Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.C(OCC)(=O)C.CCCCCC>C1C=CC=CC=1.[Rh]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:62][C@H:14]1[CH2:15][C@@H:16]([CH3:61])[C:17](=[O:18])[C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24](=[O:25])[CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]2[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]2)[CH3:45])[O:28][C:29](=[O:30])[C@H:31]2[N:36]([CH2:35][CH2:34][CH2:33][CH2:32]2)[C:37](=[O:38])[C:39](=[O:40])[C@:41]2([OH:43])[O:42][C@@H:5]([CH2:4][CH2:3][C@H:2]2[CH3:1])[CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Agent: Cl[Rh]
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(/C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)CCCCC=C1C
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)CCCCC=C1C

Procedure:
A solution of 1 g (1.1 mmol) of rapamycin and 325 mg (351 μmol) of tris(triphenylphosphine) rhodium (I) chloride in 82 mL of benzene was hydrogenated at 50 psi for 4 days. The reaction was concentrated in vacuo affording a red foam. HPLC chromatography on a 2 inch HPLC column with 80% ethyl acetate/hexane as the eluant afforded 100 mg (10%) of 1,2,3,4-tetrahydrorapamycin as a white foam.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1>C(NCCCC)CCC>[CH2:12]([N:13]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1)[CH2:14][CH2:19][CH2:18][CH3:17])[CH2:9][CH2:8][CH3:7]
Reactant: ClCCCOc1ccc(-c2cn3ccccc3n2)cc1
Solvent: CCCCNCCCC
Product: CCCCN(CCCC)CCCOc1ccc(-c2cn3ccccc3n2)cc1
Yield: 192 %

Procedure:
A suspension of 2-(4-chloropropoxyphenyl)imidazo[1,2-a]-pyridine (5.2 g, 14 mmol) in dibutylamine (30 ml) was stirred at reflux for 5 hours. The excess dibutylamine was removed by distillation and the resulting oil was flash chromatographed (silica gel, 9:1 CH2Cl2 : acetone) to give the free base of the title compound (5.1 g, 93% yield) as an oil. The HCl salt was prepared by dropwise addition of concentrated hydrochloric acid to a solution of the free base in methanol, concentrated and recrystallized from methanol acetone to yield 2-(4-dibutylaminopropoxyphenyl)imidazo- [1,2-a]pyridine as a white crystalline solid, mp 179° C. to 183° C. IR(KBr): 3400, 2620, 1650, 1620 cm-1. MS: 380 (MH+). 1H NMR (CD3OD): δ8.80 (d, J=8 Hz, 1H), 8.52 (s, 1H), 7.92-7.49 (m, 5H), 7.18 (d, J=8 Hz, 2H), 4.23 (t, J=4.6 Hz, 2H), 3.50-3.13 (m, 6H), 2.25 (m, 2H), 1.82-1.34 (m, 8H), 1.01 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([SH:17])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:25]([CH2:34][CH3:35])[C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([S:17][CH:25]([CH2:34][CH3:35])[C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: Fc1ccccc1-c1nnc2ccc(S)nn12
Reactant: CCC(Br)C(=O)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(Sc1ccc2nnc(-c3ccccc3F)n2n1)C(=O)N1CCCCC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-thiol (1 mmol) and cesium carbonate (1.5 equiv.) in DMF (5 mL) was added 2-bromo-1-(piperidin-1-yl)butan-1-one (1.5 equiv.) and the mixture was stirred at 70° C. for 3 hours. The reaction was monitored by thin-layer chromatography and was shown to be complete at this time. The solvent was removed in vacuo and the residue was flash chromatographed to give 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)-1-(piperidin-1-yl)butan-1-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][C:14]=1Br)=[O:5])[CH3:2].[CH2:26]([O:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][C:14]=1[C:39]1[C:34]([O:33][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1Cc1cc(OC)c(C(C)(C)C)cc1Br
Reactant: OB(O)c1cccnc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCC(=O)N1Cc1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Yield: 75.3 %

