Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:2]1=2.[CH3:12][C:13]([CH3:15])=[O:14].[OH-].[Na+].Cl>C(Cl)Cl.O>[O:1]1[C:2]2[CH:9]=[CH:8][C:7](/[CH:10]=[CH:12]/[C:13](=[O:14])[CH3:15])=[CH:6][C:3]=2[CH2:4][CH2:5]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)/C=C/c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
2,3-Dihydrobenzo[b]furan-5-carboxaldehyde (Aldrich Chemicals) (2 g, 13.5 mmol), acetone (2.73 ml, 37.1 mmol), water (1.35 ml) and 10% NaOH (aq.) (0.34 ml) were added together and the whole stirred at room temperature for 16 h. The yellow solid was redissolved in approx. 15 ml DCM and 2N HCl added to achieve a solution of pH 2. Water (10 ml) was added and the organic layer was extracted with DCM (2×20 ml). The aqueous layers were separated, and re-extracted with DCM (2×15 ml). The combined organics were dried (MgSO4) and concentrated in vacuo to a yellow solid which was purified by column chromatography using 15-30% EtOAc in pentane as eluant to provide the title product (2.13 g, 84%); 1HNMR (400 MHz, CDCl3) δ: 2.3 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 6.5 (d, 1H), 6.75 (d, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.45 (d, 1H); LRMS: M+H, 189. (ES+).
Reaction SMILES: Cl[CH:2]([CH3:5])[C:3]#[CH:4].C[Si](C)(C)[O:8][C:9]([O:14][CH2:15][CH3:16])=[CH:10][CH:11]([CH3:13])[CH3:12].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH:11]([CH:10]([CH:3]([CH3:4])[C:2]#[CH:5])[C:9]([O:14][CH2:15][CH3:16])=[O:8])([CH3:13])[CH3:12]
Reactant: C#CC(C)Cl
Reactant: CCOC(=CC(C)C)O[Si](C)(C)C
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C#CC(C)C(C(=O)OCC)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.3 %

Procedure:
A 250 milliliter flask was equipped with a magnetic stirrer, reflux condenser and nitrogen inlet. The flask was dried with external heat and then charged with 19.92 grams (0.22 mol) of 3-chloro-1-butyne, 30.49 grams (0.15 mol) of 1-trimethylsilyloxy-1-ethoxy-3-methylbutene prepared in Part A, 100 milliliters of dry methylene chloride, and 0.5 grams of anhydrous zinc chloride. The reaction mixture was stirred at room temperature and monitored by infrared for 48 hours. The disappearance of the ketene acetal C=C peak at 1675 cm-1 and the appearance of an ester C=O peak at 1720 cm-1 was observed. The reaction mixture was then worked up by diluting with 150 milliliters of methylene chloride and washing five times with 100 milliliters of 5% sodium bicarbonate and twice with water. The methylene chloride was dried (MgSO4) and removed under vacuum to give a residue. The residue was vacuum distilled through a vigreux column to give 8.44 grams (0.05 mol) of ethyl 2-isopropyl-3-methyl-4-pentynoate having the appearance of a colorless oil and a boiling point of 66°-76° C. at 7 millimeters pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=O)O.OC[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1CCCCC1>[CH3:13][O:12][CH2:11][CH2:10][N:9]1[CH2:14][CH2:1][O:2][CH2:3][CH2:8]1
Reactant: COC(=O)O
Reactant: OCCN1CCOCC1
Solvent: C1CCCCC1
Product: COCCN1CCOCC1

Procedure:
Using the apparatus employed in Examples 15-27, a 20 percent (volume) solution of 4-(2-hydroxyethyl)morpholine methyl carbonate Prepared in Example 30 in cyclohexane was passed through 6.0 grams of Catalyst J at a temperature of 300° C. and a liquid feed rate of 0.27 milliliters per minute. A total of 7.4 grams of product was recovered. Capillary gas chromatographic analysis (area percent) of this material showed 67.7 percent selectivity to 4-(2-methoxyethyl)morpholine at 100 percent 4-(2-hydroxyethyl)morpholine methyl carbonate conversion.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([N:15]3CCCC(O)C3)=[O:14])[N:12]=2)=[C:4]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1.N1CCCC(O)[CH2:27]1.[Cl-].[NH4+]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:27])=[C:11]([C:13]([NH2:15])=[O:14])[N:12]=2)=[C:4]([NH:22][CH:23]([CH3:24])[CH3:25])[CH:3]=1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)N2CCCC(O)C2)cs1
Reactant: OC1CCCNC1
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1sc(-c2cnc(Cl)cc2NC(C)C)nc1C(N)=O

