Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Si](C)(C)C.CC(O[O:10][P:11]([CH2:18][P:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([O:21]C(C)C)=[O:20])(=[O:17])[O:12]OC(C)C)C.C(N(CCCC)CCCC)CCC.[Na+:55].[I-].CC(C)=O>CO>[Na+:55].[Na+:55].[Na+:55].[CH2:25]([P:19]([CH2:18][P:11](=[O:10])([O-:17])[O-:12])([OH:21])=[O:20])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCCCP(=O)(CP(=O)(OOC(C)C)OOC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCCCCCP(=O)(O)CP(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Bromotrimethylsilane (0.34 mL, 2.58 mmol) was added dropwise to ((n-heptadecyl)-2-propoxyphosphinyl) methylphosphonic acid di-2-propoxy ester (0.150 g, 0.286 mmol) in a 3 mL vial. The resulting solution was stirred for 14–16 hours at ambient temperature. Excess bromotrimethylsilane was then removed by passing a steady stream of dry nitrogen over the solution for 2 hours. The solution was then placed under high vacuum for 3 hours to remove any residual bromotrimethylsilane. Tributylamine (0.24 g, 1.29 mmol) and methanol (2 mL) were then added to the vial resulting in a clear solution. This solution was then added dropwise to a 0.5 M solution of NaI in acetone (5.0 mL, 2.5 mmol). A white precipitated immediately appeared. The solid was collected by centrifugation and the acetone solution was discarded. The solid was then washed by suspension in clean acetone (20 mL), centrifugation and removal of acetone supernatant. After this washing procedure was completed 3 times, the solid was placed under vacuum for a period of 12–16 hours providing the desired product (0.113 g, 85% yield). 1H NMR (400 MHz D2O): δ 1.7 (m, 2H), 1.3 (m, 4H), 1.1 (m, 28H), 0.7 (t, 3H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:22].O1CCOCC1.CCOCC>ClCCl>[ClH:22].[NH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(SCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc(SCCN)cc1

Procedure:
A solution of methyl 4-(2-tert-butoxycarbonylaminoethylsulfanyl)benzoate (1.00 g, 3.21 mmol) in dichloromethane (8 ml) was treated with a solution of HCl in dioxane (4M, 8 ml, 10 eq.) at room temperature for 3 h. Ether (100 ml) was added and the mixture was filtered, washed with ether and pumped dry to give methyl 4-(2-aminoethylsulfanyl)benzoate hydrochloride.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C=O)C.CCCCC>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]=[N+:2]=[N-:3])[CH3:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCOC(=O)CCCCCCN=[N+]=[N-]
Reaction time: 16 h
Yield: 95.1 %

Procedure:
Sodium azide (1.7 g, 0.026 mol) was added to ethyl 7-bromoheptanoate 1 (4.1 g, 0.017 mol) in DMF (40 mL) at 23° C. The reaction was stirred for 16 h, diluted with pentane and washed with water. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 3.22 g (95%) of the azide 2 as a clear, colorless liquid.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](OCC)=[O:18])[C@@H:12]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:9][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][OH:18])[C@@H:12]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C[C@H]2[C@@H](CO)CCCN2C)cc1

Procedure:
Reduction of 8.2 g. of cis ethyl 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-piperidinecarboxylate with 1.52 g. of lithium aluminum hydride in 97 ml. of tetrahydrofuran yielded cis-1-methyl-2-(p-methoxybenzyl)-3-piperidinemethanol, isolated as its hydrochloride (in a yield of 2.8 g.), a white crystalline solid which melted at 185°-186° C. trans-1-Methyl-2-(p-methoxybenzyl)-3-piperidinemethanol, a white crystalline solid which melted at 66°-68° C., can be obtained in similar fashion.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.Cl>O.CO.C1C=CC=CC=1>[C:3]([CH:15]1[CH2:16][CH:11]([O:10][CH3:9])[CH2:12][CH2:13][C:14]1=[O:17])(=[O:5])[CH3:4]
Reactant: CCOC(C)=O
Reactant: COC1CCC(=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: COC1CCC(=O)C(C(C)=O)C1
Reaction time: 3 h

