Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([OH:31])[C:19]#[C:20][C:21]([O:24]C2CCCCO2)([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2].Cl.[O:45]1CC[CH2:47][CH2:46]1>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([O:31][C:46](=[O:45])[CH3:47])[CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@H](O)C#CC(C)(C)OC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: C1CCOC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@@H](CCC(C)(C)O)OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
109 mg of (22S)-1α,3β-diacetoxy-25-tetrahydropyranyloxy-cholest-5-en-23-yn-22-ol (IIIa1) was dissolved in a mixture of methanol and tetrahydrofuran, and after adding thereto 3 drops of 2N-hydrochloric acid, the mixture was stirred for 3 hours at room temperature. The reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and water, successively. After drying with magnesium sulfate, the solvent was distilled away. The residue obtained was dissolved in 10 ml of ethyl acetate, and after adding thereto 10 mg of 10% Pd-C, the mixture was stirred for 4 hours at room temperature under an hydrogen stream atmosphere. The catalyst was filtered off, and the mixture was washed with ethyl acetate, and a combined solution of filtrate and washing was concentrated under reduced pressure. The residue was dissolved in 0.5 ml of pyridine, and after adding thereto 0.1 ml of acetic anhydride, the mixture was stirred overnight at room temperature. After adding water to the reaction solution, the mixture was extracted with ethyl acetate. The extract organic layer was washed with 2N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and water, successively, and dried over magnesium sulfate. The solvent was distilled away, and the residue was subjected to column chromatography (n-hexane-ethyl acetate=4:1) for purification to give 71.6 mg of (22R)-1α,3β,22-triacetoxycholest-5-en-25-ol (IVa1). (IVa1): Oily material
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[C:5]([S:15][C:16]([CH3:18])=[CH2:17])=[N:4][C:3]=1[C:19](=[O:23])[C:20]([CH3:22])=[CH2:21].I([O-])(=O)(=O)=[O:25].[Na+].O>CO>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH3:14])=[CH:11][CH:12]=2)[C:5]([S:15]([CH:16]([CH3:18])[CH3:17])=[O:25])=[N:4][C:3]=1[C:19](=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(C)Sc1nc(C(=O)C(=C)C)c(Cl)n1-c1ccc(CC)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)c1nc(S(=O)C(C)C)n(-c2ccc(CC)cc2)c1Cl
Yield: 41.4 %

Procedure:
A mixture of 3.0 g (8.6 mmol) of [5-chloro-1-(4-ethylphenyl)-2-(propen-2-ylthio)-imidazol-4-yl]-2-methyl-2-propen-1-one and 2.3 g (11 mmol) of sodium metaperiodate was heated at 50° C. for 3 hours in 30 ml of 90% aqueous methanol. The mixture was cooled and poured into water. Extraction with dichloromethane yielded an oil which was purified by flash chromatography on silica (20% ethyl acetate in petroleum ether) to obtain 1.3 g (41%) of [5-chloro-1-(4-ethylphenyl)-2-(prop-2-ylsulfinyl)-imidazol-4-yl]-2-methyl-2-propen-1-one as cream-colored crystals melting at 83°-4° C.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N-].[N+:12]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])([O-:14])=[O:13].O.C(OCC)(=O)C>C(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([NH:19][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[N+:12]([O-:14])=[O:13])[C:4](=[O:11])[CH3:3])[CH3:10]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)c1ccccc1[N+](=O)[O-])C(C)=O
Temperature: 40 °C
Yield: 76.4 %

