Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1.Cl[C:13]1[C:18]([CH3:19])=[N:17][CH:16]=[CH:15][N:14]=1>>[CH3:19][C:18]1[C:13]([NH:1][CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([CH2:10][OH:11])[CH2:8][CH2:9]2)=[N:14][CH:15]=[CH:16][N:17]=1
Reactant: NCCN1CCC(CO)CC1
Reactant: Cc1nccnc1Cl
Product: Cc1nccnc1NCCN1CCC(CO)CC1
Temperature: 120 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
A mixture of 1-(2-amino-ethyl)-4-piperidinemethanol (5.2 g), 2-chloro-3-methyl-pyrazine (5.0 g) and CaO (4.5 g) was stirred for 20 hours at 120° C. The reaction mixture was cooled and purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 92/8). The pure fractions were collected and the solvent was evaporated, yielding 2.3 g (29%) 1-[2-[(3-methyl-2-pyrazinyl)amino]-ethyl]4-piperidinemethanol (intermediate 1).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[CH2:12][CH2:13][NH2:14]>CO>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[CH2:12][CH2:13][NH:14][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: NCCc1cccc(F)c1
Solvent: CO
Product: CCOC(=O)CNCCc1cccc(F)c1

Procedure:
Ethyl bromoacetate (0.166 g, 0.11 mL, 0.001 mol) and 3-fluorophenethylamine (0.139 g, 0.13 mL, 0.001 mol) were stirred in MeOH (10 mL) for 48 h. The solvent was removed in vacuo, and the residue was purified by column chromatography (silica gel, hexanes:EtOAc=2:3) to generate VIII-3 (0.083 g, 37%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[CH3:16][N:17]([CH2:28][C:29]#[CH:30])[C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.CCCCCCC>CN(C=O)C.[Cu]I.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.CCOC(C)=O>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:30]#[C:29][CH2:28][N:17]([CH3:16])[C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: C#CCN(C)C(=O)OCc1ccccc1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CC(O)c1oc(=O)c2ccccc2c1C#CCN(C)C(=O)OCc1ccccc1
Temperature: 95 °C
Yield: 91.5 %

Procedure:
To a solution of 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 2.65 g, 9.84 mmol) in dry DMF (30 ml), benzyl methyl(prop-2-yn-1-yl)carbamate (Intermediate G22, 4 g, 19.68 mmol), copper(I) iodide (0.562 g, 2.95 mmol), tetrakis(triphenylphosphine)palladium(0) (1.946 ml, 1.476 mmol), benzyl methyl(prop-2-yn-1-yl)carbamate (4 g, 19.68 mmol) and triethylamine (4.04 ml, 29.5 mmol) were added. The resulting suspension was heated to 95° C. overnight. Then, solvent was removed under reduced pressure. The product was purified by Biotage Si 10 g with a gradient of heptane and EtOAc affording the title compound (3.524 g, 9.00 mmol, 91% yield) a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1O[C:5](=[O:7])[NH:4][N:3]=1.[NH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CO>[CH3:1][C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:7])[NH:4][N:3]=1
Reactant: NC1CCOCC1
Reactant: Cc1n[nH]c(=O)o1
Solvent: CO
Product: Cc1n[nH]c(=O)n1C1CCOCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
After dissolving 5-methyl-3H-[1,3,4]oxadiazol-2-one (CAS 3069-67-8) (500 mg) in methanol (5 ml), 4-aminotetrahydropyran (1.01 g) was added and the mixture was heated to reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, and then a 1N aqueous solution of sodium hydroxide (5.5 ml) was added to the residue and the mixture Was stirred at 100° C. for 2 hours. After then adding 5N hydrochloric acid (1.1 ml) to the reaction mixture, it was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with water and ethyl acetate in that order to obtain the title compound (400 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([OH:17])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9].[H-].[Na+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([O:17][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C(O)CCNC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CCNC(=O)c1ccc(Cl)cc1)OCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 165.6 %

Procedure:
A solution of 4-(N-(4-chlorophenylcarbonyl)amino)-2-hydroxybutyric acid methyl ester (3 g) in tetrahydrofuran (15 ml) was dropped to a mixture of 60% sodium hydride (2.38 g) in tetrahydrofuran (10 ml) at −78° C. The mixture was stirred at 0° C. for 30 minutes. t-Butyl bromoacetate (0.975 g) was dropped to the mixture at −78° C. The mixture was stirred at 0° C. for 1.5 hours. To the reaction mixture, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-Hexane:Ethyl acetate=1:1) to give the title compound (3.194 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]=[O:22])=[N:6][CH:7]=1.[CH3:23][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]([OH:22])[CH3:23])=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Temperature: 25 °C