Procedure:
1.12 g of 60% sodium hydride was added to 2.5 g of ethyl acetate and 1.78 g of a benzene solution of 4-methoxycyclohexanone was added thereto. After reacting at 40° C. for three hours, methanol was added to thereby decompose excessive sodium hydride and the reaction mixture was poured into water, neutralized with hydrochloric acid and extracted with ether to give 1.02 g of 2-acetyl4-methoxycyclohexanone. NMRδTMSCCl4 : 2.06 (3H, s). 1.7-2.5 (8H, s), 3.28 (3H , s), 3.4 (1H, m) and 15.9 (1H, s).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH3:28][NH:29][O:30][CH3:31].Cl>ClCCl.O>[CH3:31][O:30][N:29]([CH3:28])[C:11]([CH2:10][CH2:9][C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8])=[O:13]
Reactant: CNOC
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 34.6 %

Procedure:
3-Benzoylpropionic acid (3.56 g, 20.0 mmol) was dissolved in dichloromethane (50 mL), to the solution was added triethylamine (2.22 g, 22.0 mmol) and trimethylacetyl chloride (2.41 g, 20.0 mmol) at 0° C., and the mixture was stirred at room temperature for 60 hours. Subsequently, to the reaction mixture was successively added triethylamine (4.04 g, 40.0 mmol) and N,O-dimethylhydroxylamine (1.95 g, 20.0 mmol), and the mixture was further stirred at room temperature for 5 hours. To the reaction mixture was added water and 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with aqueous sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (chloroform/methanol=50/1→40/1) to give 3-(N-methoxy-N-methylcarbamoyl)-propiophenone (1.53 g, 35%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]4[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:17][C:15]4=3)[C:10](=[O:28])[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.[Cl:29][C:30]1[S:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1.B.N1C=CC=CC=1C.C(O)(=O)C>CO>[Cl:29][C:30]1[S:34][C:33]([CH2:35][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]5[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[CH:18]=[CH:17][C:15]5=4)[C:10](=[O:28])[CH:9]=[CH:8]3)[CH2:3][CH2:2]2)=[CH:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)ccn(C3CCNCC3)c12
Reactant: O=Cc1ccc(Cl)s1
Agent: B
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccn1
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)ccn(C3CCN(Cc4ccc(Cl)s4)CC3)c12
Yield: 75.6 %

Procedure:
1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (20 mg, 0.050 mmol) in methanol was stirred with 5-chlorothiophen-2-carbaldehyde (6.3 μL, 0.06 mmol), 2-picoline borane (6.4 mg, 0.06 mmol) and acetic acid (100 μL) for one day. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=10/1 (v/v)) to give the title compound as a colorless oil (20 mg, yield 75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([CH2:21][CH2:22][C:23]2[S:24][C:25]([CH2:29][CH3:30])=[C:26]([CH3:28])[N:27]=2)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]=[C:42]([CH2:44]Cl)[CH:43]=1)[C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:14]=[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:12]=[C:11]([CH2:21][CH2:22][C:23]2[S:24][C:25]([CH2:29][CH3:30])=[C:26]([CH3:28])[N:27]=2)[N:10]=1)[CH2:44][C:42]1[CH:41]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[CH:35]=[C:34]([Cl:33])[CH:43]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)cc(CCl)c1
Reactant: CCc1sc(CCc2cc(N3CCOCC3)cc(NC(=O)OC(C)(C)C)n2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1sc(CCc2cc(N3CCOCC3)cc(N(Cc3cc(Cl)cc(C(=O)OC)c3)C(=O)OC(C)(C)C)n2)nc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-tert-butoxycarbonylamino-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine (500 mg) obtained in Example 109-(1) was dissolved in dimethylformamide (12 ml), and 60% sodium hydride (58 mg) was added under cooling with ice, followed by stirring at room temperature for one hour. The reaction solution was cooled with ice, and a solution of methyl 3-chloro-5-chloromethylbenzoate (438 mg) in dimethylformamide (5 ml), was added thereto, followed by stirring at room temperature for 13 hours. The reaction solution was diluted with ethyl acetate, washed with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the above identified compound (628 mg).
Reaction SMILES: [C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[OH:19])[CH2:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O[C:21]1C=CC=[C:25]2[C:30]=1[NH:29][CH2:28][CH2:27][CH2:26]2.Cl.C(Cl)(=[O:39])C1C=CC=NC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:19][CH2:26][CH:27]([OH:39])[CH2:28][NH:29][CH:30]([CH3:25])[CH3:21])[CH2:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(c1cccnc1)N1CCCc2cccc(O)c21
Reactant: Oc1cccc2c1NCCC2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)NCC(O)COc1cccc2c1N(C(=O)c1cccnc1)CCC2