Procedure:
Rh2(OAc)4 (30 mg, 0.063 mmol) was added to a solution of ethyl diazoacetoacetate (1.0 g, 6.32 mmol) and 2-nitrobenzamide (1.05 g, 6.32 mmol) in methylene chloride (15 mL), and the mixture was stirred at 40° C. for a day and a night. Water was then added to the reaction mixture, extraction was performed with ethyl acetate, and the organic extract was washed with water and saturated saline. After drying over magnesium sulfate, it was concentrated under reduced pressure to yield a crude product, which was then purified by column chromatography to yield the title compound (1.42 g, 77%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:31])=[C:11]([CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]4)[N:12]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]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].C1(C)C=CC=CC=1>[CH3:31][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(Br)cc4)oc3C)ccc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(N5CCOCC5)cc4)oc3C)ccc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a vacuum dried flask charged with argon were added ethyl ((1 S)-5-{2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl )acetate (0.1 g, 0.2 mmol), sodium t-butoxide (0.03 g, 0.3 mmol), 1,1′-biphenyl-2-yl[di(tert-butyl)]phosphine (0.012 g, 0.04 mmol), morpholine (0.022 g, 0.25 mmol), Pd2(dba)3 (0.019 g, 0.02 mmol), and toluene (1 mL). The reaction was degassed by bubbling argon through the flask for 15 minutes. The reaction was stirred at 80° C. for 16 h, then was cooled to rt and filtered through a silica gel plug. The filtrate was evaporated under vacuum and the residue was purified by HPLC to obtain ethyl [(1S)-5-(2-{5-methyl-2-[4-(4-morpholinyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-2,3-dihydro-1H-inden-1-yl]acetate (0.06 g, 0.1 mmol) in 60% yield. 1H NMR ( CDCl3) δ 1.3 (m, 3H), 1.7 (m, 1H), 2.4 (m, 5H), 2.8 (m, 3H), 3.0 (m, 2H), 3.3 (m, 4H), 3.5 (m, 1H), 3.9 (m, 4H), 4.2 (m, 4H), 6.7 (m, 2H), 6.9 (d, 2H), 7.1 (d, 1H), 7.9 (m, 2H); MS (ES) 491 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:34])=[C:5]([C:25]([O:27][CH2:28][CH2:29][O:30]C(=O)C)=[O:26])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[N+:8]([O-:10])=[O:9].C[O-].[Na+]>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:34])=[C:5]([C:25]([O:27][CH2:28][CH2:29][OH:30])=[O:26])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)OCCOC(=O)C1=C(C)NC(C)=C([N+](=O)[O-])C1c1ccccc1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(C(=O)OCCO)C(c2ccccc2OCc2ccccc2)C([N+](=O)[O-])=C(C)N1

Procedure:
1 g of β-acetoxy-ethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-benzyloxyphenyl)-pyridine-5-carboxylate is suspended in 120 ml of absolute methanol, and 2 ml of 1 molar sodium methylate solution are added, a dark red solution soon being formed. When the reaction has ended (check by thin layer chromatography), the mixture is rendered neutral with Amberlite IR 120 H⊕ and filtered and the filtrate is concentrated. The solid evaporation residue is stirred with ethanol and filtered off with suction. 600 mg (65.8% of theory) of a yellow-colored compound of melting point 183°-185° C. are obtained.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:19][CH3:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[C:24]([NH:32][C:33](OC2C=CC=CC=2)=[O:34])[C:25](=[CH:30][CH:31]=1)[C:26]([O:28][CH3:29])=[O:27]>>[C:15]([O:14][C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH:1][C:33]([NH:32][C:24]2[CH:23]=[C:22]([Cl:21])[CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[O:34])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[CH2:19][CH3:20])=[O:13])([CH3:16])([CH3:18])[CH3:17]
Reactant: CCC(C(=O)OC(C)(C)C)c1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: CCC(C(=O)OC(C)(C)C)c1ccc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OC)cc1
Yield: 83.8 %