Procedure:
To a solution of 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carbaldehyde (intermediate B4.1, 0.05 g, 0.15 mmol) in THF (1.3 ml) was added 3M methylmagnesium bromide (0.06 ml, 0.18 mmol) at 0° C. The reaction was allowed to warm to rt and satd. aq. NH4Cl was added. Extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, concentrated and purified by flash chromatography (silica, 20-50% EtOAc/hexanes) to give 1-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}ethanol. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, 2.5 Hz, 1H), 8.06 (m, 2H), 7.52 (dd, J=8.4, 2.5 Hz, 1H), 7.12 (m, 3H), 5.02 (m, 1H), 3.22 (d, J=5.2 Hz, 1H), 1.56 (m, 3H); LCMS [M+H]+=351.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:17][C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1.CO>[C:18]([CH2:17][C@H:16]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([Cl:8])[CH:4]=2)=[CH:10][CH:11]=1)([OH:20])=[O:19]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)NC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Reaction time: 4.5 h
Yield: 70.2 %

Procedure:
To a solution of (R)-4-(1-(2′,5′-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (106 mg, 0.234 mmol) in THF (2 ml) and MeOH (0.1 ml), 1M aqueous NaOH solution (1.406 mL, 1.406 mmol) is added at room temperature. After stirring for 4.5 hours, the reaction is quenched with 0.1 M aqueous HCl (3 ml), and the products are extracted with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude is triturated in DCM. The precipitates are collected on a funnel, washed with DCM, and dried under reduced pressure to give (R)-4-(1-carboxy-3-(3′-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoic acid (64.0 mg) as white solid; HPLC retention time=1.24 minutes (condition A); MS (m+1)=424.07; 1H NMR (400 MHz, CD3OD) δ ppm 2.38-2.42 (m, 2H) 2.45-2.57 (m, 4H) 2.87 (A of ABX, Jab=13.6 Hz, Jax=7.6 Hz, 1H) 2.95 (B of ABX, Jab=13.6 Hz, Jbx=6.1 Hz, 1H) 4.44-4.51 (m, 1H) 7.30-7.37 (m, 6H) 7.47 (d, J=8.4 Hz, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2.[OH-].[Na+]>S(=O)(=O)(O)O.O1CCOCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:14]3[CH:15]4[CH2:18][CH2:19][N:11]([CH2:12][C:13]=3[C:5]=2[CH:4]=1)[CH2:17][CH2:16]4
Reactant: O=C1CCN2CCC1CC2
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of (4-fluorophenyl)hydrazine hydrochloride (10.67 g, 65.6 mmol; Aldrich) and 1-azabicyclo[3.2.2]nonan-4-one (9.13 g, 65.6 mmol; Example 2A) in 100 mL of 7% sulfuric acid in dioxane was heated to 100° C. for 30 hours. The reaction mixture was basified (˜pH 11) by the addition of 50% aqueous sodium hydroxide then stirred in an ice-bath for 30 minutes. The resulting solid was collected by filtration, washed sequentially with water, hexanes and ether (3×30 mL), and dried to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ 2.06 (m, 4H), 3.03 (m, 3H), 3.23 (m, 2H), 3.65 (s, 1H), 4.18 (s, 2H), 6.77 (ddd, J=2.6, 8.8, 9.6 Hz, 1H), 6.94 (dd, J=2.8, 9.6 Hz, 1H), 7.20 (dd, J=4.0, 8.8 Hz, 1H); MS (ESI) m/z 231 (M+H)+.
Reaction SMILES: C(O)C(N)(CO)C[OH:4].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OP(O)(O)=O)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O.[CH3:73][C:74]1[S:78][CH:77]=[C:76](/[CH:79]=[C:80](/[C@H:82]2[O:99][C:97](=[O:98])[CH2:96][C@H:95]([OH:100])[C:94]([CH3:102])([CH3:101])[C:92](=[O:93])[C@H:91]([CH3:103])[C@@H:90]([OH:104])[C@@H:89]([CH3:105])[CH2:88][CH2:87][CH2:86][C:85]([CH3:106])=[CH:84][CH2:83]2)\[CH3:81])[N:75]=1>>[CH3:105][C@@H:89]1[C@H:90]([OH:104])[C@@H:91]([CH3:103])[C:92](=[O:93])[C:94]([CH3:102])([CH3:101])[C@@H:95]([OH:100])[CH2:96][C:97](=[O:98])[O:99][C@H:82](/[C:80](/[CH3:81])=[CH:79]/[C:76]2[N:75]=[C:74]([CH3:73])[S:78][CH:77]=2)[CH2:83][C@@H:84]2[O:4][C@:85]2([CH3:106])[CH2:86][CH2:87][CH2:88]1
Reactant: NC(CO)(CO)CO
Reactant: CC1=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: 90 °C
Reaction time: 1.12 h