Procedure:
Followed the same procedure as mentioned in the synthesis of compound no. 24a, instead of piperidin-3-ol, ammonium chloride was used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]2)=[O:49])[CH:45]=[N:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH3:56])[CH2:54][CH2:55]6)=[O:49])[CH:45]=[N:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CN1CCN(C(=O)c2cncc(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cncc(C(=O)N4CCN(C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and (5-bromo-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (40 mg, prepared according to Step A in Example 1-D-25) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-3-yl]-(4-methyl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-229) as a pale yellow powder (42 mg, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[F-].[Cs+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:17][C@H:18]1[O:20][CH2:19]1)(=O)=O.O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:17][C@H:18]1[O:20][CH2:19]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
2-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF. Cesium fluoride (3.02 g, 19.9 mmol) was added to the reaction. The reaction mixture was stirred for 1 hour at room temperature and (S)-glycidyl nosylate (1.71 g, 6.6 mmol) was added. The reaction was stirred for 16 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent to give (S)-glycidyl o-nitrophenyl ether (1.21 g, 90% yield, m.p. 46-47° C.) as a white solid.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Li]CCCC.Br[CH2:20][C:21]1[CH:25]=[C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[O:23][N:22]=1>C1COCC1>[Cl:31][C:28]1[S:27][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][C@H:7]3[C:6]([O:12][CH3:13])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]3)[CH:25]=2)=[CH:30][CH:29]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Commercially available (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (2.0 g, 10.86 mmol) in dry THF (12 ml) under argon was cooled to −75° C. n-BuLi (8 ml, 13.03 mmol, 1.6M solution in hexanes) was added slowly and stirring was continued for 30 min. After that 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (3.628 g, 13.03 mmol), (preparation described in J. Med. Chem. 2005, 4511-4525; Bioorg. Med. Chem. Lett. 2004, 4191-4195), in THF (15 ml) was added dropwise under stirring and stirring was continued for 30 min at −75° C. Then the mixture was warmed to 0° C. and stirred for 1 h before it was quenched with sat. aq. NaHCO3-solution. The mixture was extracted with ethyl acetate, the organic layers were combined and dried with MgSO4, filtered and evaporated to dryness. A crude oil was obtained (4.1 g) and the diastereomeric excess (d.e.: 88%) was determined by H-NMR from that crude mixture. The mixture was separated by column chromatography on silica gel (n-heptane-ethyl acetate 6:1). Yield: 3.3 g, 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[Li][CH2:13]CCC.CI.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH3:13])[O:10][C:3]=12
Reactant: Clc1ccnc2cc(I)oc12
Reactant: [Li]CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2nccc(Cl)c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven-dried round bottom flask, 7-chloro-2-iodofuro[3,2-b]pyridine (0.200 g, 0.72 mmol) was dissolved in 3 mL THF and cooled to −78° C. nBuLi (0.43 ml, 1.1 mmol) was slowly added and the reaction was stirred for one hour. Meanwhile, a vial was filled with MeI and warmed to RT. Magnesium sulfate was added and the mixture was stirred for 5 minutes and filtered into another vial. Immediately from this vial, MeI (0.11 ml, 1.8 mmol) was added to the reaction which was stirred at −78° C. for 3 hours. The reaction was quenched with saturated ammonium chloride solution and warmed to RT. DCM was added, the layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-50% EtOAc:Hex) to afford 7-chloro-2-methylfuro[3,2-b]pyridine as a light brown oil. MS: M+H+=168.3.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH2:19][C:20]([O:22][CH2:23]C)=O)[CH:7]=[CH:8][C:9]=1[O:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])[CH:2]=[CH2:3].C(C1C=C(O)C=CC=1CCCOC)C=C>>[F:16][C:14]([F:15])([F:17])[S:11]([O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:18][CH2:19][CH2:20][O:22][CH3:23])=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])(=[O:12])=[O:13]
Reactant: C=CCc1cc(CCC(=O)OCC)ccc1OS(=O)(=O)C(F)(F)F
Agent: C=CCc1cc(O)ccc1CCCOC
Product: C=CCc1cc(CCCOC)ccc1OS(=O)(=O)C(F)(F)F