Procedure:
step 2—A sealed tube containing 100 (150 mg, 0.36 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (125 mg, 0.56 mmol), Na2CO3 (116 mg, 1.1 mmol) and Pd(PPh3)4 (42 mg, 0.036 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated on a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE, and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 50% EtOAc/hexanes to afford 140 mg (84%) of (R)-1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester (102).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11]([CH3:15])[CH2:12][CH2:13]O>>[CH2:13]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:13][CH2:12][CH:11]([CH3:15])[CH3:10])=[O:6])[OH:3])[CH2:12][CH:11]([CH3:15])[CH3:10]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CC(C)CCO
Product: CC(C)CCOC(=O)CC(O)C(=O)OCCC(C)C
Temperature: 110 °C

Procedure:
Diisoamyl-DL-malate was prepared using a procedure similar to that in Example 4. To the reaction flask, DL-malic acid (87.54 g), 3-methyl-1-butanol (285 mL) and Amberlyst® 15 ion exchange resin (11.9) were added. The mixture was placed under nitrogen and heated to reflux. At 109° C., two phases started to collect in the Dean-Stark trap. The reaction was maintained at 110° C. for 8 hr, during this time water was continuously removed. The product was dissolved in diethyl ether and separated from the catalyst via filtration over a bed of silica. The organic layer was washed with saturated sodium bicarbonate a number of times, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Diisoamyl-DL-malate was obtained as a low viscosity, clear colorless liquid with a slight odor (130 g, 72% yield) after pumping on the sample in vacuo to remove residual 3-methyl-1-butanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1B1OC(C)(C)C(C)(C)O1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][N:19]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:18]1[N:23]=[C:22]([CH3:24])[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][N:19]=1
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1cnc(Cl)nc1C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc(-c2c(Cl)cnn2C)nc1C
Temperature: 110 °C
Reaction time: 0.67 h
Yield: 59.4 %

Procedure:
A mixture of 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.45 g, 5.98 mmol), ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (0.999 g, 4.98 mmol), bis(tri-t-butylphosphine)palladium (509 mg, 0.996 mmol), and N,N-diisopropylethylamine (1.74 mL, 9.98 mmol) in 1,4-dioxane (10 mL) and water (0.5 mL) was stirred at 110° C. for 40 mins under microwave. Direct purification by combi-flash chromatography afforded 0.83 g (59% yield) of the desired product. LC-MS found: 281.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][CH:21]=1)[O:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][CH:21]=1)[O:12][CH2:13][C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1cc(OCc2ccccc2)ccc1C(=O)CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)c1ccc(OCc2ccccc2)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A mixture of 5.0 g of 2',4'-dihydroxypropiophenone, 5.4 g of benzyl bromide, 6.2 g of potassium carbonate and 50 ml of acetone was refluxed for 7 hours. After cooling, the solid was separated by filtration. The filtrate was concentrated, and the residue was separated by column chromatography to give 4.7 g of 4'-benzyloxy-2'-hydroxypropiophenone as a white solid (yield 61%, melting point 111.5°-112.5° C.). Then, a mixture of 4.5 g of this solid, 3.5 g of ethyl bromoacetate, 6.1 g of potassium carbonate and 45 ml of acetone was refluxed for 7.5 hours. After cooling, the solid was separated by filtration. The filtrate was concentrated, and the residue was purified by column chromatography to give 5.8 g of ethyl 3-benzyloxy-6-propionylphenoxyacetate as white crystals (yield 97%, melting point 81.5° to 82.0° C.). This ester (5.5 g) was dissolved in a solution composed of 1.3 g of potassium hydroxide and 55 ml of methanol, and the solution was stirred at room temperature for 2 hours to hydrolyze the ester. The hydrolysis product was worked up in a customary manner to give 3.9 g (yield 77%) of 3-benzyloxy-6-propionylphenoxyacetic acid as a pale yellowish orange solid. Then, 9.3 g of sodium acetate and 39 ml of acetic anhydride were added to this solid, and the mixture was heated at 155° C. for 30 minutes. The solvent was evaporated, and the residue was purified by column chromatography to give 2.8 g (yield 95%, melting point 69.5°-70.5° C.) of 6-benzyloxy-3-ethylbenzofuran as a white solid. Palladium (5%)-carbon (0.27 g) and 27 ml of acetic acid were added to 2.7 g of the resulting benzofuran, and the mixture was stirred at room temperature for 3 hours in an atmosphere of nitrogen. The catalyst was separated by filtration, and the filtrate was concentrated and then purified by column chromatography to give 1.7 g (yield 90%) of the desired product as a pale orange liquid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].Cl>O1CCCC1.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:25](=[O:29])[CH2:26][CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 1.27 ml, 2.00 mmol) was added to a tetrahydrofuran (10 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (606 mg, 2.00 mmol) obtained in Example 5. The temperature of the resulting mixture was then raised to room temperature. After cooling to −78° C., butyryl chloride (0.218 ml, 2.10 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at −78° C. for 1.5 hours, and added with 1N hydrochloric acid (2.0 ml). The temperature of the mixture was then raised to room temperature. The reaction mixture was extracted with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane). The solid thus obtained was recrystallized from hexane, whereby the title compound (330 mg, 44%) was obtained as colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:42]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C@H:18]1[O:23][CH2:22][C@@H:21]([CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-])=O)[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:19]1)=[O:8])=[O:4]>CCO.[Pd]>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][C@H:21]1[N:20]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:19][C@@H:18]([CH2:17][CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[O:23][CH2:22]1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C=Cc2ccccc2[N+](=O)[O-])CO1)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CCc2ccccc2N)CO1)C(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Tert-Butyl(2R,5R)-2-{2-[2-({(2S)-2-[(methoxycarbonyl)amino]-3,3-diphenylpropanoyl}amino)phenyl]ethyl}-5-[2-(2-nitrophenyl)vinyl]morpholine-4-carboxylate (1.0 equiv) was dissolved in EtOH (0.07 M) in a Parr shaker vessel. Palladium on carbon (12 wt %) was added. The reaction mixture was flushed with nitrogen, and then submitted to 45 psi hydrogen with shaking for 18 h. The crude mixture was flushed with nitrogen, filtered on solka floc and concentrated to yield the desired product.
Reaction SMILES: CO[C:3]([C@H:5]([C@@H:17]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]([CH3:15])[C:8]1=[O:16])=[O:4].Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>C1COCC1>[CH2:33]([O:40][NH:41][C:3]([C@H:5]([C@@H:17]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]([CH3:15])[C:8]1=[O:16])=[O:4])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NOCc1ccccc1
Reactant: COC(=O)[C@@H](CN1C(=O)N(C)C(C)(C)C1=O)[C@@H](CC1CCCC1)C(=O)N1CCCCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)N(C[C@H](C(=O)NOCc2ccccc2)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C