Procedure:
40 g of 1-nicotinoyl-8-hydroxy-1,2,3,4-tetrahydroquinoline ##STR9## are dissolved in 300 ml of dimethylformamide and 21 g of potassium tert.-butylate are then added at 5° C., while stirring. The mixture is stirred at 5° C. for 20 minutes, 66 g of epichlorohydrin are then added dropwise at this temperature, while stirring, and the mixture is then allowed to warm to room temperature and is subsequently stirred for 20 hours. Thereafter, the mixture is concentrated under a waterpump vacuum. The oil which remains is dissolved in water/toluene; the toluene phase is separated off, washed twice with dilute aqueous sodium hydroxide solution and once with water, dried and concentrated under a waterpump vacuum. A solid residue, which can be reacted directly with isopropylamine to give 1-nicotinoyl-8-[(3-isopropylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydroquinoline, remains. The 1-nicotinoyl-8-hydroxy-1,2,3,4-tetrahydroquinoline used as the starting material is obtained in the customary manner by reacting 8-hydroxy-1,2,3,4-tetrahydroquinoline with nicotinic acid chloride hydrochloride in toluene at room temperature in the presence of triethylamine. (Melting point: 122° C.).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C@@H:6]1[CH2:28][C:27]2[C:29](=[O:30])[C:22](=[CH:23][C:24]([C:26]=2OC)=[O:25])[NH:21][C:19](=[O:20])[C:18]([CH3:33])=[CH:17][CH:16]=[CH:15][C@H:14]([O:34][CH3:35])[C@@H:13]([O:36][C:37]([NH2:39])=[O:38])[C:12]([CH3:40])=[CH:11][C@H:10]([CH3:41])[C@@H:9]([OH:42])[C@@H:8]([O:43][CH3:44])[CH2:7]1.[CH2:45]([NH2:48])[CH2:46][CH3:47].Cl>O>[CH3:47][CH2:46][CH2:45][NH:48][C:26]1[C:24](=[O:25])[CH:23]=[C:22]2[C:29](=[O:30])[C:27]=1[CH2:28][CH:6]([CH3:5])[CH2:7][CH:8]([O:43][CH3:44])[C@@H:9]([OH:42])[C@H:10]([CH3:41])[CH:11]=[C:12]([CH3:40])[CH:13]([O:36][C:37]([NH2:39])=[O:38])[CH:14]([O:34][CH3:35])[CH:15]=[CH:16][CH:17]=[C:18]([CH3:33])[C:19]([NH:21]2)=[O:20]
Reactant: CCCN
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Agent: CCCNC1=C2CC(C)CC(OC)[C@@H](O)[C@H](C)/C=C(\C)C(OC(N)=O)C(OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCNC1=C2CC(C)CC(OC)[C@@H](O)[C@H](C)C=C(C)C(OC(N)=O)C(OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 50 ml. of chloroform, 280 mg. of Geldanamycin was dissolved and then, 1 ml. of n-propylamine was added. The mixture was stirred at room temperature for 1 hour and the mixture was charged into 50 ml. of cold water and then, pH was adjusted 3 with 6 N-HCl. The chloroform layer was separated and the water layer was extructed with 50 ml. of chloroform. Both chloroform layers were combined and dehydrated over anhydrous sodium sulfate for 2 hours. Chloroform was distilled off under a reduced pressure to remain a reddish violet solid product. The solid product was recrystallized from acetone-n-hexane to obtain 286 mg. (yield 98%) of 17-n-propylamino-Geldanamycin as reddish violet acicular crystal.
Reaction SMILES: [CH2:1]([N:8]1[C:13](Cl)=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([OH:28])[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13]([O:28][C:21]2[CH:20]=[CH:19][C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=2)=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Cl)=N1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Oc2ccc([N+](=O)[O-])cc2)=N1