Procedure:
The EpoK assay was performed as follows (See Betlach et al., Biochem (1998) 37:14937, incorporated herein by reference). Briefly, reactions consisted of 50 mM Tris (pH7.5), 21 μM spinach ferredoxin, 0.132 units of spinach ferredoxin: NADP+ oxidoreductase, 0.8 units of glucose-6-phosphate dehydrogenase, 1.4 mM NADP, and 7.1 mM glucose-6-phosphate, 100 μM or 200 μM epothilone D (a generous gift of S. Danishefsky), and 1.7 μM amino terminal his tagged EpoK or 1.6 μM carboxy terminal his tagged EpoK in a 100 μL volume. The reactions were incubated at 30° C. for 67 minutes and stopped by heating at 90° C. for 2 minutes. The insoluble material was removed by centrifugation, and 50 μL of the supernatant were analyzed by LC/MS. HPLC conditions: Metachem 5μ ODS-3 Inertsil (4.6×150 mm); 80% H2O for 1 min, then to 100% MeCN over 10 min at 1 mL/min, with UV (λmax=250 nm), ELSD, and MS detection. Under these conditions, epothilone D eluted at 11.6 min and epothilone B at 9.3 min. the LC/MS spectra were obtained using an atmosphere pressure chemical ionization source with orifice and ring voltages set at 20 V and 250 V, respectively, at a mass resolution of 1 amu. Under these conditions, epothilone E shows an [M+H] at m/z 493, with observed fragments at 405 and 304. Epothilone B shows an [M+H] at m/z 509, with observed fragments at 491 and 320.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[CH2:11][C:12]([NH2:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([NH2:14])=[O:13]
Reactant: NC(=O)CBr
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)COc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
To a solution of 3-hydroxybenzyl alcohol (500 mg, 4 mmol) in acetonitrile (10 mL) was added 2-bromoacetamide (1 eq) and potassium carbonate (1 eq). The resulting suspension was stirred at rt for 18 h. The solvent was removed in vacuo and the residue partitioned between EtOAc and H2O. The aqueous layer was acidified with dilute HCl (2M) and then re-extracted with EtOAc (3×50 mL). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (EtOAc: methanol) to give 2-(3-(hydroxymethyl)phenoxy)acetamide (320 mg, 43%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17](=[O:19])[CH3:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C:7]2[CH:16]=[C:15]([CH:17]([OH:19])[CH3:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cc(-c2ccccc2)nc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(-c2ccccc2)nc2ccccc12
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To 1-(2-phenylquinolin-4-yl)-ethanone (0.233 g, 0.943 mmol) in 5 ml methanol, at room temperature sodium borohydride (0.036 g, 0.943 mmol) was added and the solution stirred for 30 minutes. The reaction mixture was concentrated and partitioned between EtOAc (10 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified (hexane:EtOAc; 3.5:1.5) to give 0.145 g (62%) of the product as a syrup which was used as such for the subsequent step.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[S:15]C#N)[NH:11][C:10](=[O:18])[C:9](=[O:19])[NH:8]2)([CH3:4])([CH3:3])[CH3:2].S.[Na].[BH4-].[Na+].CO>CC(O)=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[SH:15])[NH:11][C:10](=[O:18])[C:9](=[O:19])[NH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2[nH]c(=O)c(=O)[nH]c2cc1SC#N
Agent: S
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)c1cc2[nH]c(=O)c(=O)[nH]c2cc1S

Procedure:
The title compound was prepared according to General Method 14b using 6-tert-butyl-7-thiocyanato-1,4-dihydro-quinoxaline-2,3-dione (prepared in Example CCC; 1.5 g, 9.1 mmol), sodium hydrogen sulfide (0.51 g, 27 mmol), sodium borohydride (2.1 g, 55 mmol), MeOH (30 mL), H20 (3 mL), and glacial AcOH (5 mL). The crude product was used without purification. MS(APCI): 251 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:28][CH2:29][O:30]C3CCCCO3)[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH2:28][CH2:29][OH:30])[S:24]([CH3:27])(=[O:25])=[O:26])=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N(CCOC4CCCCO4)S(C)(=O)=O)cc3)CC2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N(CCO)S(C)(=O)=O)cc3)CC2)c(C)c1
Temperature: 25 °C