Procedure:
A solution of 1.10 g of methyl ester from Example 10 and 568 mg of O-benzylhydroxylamine hydrochloride in 7 ml of THF was treated at −20° with 3.5 ml of a 2M i-PrMgCI solution in THF and, after 1 hr. at −20°, treated with a further 1.7 ml of the Grignard reagent. After a further 2½ hrs. at −20° the mixture was treated with ammonium chloride solution and extracted with methylene chloride. The extracts were dried and concentrated. The residue was crystallized from t-butyl methyl ether/hexane and the crystallizate was dried, there being obtained 1-[2(R)-[1(R)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine VII, m.p. 135-137°.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[C:14]2[C:13]3C=C[CH:17]=[CH:18][C:12]=3[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(I)C.Cl>C1COCC1>[CH2:3]([C:2]1[C:1]2[S:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:14]=3[C:13]=2[CH:12]=[CH:18][CH:17]=1)[CH3:4]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cccc2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
n-Butyllithium (108 mmols, 46 ml of 2.4M solution in hexane) was added to a stirred solution of dibenzothiophene (10 g, 54 mmole) in dried THF (150 ml) at 0° C. over a period of 1 hr under dry N2 atmosphere. This reaction mixture was stirred 5 hrs at room temperature then the reaction mixture was cooled to −70° C. and a solution of ethyl iodide in dry THF was added dropwise and stirred at room temperature for over night. This reaction mixture was poured slowly into a cold 1N HCl (200 ml). Organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×500 ml). Organic layers mixed together and concentrated to dryness to get crude product. The crude product was purified by silica gel column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.C[O:12][C:13](=[O:20])[C:14](=[O:19])[CH:15]=[C:16]([CH3:18])[CH3:17].C[Si](C)(C)Cl.Cl>O1CCCC1.[Cu].C(OCC)(=O)C.CN1CCCN(C)C1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([CH3:18])([CH3:17])[CH2:15][C:14](=[O:19])[C:13]([OH:20])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(=O)C=C(C)C
Reactant: COc1cccc([Mg]Br)c1
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(C(C)(C)CC(=O)C(=O)O)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
4.2 ml of a 0.6 m solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran is mixed at −70° C. with 257 mg of copper bromidedimethylsulfide complex and then stirred at −40° C. for 20 minutes. It is cooled again to −70° C., and 0.33 ml of 1,3-dimethyl-tetrahydro-2-1H-pyrimidinone and a mixture of 400 mg of 4-methyl-2-oxo-3-pentenoic acid methyl ester (Liebigs Annalen [Liebigs Annals] 1974, 477) and 0.71 ml of trimethylchlorosilane in 3.5 ml of tetrahydrofuran are slowly added. It is stirred for one hour at −70° C. and then heated to room temperature. Then, 2N hydrochloric acid and ethyl acetate are added, the ethyl acetate phase is separated, it is concentrated by evaporation, and the residue is dissolved in 5 ml of dichloromethane. After 200 mg of tetrabutylammonium fluoride is added, it is left at room temperature for one hour, then washed with water, and the dichloromethane phase is dried (Na2SO4) and concentrated by evaporation. After chroma-tography on silica gel with hexane/ethyl acetate (97:3), 63 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid-methyl ester, which is mixed with 1 ml of potassium hydroxide in methanol (10%), is obtained. After 45 minutes, it is concentrated by evaporation, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is then acidified with 6N hydrochloric acid and extracted with diethyl ether. The diethyl ether phase is dried (Na2SO4) and concen-trated by evaporation. 50 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH:9]1([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([O:26][CH2:27][O:28][CH3:29])[CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:17]([CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([O:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25]1)[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COCOC1CCN(CCNC2CCCCCCC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC1CCN(CCN(C2CCCCCCC2)S(=O)(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.49 ml of 3-chloropropanesulfonyl chloride was dropwise added, at 0° C., to a solution of 1.19 g of 1-(2-cyclooctylaminoethyl)-4-methoxymethoxypiperidine and 0.67 ml of triethylamine in 10 ml of dichloromethane. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography (eluant: 2% methanol/dichloromethane) to obtain 1.2 g of 1-{2-[N-(3-chloropropylsulfonyl)-N-cyclooctylamino]-ethyl}-4-methoxymethoxypiperidine.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][NH:11][C:5]=2[NH:4][C:3]1=O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]2[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][NH:11][C:5]=2[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2[nH]nc(Nc3ccccc3)c2c1=O
Product: Cn1c(Cl)nc2[nH]nc(Nc3ccccc3)c2c1=O
Yield: 72 %