Procedure:
A solution of 2-benzyl-3-chloro-5-methoxy-2H-1,2,4,6-thiatriazine-1,1-dioxide (3.8 g) in methylene chloride (10 ml) is added dropwise to a stirred mixture of p-nitrophenol (1.7 g) and pyridine (2.4 g) in methylene chloride (20 ml). The reaction mixture is heated to reflux for 3 hours, cooled, washed with 3N aq. HCl and sat'd aq. Na2CO3. The methylene chloride layer is dried, filtered and evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]3[CH2:20][CH2:21][CH2:22][C:15]=3[C:14]=2[CH:23]=1)(=O)=O.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH3:25][O:24][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:35]2[CH2:36][CH2:37][CH:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)=[CH:23][C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:16]=3[C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCC(c2ccccc2)CC1)CCC3
Yield: 65 %

Procedure:
Method B (60 h at 25° C.); starting materials: 2,3-dihydro-8-[3-(methanesulfonyloxy)propoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 82) and 4-phenylpiperidine; yield 65%; fusion point 164°-166° C. (from isopropanol). Fumarate: method E; yield 86%; fusion point 195°-198° C. (from ethanol).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[N+:10]([CH3:13])([O-:12])=[O:11].[O-]CC.[Na+].C(O)C.C(O)(=O)C>C(O)C>[N+:10]([CH2:13][C:3]1([OH:9])[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CN2CCC1CC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A mixture of 3-quinuclidinone (24.4 g, 0.195 mole) and nitromethane (15.9 g, 0.260 mole) in absolute ethanol (100 ml) was added to a cooled (0° C.) mechanically stirred solution of 21% sodium ethoxide/ethanol (64.8 g, 200 mole) in absolute ethanol (300 ml) under nitrogen. The mixture was stirred at room temperature for one hour, then at 55°(±5°) C. for 18 hours. The cooled suspension was treated dropwise with acetic acid (13.2 g, 0.220 mole), filtered through Celite®, washed with methanol, and concentrated in vacuo. The residue was filtered through alumina (eluted with 1:2 methylene chloride/methanol), concentrated in vacuo, and triturated from acetonitrile to afford 8.44 g (23%) of the title compound as an off-white solid.
Reaction SMILES: Cl.[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1.C(N(CC)C(C)C)(C)C.CC1(C)O[C@H](CN2C=CC(NC(=O)[C@@H](N3[CH2:53][C:52]([O:54][C:55]4[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=4[F:65])=[CH:51][C:50]3=[O:66])CC(C)C)=N2)CO1>C(#N)C>[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([N:17]2[CH2:53][C:52]([O:54][C:55]3[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=3[F:65])=[CH:51][C:50]2=[O:66])[CH2:13][CH:14]([CH3:15])[CH3:16])=[N:6]1
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccn(CC(C)(C)O)n1
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A suspension of (S)-2-amino-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]amide hydrochloride salt (2.0 g, 5.8 mmol) in acetonitrile (25 mL) was treated with N,N-diisopropylethylamine (4.0 mL) and stirred at 60° C. for 15 min. At this time N,N-diisopropylethylamine (2.5 mL) and a solution of (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 116, 1.37 g, 3.75 mmol) in acetonitrile (10 mL) were added and the resulting solution refluxed for 48 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (295 mg, 16%): HR-ES-MS (m/z) calculated for C25H32F2N4O5 [M+H]+ 507.2414, observed 507.2414; 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (br. s., 6H), 1.13 (br. s., 6H), 1.42 (br. s., 3H), 1.48-1.64 (m, 1H), 1.66-1.95 (m, 2H), 3.73 (br. s., 1H), 3.91 (br. s., 2H), 4.01-4.24 (m, 3H), 4.38 (d, J=17.8 Hz, 1H), 4.88 (br. s., 1H), 4.99 (br. s., 1H), 6.66 (br. s., 1H), 6.73-7.00 (m, 2H), 7.27 (br. s., 1H), 8.79 (br. s., 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])OCC1CO1>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:41][CH:31]([OH:30])[CH2:32][C:33]3[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Reactant: COc1cc(OCC2CO2)cc(OC)c1OC
Solvent: CC(C)O
Product: COc1cc(CC(O)CN2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)cc(OC)c1OC
Temperature: 70 °C
Yield: 121 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (150.7 mg; 0.4 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (+/−)-2-(3,4,5-Trimethoxy-phenoxymethyl)-oxirane(95.2 mg; 0.4 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (10%→100% acetone in hexanes) affording the desired product (145.9 mg) as an oil. ESMS: MH+ 619.4 (base).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH2:12][CH2:13][C:14]([OH:16])=O)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[CH2:17]([NH:19][CH2:20][CH2:21][OH:22])[CH3:18].Cl.C(N=C=NCCCN(C)C)C.O.[OH:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38]1.CN1CCOCC1>CN(C=O)C>[N:37]1([O:36][C:2]2[C:3]3[N:4]([C:8]([CH2:12][CH2:13][C:14]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][OH:22])=[O:16])=[N:9][C:10]=3[I:11])[CH:5]=[CH:6][N:7]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CCc1nc(I)c2c(Cl)nccn12
Reactant: CCNCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CCO)C(=O)CCc1nc(I)c2c(On3nnc4ccccc43)nccn12