Procedure:
Using N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}methanesulfonamide (271 mg) described in Example 461 and 2-(2-bromoethoxy)tetrahydropyran (1.21 mL) and by the reaction and treatment in the same manner as in Example 36, N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-N-[2-(tetrahydropyran-2-yloxy)ethyl]methanesulfonamide was obtained. The obtained N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-N-[2-(tetrahydropyran-2-yloxy)ethyl]methanesulfonamide was dissolved in methanol (5 mL), p-toluenesulfonic acid 1 hydrate (121 mg) was added, and the mixture was stirred at room temperature. To the reaction mixture was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (185 mg).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[N:10]=[C:9]2[Br:21].[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[Br:21][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:5]3[N:4]=[N:3][N:2]([C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:1]=3)[CH:7]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3nn[nH]n3)cc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1nn(C2CCCCO2)c2ccc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(2H-1,2,3,4-tetrazol-5-yl)-3-bromo-1H-indazolyl)perhydro-2H-pyran (0.554 g, 1.59 mmol) in dimethyl formamide (5 mL) was added triphenylmethyl chloride (0.662 g, 2.38 mmol), and triethyl amine (1.110 mL, 7.95 mmol). The reaction was heated to reflux temperature for 3.5 hours and maintained at room temperature overnight. The solvent was removed under reduced pressure. The resulting solid was dissolved in 20 mL of ethyl acetate and was washed with 10 ml-portions of water. The title compound was purified by column chromatography (SiO2, 20% ethyl acetate in hexanes) (0.754 g, 70%): ES-MS (m/z) mass not detected.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@H:13]2[C@H:11]([O:12]2)[C@H:10]1[CH:15]([F:20])[C:16]([O:18][CH3:19])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.C([Al](CC)CC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C1COCC1>[Si:1]([O:8][C@@H:9]1[CH2:14][C@H:13]([OH:12])[C@@H:11]2[C@H:10]1[C@@:15]2([F:20])[C:16]([O:18][CH3:19])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C(F)[C@@H]1[C@H]2O[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC[Al](CC)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@]1(F)[C@@H]2[C@H]1[C@@H](O)C[C@H]2O[Si](C)(C)C(C)(C)C
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A THF (270 mL) solution of the compound of Formula 13a thus obtained was cooled to −50° C., and 210 mL (197.40 mmol) of a 0.94 mol/L triethylaluminum hexane solution was added thereto over 30 minutes while keeping the internal temperature between −55° C. and −50° C. After stirring at −50° C. for 30 minutes, 143 mL (228.80 mmol) of a 1.6 mol/L lithium hexamethyldisilazide (LiHMDS) hexane solution was added thereto over 10 minutes while keeping the internal temperature between −50° C. and −40° C. After stirring at −50° C. for 2 hours the reaction mixture was added over 20 minutes to 265.08 g of a 25% citric acid aqueous solution cooled at 5° C. 270 mL of ethyl acetate was added to the reaction mixture, which was stirred and then separated. Extraction was carried out with 100 mL of ethyl acetate, the organic layers were combined, washed with 50 mL of water, and then concentrated under reduced pressure, thus giving 56.65 g of methyl (1R,2R,4S,5S,6R)-2-[(tert-butyl(dimethyl)silyl]oxy)-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-6-carboxylate (14a) as a brown oily material.
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].O>C1COCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCc1ccsc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccsc1[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To magnesium turnings (0.160 g, 6.6 mmol) in anhydrous THF (8.0 mL), heated to maintain a mild reflux, was added dropwise 2-bromo-3-dodecylthiophene (23; 2.00 g, 6.0 mmol). The reaction mixture was refluxed for 2 hours before being transferred to a solution of tributyltin chloride (1.80 mL, 6.41 mmol) in 10.0 mL of anhydrous THF at −78° C. The mixture was warmed to room temperature and stirred overnight before being poured into water. The aqueous layer was extracted with hexanes and the combined organic phase was washed with brine and dried over magnesium sulfate. After filtration, the solvent was removed in vacuo to yield 2-tributylstannyl-3-dodecylthiophene (24) as a yellow liquid (3.10 g, 95% yield). 1H NMR (CDCl3): δ 0.90-1.63 (m, 50H), 2.62 (t, 2H), 7.12 (d, 1H, J=4.5 Hz), 7.55 (d, 1H, J=4.5 Hz) ppm.
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=O)(C)(C)C.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)#[N:5]
Reactant: CC(C)(C)NC(=O)c1ccc(-c2cccc3cncn23)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2cccc3cncn23)cc1

Procedure:
A solution of 0.1 g of 5-(p-tert-butylaminocarbonylphenyl)imidazo[1,5-a]pyridine in 3 ml of toluene is treated with 40 μl of phosphorus oxychloride at 90° for 5 h. The solvent is evaporated and the residue is redissolved in 30 ml of chloroform at 0°. An ice-cold ammonium hydroxide solution is added and the organic phase is separated, dried over sodium sulfate and evaporated. The residue is chromatographed on silica with ethyl acetate to yield the title compound, m.p. 117°-118°.