Procedure:
From 1.02 g (3.41 mmol) of tert-butyl (±)-2-(4-aminosulfonylphenyl)butyrate and 1.04 g (3.41 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate in a manner similar to Preparation Example 1, 1.46 g (yield 84%) of methyl 2-[({4-[1-(t-butoxycarbonyl)propyl]benzenesulfonylamino}carbonyl)amino]-4-chlorobenzoate (property: colorless amorphous, PMR (δppm, CDCl3): 0.89 (3H, t), 1.38 (9H, s), 1.69-1.76 (1H, m), 2.03-2.10 (1H, m), 3.42 (1H, t), 3.94 (3H, s), 7.04 (1H, d), 7.47 (2H, d), 7.93 (1H, d), 8.01 (2H, d), 8.45 (1H, br), 11.04 (1H, br)) was obtained. Then, 4.3 ml (8.6 mmol) of 2N sodium hydroxide was used in a similar manner to prepare 1.43 g of a carboxylic acid. Using 463 mg (2.86 mmol) of CDI, 970 mg (yield 71%: 2 steps) of (±)-2-{4-[(7-chloro-2,4(1H,3H)-quinazoline-3-yl)sulfonyl]phenyl}butyric acid t-butylester was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][N:33]([C:12]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[C:19]3[C:14]([C:13]=2[CH:20]=[O:21])=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:32][CH2:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(C(C)(C)C)cc2)CC1
Yield: 70 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with 1-Boc-piperazine as described in Step 2 of Example 29 to afford 4-[1-(4-tert-butylphenyl)-3-formyl-1H-indol-2-yl]piperazine-1-carboxylic acid tert-butyl ester (70% yield) as a light yellow solid. TLC (heptane-30% ethyl acetate) Rf 0.19; ESI/MS 462 (M+H); RT=4.42 min.; NMR10.13 (1H, s); 8.13 (1H, d, J=9 Hz); 7.68 (2H, d); 7.49 (2H, d); 7.21 (2H, m); 6.95 (1H, d, J=9 Hz); 3.20 (8H, m); 1.37 (18H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)([O-:3])=[O:2].Br[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].CC(C)(C)C(O)=O>CN(C)C(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2.C(OCC)(=O)C>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][CH3:26])=[C:18]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=2)[CH:23]=1
Reactant: C[Si](C)(C)CCOCn1cc([N+](=O)[O-])cn1
Reactant: COc1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cl)cc1-c1nn(COCC[Si](C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (4.26 g, 17.5 mmol) in 40 mL N,N-dimethylacetamide was added 2-bromo-4-chloroanisole (3.35 mL, 24.6 mmol), palladium (II) acetate (197.2 mg, 0.878 mmol), di(1-adamantyl)-n-butylphosphine (469.5 mg, 1.309 mmol), potassium carbonate (7.27 g, 52.6 mmol), and trimethylacetic acid (0.452 g, 4.43 mmol). While stirring at room temperature, nitrogen gas was bubbled through the reaction mixture for 10 minutes, and the reaction then heated at 120° C. for 6 hours. The reaction was then cooled to room temperature, diluted into ethyl acetate, and washed with water and brine, dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel (0 to 25% ethyl acetate in heptanes) to obtain 6.719 g (89%) of 3-(5-chloro-2-methoxyphenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. LCMS (ESI) m+H=384.2; 1H NMR (400 MHz, CDCl3) δ: 8.22 (s, 1H), 7.46 (d of d, 1H), 7.36 (d, 1H), 6.95 (d, 1H), 5.23 (m, 2H), 3.56 (m, 2H), 0.87 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([CH:11]([C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][C:25]=2[O:27][CH3:28])[NH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])C.O.[OH-].[K+]>C1COCC1.CCO>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]2[NH:20][CH:19]=[C:18]([CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]([C:4]([OH:29])=[O:3])[C:6]([OH:8])=[O:7])[C:26]=12
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1c[nH]c2nccc(OC)c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccnc2[nH]cc(C(c3ccccc3)C(C(=O)O)C(=O)O)c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
To a suspension of 2-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic acid diethyl ester (1.0 g, 2.52 mmol) in a mixture of THF/EtOH (1/1, 24 ml) was added H2O (2 ml) followed by KOH (1.41 g, 25.2 mmol). The reaction mixture was stirred at 50° C. for 4 h, and then cooled to RT and concentrated. The solid residue was dissolved in H2O. The resulting solution was cooled to 0° C. and acidified to pH 4-5 by addition of HCl (I M). The white solid precipitate was collected by filtration, washed with cold H2O and dried to afford 2-[(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic acid (809 mg, 94% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C1C=CC=CC=1.CO>O(CC)CC>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=3[O:3][CH2:1][CH3:2])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: CCOc1ccccc1C(=O)N1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CO
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOc1ccccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
A mixture of 0.96 parts of 1-(2- ethoxybenzoyl)aziridine, 1.06 parts of 4-(4-chlorophenyl)-4-piperidinol, 5.4 parts of benzene and 0.8 parts of methanol is stirred and refluxed for 2 hours. The reaction mixture is cooled. Upon the addition of 1,1'-oxybisethane, the product is precipitated. It is filtered off, crystallized from 2-propanol, filtered off again and dried overnight in vacuo at 80° C, yielding 1.4 parts of N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}-2-ethoxybenzamide; mp. 171°-173° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCCCC3)cc2F)CC1
Yield: 30 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.4 g, 3.1 mmol) by using piperidine (3.1 ml) as an amine to yield the titled compound (487 mg, 30%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O)(=O)=[O:16]>>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][OH:16])=[O:10])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CS(=O)(=O)c1ccc(C(=O)OO)cc1

Procedure:
A stirred mixture of 5 g of 4-(methylsulfonyl)-benzoic acid and 50 mL of methanesulfonic acid froze when it was cooled in an ice bath. The ice bath was removed and when the mixture was partially melted, stirring was resumed and the addition of 2.83 g of 90% hydrogen peroxide was started. The 90% hydrogen peroxide was added gradually over ten minutes. When the addition of the hydrogen peroxide was completed, the reaction mixture was still partially frozen. A water bath of cold tap water was used to warm the reaction mixture. The temperature of the reaction mixture rose briefly to 28° C. One hour after the addition of the hydrogen peroxide was started, the reaction mixture was heated for 70 minutes within a temperature range of 40° C.-45° C. The stirred reaction mixture was then cooled in an ice bath. A solid precipitated from solution. When the temperature of the reaction mixture was between 10° C.-15° C., the solid product was filtered from solution. A second fraction of solid product was collected when the filtrate was poured onto ice prepared from deionized water and the solid which formed was filtered away from solution. Fraction one was washed four times with 60 mL each time of cold deionized water. Fraction two was washed four times with 150 mL each time of cold deionized water. Both fractions of the solid product were very easy to wash and to isolate by filtration. The two fractions were each transferred to a watchglass and dried overnight. The dried solids were fine, dry powders.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].Cl[C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C(#N)C>[CH2:3]([CH:2]([NH:1][C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:5][CH3:6])[CH3:4]
Reactant: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Reactant: CCC(N)CC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1NC(CC)CC