Procedure:
A mixture of EXAMPLE 74B (1.3 g), 2-(ethylamino)ethanol (0.363 g), 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride (0.78 g), 1-hydroxybenzotriazole hydrate (0.623 g), and N-methylmorpholine (0.748 g) in 5 mL DMF was stirred at room temperature for 10 hours. The reaction mixture was extracted with ethyl acetate 3 times and the combined extracts were washed (brine), dried (MgSO4) and concentrated. The residue was purified by flash chromatography with 0-4% methanol/CH2Cl2 to afford 3-(8-(1H-benzo(d)(1,2,3)triazol-1-yloxy)-1-iodoimidazo[1,5-a]pyrazin-3-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide. MS (ESI(+)) m/e 522 (M+H)+ This product was placed in a high pressure tube with 7N ammonia (15 ml) in methanol, heated at 60 C overnight then concentrated to dryness. The residue was purified by flash column with 0-10% methanol/CH2Cl2 to give the title compound. MS (ESI(+)) m/e 404 (M+H)+
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]1[O:11][C:10]2[C:5](=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:4]=[C:3]([Si:2]([CH3:14])([CH3:13])[CH3:1])[O:11][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[Si](C)(C)c1cc2c(ccc[n+]2[O-])o1
Product: C[Si](C)(C)c1cc2nccc(Cl)c2o1
Temperature: 25 °C

Procedure:
A solution of 2-(trimethylsilyl)furo(3,2-b)pyridine N-oxide (32 g, 0.153 mol) in POCl3 (150 ml) is heated to 100° C. for 2 h in a sealed pressure tube. The reaction mixture is cooled to RT, concentrated under vacuum, the residue is dissolved in DCM (500 ml), washed with saturated sodium bicarbonate (100 ml×2), water (50 ml×2) and with sat brine (50 ml), dried over sodium sulphate and concentrated under vacuum. The crude material is purified by column chromatography by using petrolether/ethyl acetate (9:1) as an eluent to afford the title compound as (18 g, 52%) light brown oil. TLC: hexane/ethyl acetate: (8/2): Rf=0.80; 1H NMR (DMSO-d6, 400 MHz) δ [ppm] 8.461-8.448 (1H, d, J=5.2 Hz), 7.502-7.477 (2H, m), 0.372-0.355 (9H, s); LCMS (method C): 3.29 min (purity 95.8%), M+H+ 226.0.