 mmol) and sodium methoxide (0.026 mg, 0.481 mmol) was heated to 85° C. for nine hours. The reaction mixture was cooled to room temperature and concentrated. To the resulting residue was added methylamine (1.91 mL, 55.5 mmol), 40% H2O). After stirring at room temperature for 16 hours, the reaction mixture was diluted with diethyl ether and washed with water. The aqueous phase was acidified to pH 1 with 10% HCl solution and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. Trituration of the resulting residue with diethyl ether and flash column chromatography (3% MeOH in methylene chloride) gave 3.55 g (34%) desired product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([C:19](=[S:21])[NH2:20])[N:3]=1.Cl[CH2:23][C:24](=O)[CH3:25]>C(O)(C)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[C:19]1[S:21][CH:23]=[C:24]([CH3:25])[N:20]=1
Reactant: NC(=S)c1nc(N)nc2c1ncn2Cc1ccccc1F
Reactant: CC(=O)CCl
Solvent: CC(C)O
Product: Cc1csc(-c2nc(N)nc3c2ncn3Cc2ccccc2F)n1
Temperature: 80 °C
Yield: 12 %

Procedure:
A stirred suspension of 2-amino-9-(2-fluorobenzyl)-9H-purine-6-thiocarboxamide (200 mg, 0.5 mmol) and chloroacetone (1 mL) in isopropanol (5 mL) was heated at 80° C. for 2 h, filtered and the filtrate concentrated in vacuo and purified by chromatography [SiO2; EtOAc] to give the title compound (26 mg, 12%) as a yellow solid.