Procedure:
3-Aminopentane (0.6 mL) was added to a solution of ethyl 2-(7-chloro-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (130 mg) in acetonitrile (5 mL), followed by heating under reflux overnight. After cooling the reaction solution, water was added thereto. The mixture was extracted twice with ethylacetate, and the organic layer was washed with an aqueus saturated solution of sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography, to give the title compound (84 mg) as a green oil.
Reaction SMILES: [CH:1]([C@@H:3]1[C@H:8]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4]1)=[CH2:2]>Cl.CO.[Pt]=O>[CH2:1]([C@@H:3]1[C@H:8]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4]1)[CH3:2]
Reactant: C=C[C@H]1CNCC[C@H]1CCc1c[nH]c2ccccc12
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CC[C@H]1CNCC[C@H]1CCc1c[nH]c2ccccc12
Yield: 71.4 %

Procedure:
0.250 g of 3-{[3-(R)vinyl-4(R)piperidyl]-ethyl}-indole in 1 ml of normal hydrochloric acid and 9 ml of methanol in the presence of 0.04 g of platinum oxide as catalyst were hydrogenated for 3 hours at ambient temperature and at atmospheric pressure. The catalyst was filtered, the filtrate evaporated to dryness, the residue made up in 100 ml of water, the aqueous phase washed with ether and alkalinized with an aqueous solution of sodium hydroxide and the insoluble substance was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to dryness under reduced pressure. 0.180 g of product which melted at 150° C. was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.Cl.[CH:31]1([N:34]([CH3:41])[CH2:35][CH:36]=[CH:37][C:38](O)=[O:39])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][CH:22]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][N:13]([C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][N:34]([CH:31]2[CH2:33][CH2:32]2)[CH3:41])[CH2:12]1
Reactant: Nc1ncnc2c1n(-c1ccc(Oc3ccccc3)cc1)c(=O)n2[C@@H]1CCNC1
Reactant: CN(CC=CC(=O)O)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
A solution of (R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one (62) (95 mg, 0.24 mmol), 4-(cyclopropyl(methyl)amino)but-2-enoic acid hydrochloride (69 mg, 0.36 mmol) and DIPEA (213 μL, 1.2 mmol) in 5 mL dry DMF was cooled to 0° C. HBTU (190 mg, 0.49 mmol) was added in one portion. The reaction mixture was allowed to warm to rt, and stirred for 2 hrs under N2, then purified directly by Gilson using 10 to 95% acetonitrile in water (0.2% NH3.H2O) to give (R,E)-6-amino-9-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (63) (31 mg, 17.7%) as a light yellow solid. LC-MS (ESI): m/z (M+1) 526. 1H NMR (400 MHz, DMSO) δ 8.14 (d, J=6.0 Hz, 1H), 7.55-7.34 (m, 4H), 7.30-7.08 (m, 5H), 6.76-6.59 (m, 1H), 6.36 (dd, J=37.4, 15.1 Hz, 1H), 5.82 (d, J=9.1 Hz, 2H), 5.20-4.99 (m, 1H), 4.11-3.40 (m, 4H), 3.26 (dd, J=17.7, 6.4 Hz, 2H), 2.78-2.59 (m, 1H), 2.24 (d, J=12.4 Hz, 3H), 1.80-1.63 (m, 1H), 0.51-0.37 (m, 2H), 0.37-0.24 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH2:13][CH2:12][CH:11]([C:14]([F:17])([F:16])[F:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:23])=[CH:25][CH:26]=3)[CH2:13][CH2:12][CH:11]([C:14]([F:15])([F:16])[F:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C2(c3ccc(O)cc3)CCC(C(F)(F)F)CC2)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C2(c3ccc(O)cc3)CCC(C(F)(F)F)CC2)cc1
Temperature: 50 °C

Procedure:
To a solution of the title compound of Example 4, Step A (43 mg, 0.09 mmol), β-alanine ethyl ester hydrochloride (28 mg, 0.18 mmol), HOBt (28 mg, 0.18 mmol) and EDC (35 mg, 0.18 mmol) in 1 mL of DMF was added DIEA (0.047 mL, 0.27 mmol). The reaction was heated at 50° C. for 1.5 h, then partitioned between EtOAc/brine. The organic layer was collected and the aqueous layer was washed twice with EtOAc. The combined organic phase was concentrated under reduced pressure to provide the title compound. LC-MS (ESI): m/z=464.3 [M+1]+.