Procedure:
Using a similar procedure to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate but using 3-(2-allyl-4-hydroxyphenyl)-1-methoxypropane as starting material there was obtained 2-allyl-4-(3-methoxypropyl)phenyl trifluoromethane sulphonate as a colourless oil; NMR(CDCl3): 1.8-1.95(2H,m), 2.65-2.75(2H,t), 3.3-3.5(7H,m), 5.05-5.2(2H,m), 5.8-6.0(1H,m) and 7.0-7.3(3H,m).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([NH:5]/[C:6](/[C:13]([F:16])([F:15])[F:14])=[CH:7]\[C:8]([O:10]CC)=[O:9])=O.P(Cl)(Cl)(Cl)(Cl)Cl>O=P(Cl)(Cl)Cl>[CH3:17][N:2]([CH3:1])[C:3]1[O:10][C:8](=[O:9])[CH:7]=[C:6]([C:13]([F:14])([F:15])[F:16])[N:5]=1
Reactant: CCOC(=O)/C=C(\NC(=O)N(C)C)C(F)(F)F
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of ethyl 3-[N-(N,N-dimethylcarbamoyl)-amino]-4,4,4-trifluorocrotonate (5.08 g, 0.02 mol) in phosphorus oxytrichloride (3 mL) is treated with phosphorus pentachloride (4.16 g, 0.02 mol) in three portions at 15 minute intervals, stirred for 30 minutes, and quenched with ice and water. The resultant aqueous mixture is extracted with ethyl acetate. The organic layer is washed sequentially with saturated sodium bicarbonate and water, and evaporated to give the title product as a white solid (3.9 g, 93.8% yield) which is identical by 1H and 19F NMR to a sample prepared by the literature procedure (Bull. Soc. Chem. Belg. 101, 313, 1992). The title product is further purified by crystallization from heptane (74.5% crystallized yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1.ClCCl>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])=[N:7][C:2]([C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)=[N:33][CH:34]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reaction time: 1.5 h

Procedure:
(R)-4-((R)-1-((6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (150 mg, 0.51 mmol), tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (277.37 mg, 0.71 mmol), potassium phosphate tribasic (324 mg, 0.1.53 mmol), Bis[di-tert-butyl(4 dimethylaminophenyl)phosphine]dichloropalladium(II) (11.92 mg, 0.017 mmol) were combined in water (0.72 ml) and 1,4-Dioxane (9 ml). The reaction was stirred at 100 C for 90 mins. The reaction was diluted with dichloromethane, washed with water, dried, filtered and concentrated. Residues were purified by silica gel column chromatography to yield the title compound as a free base.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][N:33]1[CH:38]=[CH:37][C:36]([Sn](C)(C)C)=[CH:35][C:34]1=[O:43]>[Pd].C1(C)C=CC=CC=1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([S:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([C:36]5[CH:37]=[CH:38][N:33]([CH3:32])[C:34](=[O:43])[CH:35]=5)=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[CH:21][CH:22]=[N:23]2)=[N:28][CH:27]=1
Reactant: Cn1ccc([Sn](C)(C)C)cc1=O
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COc1cnc2c(Sc3ccc(Nc4nnc(-c5ccn(C)c(=O)c5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C

Procedure:
4-Chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (148 mg, 331 μmol), 1-methyl-4-(trimethylstannyl)pyridin-2(1H)-one (90 mg, 331 μmol), and the Pd catalyst were added to toluene and heated to 100° C. for 2 h. The mixture was concentrated and purified by silica gel chromatography using 0 to 30% MeOH in ethyl acetate. MS: M+H+=519.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][CH2:18][CH2:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.C(O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCCCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 90 °C
Reaction time: 288 h