Procedure:
5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (4.3 g, 16.7 mmol) is refluxed in POCl3 (120 mL) for 2 days, and then POCl3 is removed under reduced pressure. The residue is suspended in 100 mL of water and carefully adjusted to pH=1˜2 with 7% NH4OH upon cooling. The mixture is then extracted with CH2Cl2 and MeOH (10:1, v/v) five times. The combined organic phase is washed with water, dried over Na2SO4, and then evaporated under reduced vacuum to give 3.3 g of crude product (Yield: 72%). MS (ESI) m/z 276.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=4)[C:15]3=[O:27])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:28][S:29](O)(=[O:31])=[O:30].O>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([S:29]([Cl:28])(=[O:31])=[O:30])=[C:21]([F:26])[CH:20]=4)[C:15]3=[O:27])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)cc(F)c1
Solvent: ClCCCl
Solvent: O
Product: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)c(S(=O)(=O)Cl)c(F)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Synthesized according to General Procedure 11. To a solution of (3′S)-3-(3,5-dichlorophenyl)-1′-(3,5-difluorophenyl)-1,3′-bipyrrolidin-2′-one (50 mg, 0.12 mmol) in DCE (0.4 mL) at 0° C. was added chlorosulfonic acid (71 mg, 40 μL, 0.61 mmol) dropwise and the reaction mixture stirred from 0° C. to RT over 1 hour, the temperature was raised to 50° C. and the reaction mixture stirred at this temperature for 2 hours. More chlorosulfonic acid was added (71 mg, 40 μL, 0.61 mmol) and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organic extracts were washed with saturated aqueous NaHCO3, water, and brine, dried (Na2SO4) and evaporated to dryness. The crude product was used without further purification in the next reaction step. (LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=411.3; tR=1.46 min.