Procedure:
A mixture comprising-500 mg of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine, 326 mg of 1,4-dichlorobutane, 805 mg of potassium carbonate, 70 mg of sodium iodide and ethanol-water (8 ml-2 ml) was stirred at 90° C. for 12 days. Water was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol-aqueous ammonia=100/5/0.5 to 100/10/0.5) to obtain 453 mg of N-tert-butoxycarbonyl trans-4-(1-pyrrolidinyl)cyclohexylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH:27]=[C:28]([C:13]2[C:7]3[S:6][C:5]([NH:4][C:3]([O:2][CH3:1])=[O:17])=[N:9][C:8]=3[C:10]([O:15][CH3:16])=[CH:11][CH:12]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2s1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
To a stirred solution of 2.2 g (0.006 Mol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 60 ml DMF were added 3.4 g (0.007 Mol) 4-tributylstannanyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, 0.424 g (0.001 Mol) PdCl2(PPh3)2 and 0.12 g (0.001 Mol) CuI. The mixture was heated at 100° C. for 19 h and then concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1:1) afforded 0.91 g (36%) 4-(4-methoxy-2-methoxycarbonylamino-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a light yellow foam. ES-MS m/e (%): 362 ([M+H]+, 100).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:18]([C:23]3([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)=[N:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O1CCOCC1>CO.[OH-].[Pd+2].[OH-]>[CH:20]1([N:19]2[C:18]([C:23]3([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH2:24][CH2:25][CH2:26]3)=[N:17][N:16]=[C:15]2[C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:22][CH2:21]1
Reactant: c1ccc(COc2ccc(-c3nnc(C4(c5cccs5)CCC4)n3C3CC3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Oc1ccc(-c2nnc(C3(c4cccs4)CCC3)n2C2CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-[4-(Benzyloxy)phenyl]-4-cyclopropyl-5-[1-(2-thienyl)cyclobutyl]-4H-1,2,4-triazole was dissolved in methanol (4 ml) and 1,4-dioxane (3 ml) and, after palladium hydroxide (236 mg) was added thereto, the whole was stirred under a hydrogen atmosphere of 1 atm at room temperature for 15 hours. After filtration through celite, the filtrate was purified by silica gel chromatography (chloroform:methanol=99:1 to 95:5) and the resulting crystals were washed with diisopropyl ether to obtain 32 mg of 4-{4-cyclopropyl-5-[1-(2-thienyl)cyclobutyl]-4H-1,2,4-triazol-3-yl}phenol (white crystals).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.C[Al](C)C.N#N.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[F:15][C:4]1[CH:3]=[C:2]([N:1]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(N2CCC(O)CC2)c(F)c1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCC(O)CC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To a solution of 1-(4-amino-2-fluorophenyl)piperidin-4-ol (1.68 g, 8.00 mmol) in CH2Cl2 (20 mL) was added trimethylaluminium (32 mL, 64 mmol, 2 M in heptane) carefully under N2. The mixture was stirred at rt for 30 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.40 g, 8.90 mol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt for another 5 h, then quenched with saturated NH4Cl aqueous solution (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by recrystallized from EtOAc to give the title compound as a yellow solid (1.25 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([CH2:17][OH:18])=[CH:9][O:8]1)[CH3:5])[CH3:2].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(OCC)(=O)C>ClCCl>[C:25]([O:18][CH2:17][C:10]1[C@H:11]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]2[C@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[O:8][CH:9]=1)(=[O:27])[CH3:26]
Reactant: CCOC(C)O[C@@H]1OC=C(CO)[C@H]2CC[C@@H](C)[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@@H](C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
(1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4-(hydroxymethyl)-7-methylcyclopenta[c]pyran (100 mg, 0.00039 mol) obtained in Example 25 was dissolved in 5 ml of dichloromethane, and 0.15 ml (0.0016 mol) of pyridine and 0.1 ml (0.0012 mol) of acetic anhydride were added. Furthermore, 5 mg of N, N-dimethylaminopyridine was added, the reaction mixture was stirred at room temperature for 5 hours. Then, the reaction mixture was poured into 30 ml of ethyl acetate, and the organic layer was washed with water (30 ml), 2N hydrochloric acid solution (30 ml), saturated sodium bicarbonate solution (30 ml) and saturated sodium chloride solution (30 ml), was dried by adding magnesium sulfate, was filtered, and then concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the fraction obtained from hexane ether=6:4 eluent was concentrated A colorless oily substance was thus obtained, i.e., (1S, 4aS, 7R, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran (71 mg, yield=61.0%). This (1S, 4aS, 7R, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran had the following physicochemical properties:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([CH2:18][OH:19])[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C.C(OCC)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([CH2:18][O:19][C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](CO)CC[C@@H]2C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](COc3ccc(F)cc3)CC[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A solution of 0.39 g (1.4 mmol) of (7S,9aR)-2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 0.24 g (2.2 mmol) of 4-fluorophenol and 0.45 g (1.7 mmol) of triphenyl phosphine in 20 mL of dry THF was treated with 0.27 mL (1.7 mmol) of diethyl azodicarboxylate, and stirred at ambient temperature for 16 h. The solution was diluted with ethyl acetate and treated with, excess HCl(g) in ethyl ether. The solvent was evaporated and the white, solid residue was washed with 1:1 ethyl acetate:ethyl ether. The solid remaining was :dissolved in chloroform and washed with 1M NaOH, dried (magnesium sulfate), filtered and evaporated to give 0.45 g of (7S,9aR)-2-BOC-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.