Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.CCC([O-])(C)C.[Na+].[CH3:29][S:30](Cl)(=[O:32])=[O:31].S(OC)(O[CH3:38])(=O)=O.[Cl-].[Na+]>C(COC)OC.O>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=[C:2]([N:1]([CH3:38])[S:30]([CH3:29])(=[O:32])=[O:31])[N:7]=2)=[CH:13][CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(N)nc1C(C)C
Reactant: CS(=O)(=O)Cl
Agent: CCC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate (19.0 g), sodium tert-pentoxide (22.95 g) and dimethoxyethane (190 ml) was stirred for 30 minutes at 25° C. The stirred mixture was cooled to −10° C. and methanesulfonyl chloride (8.4 ml) was added dropwise, maintaining the temperature of the mixture at −5° C. After 20 minutes, dimethyl sulfate (8.1 ml) was added and the mixture allowed to warm to 25° C. The mixture was stirred for one hour at 25° C. and a solution of sodium tert-pentoxide (1.91 g) in dimethoxyethane (10 ml) added. The mixture was stirred for one hour at 25° C. A solution of sodium chloride (13.3 g) in water (133 ml) was added and the mixture was stirred for 10 minutes at 25° C. The mixture was allowed to settle for 15 minutes and the lower aqueous phase was separated and discarded. Water (38 ml) was added to the remaining mixture and the mixture was stirred for 30 minutes at 25° C. The mixture was then heated to obtain a complete solution. The mixture was cooled slowly to 25° C. over one hour. The mixture was cooled to 0° C., stirred for one hour, and the suspended solid collected by filtration. The solid was washed with cold (0° C.) solution of 50:50 water/dimethoxyethane (20 ml). The solid was dried under vacuum at 60° C. to give methyl 4-(4-fluorophenyl)-6isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-carboxylate (19.35 g); 1HNMR (270 MHz, CDCl3): 7.69 (m,2H), 7.14 (m,2H), 3.71, 3.60, 3.51(3× s, 9H), 3.20 (m, 1.(d,6H).
Reaction SMILES: [CH2:1]([O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[CH:32](NC(C)C)(C)[CH3:33].[Li].C(I)C.[NH4+].[Cl-]>O1CCCC1>[CH2:30]([C:22]([O:21][CH2:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])([CH2:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:31]
Reactant: CC(C)NC(C)C
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (480 mg, 1.11 mmol) was added dropwise over 30 minutes to a solution of lithium diisopropylamine (LDA) (2.0 M, 750 μL, 1.50 mmol) in dry tetrahydrofuran (10 mL) held at −70° C. under nitrogen. The reaction mixture was stirred for 30 minutes. Ethyl iodide (312 mg, 2.00 mmol) was added in one portion and the resulting mixture was warmed to ambient temperature during 1 hour. The reaction mixture was stirred at ambient temperature for 17 hours. The mixture was poured into saturated NH4Cl (aq.) (50 mL) and extracted with heptane (2×50 mL). The combined organic phases was washed succesively with brine (50 mL), 0.25 M HCl (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (100:0→95:5) as eluent. Concentration of the appropriate fractions afforded 343 mg (67% yield) of the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ 0.84 (t, 6H), 0.99 (td, 3H), 1.35-1.55 (m, 11H), 1.54-1.69 (m, 2H), 1.68-1.87 (m, 4H), 1.99-2.24 (m, 4H), 2.74-2.99 (m, 8H), 3.31 (t, 2H), 5.23-5.52 (m, 10H); MS (electro spray): 401.3 [M−H]−
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[O:18]=[C:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O1C2C=CC(O)=CC=2OC1.[CH2:45]1[C:53]2[C:48](=[CH:49][C:50]([OH:54])=[CH:51][CH:52]=2)[CH2:47][CH2:46]1>>[OH:28][C:27]1([C:51]2[CH:52]=[C:53]3[C:48](=[CH:49][C:50]=2[OH:54])[CH2:47][CH2:46][CH2:45]3)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]1=[O:18]
Reactant: CCOC(=O)CN1C(=O)C(=O)c2ccccc21
Reactant: Oc1ccc2c(c1)CCC2
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)CCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with ethyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 5-indanol, the title compound was obtained (84%): 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 7.55 (d, 1H), 7.38 (td, 1H), 7.20 (t, 1H), 6.9 (s, 1H), 6.80 (d, 1H), 6.65 (s, 1H), 4.45 (ABq, 2H), 4.32-4.25 (br, 1H), 4.20 (q, 2H), 2.83 (t, 2H), 2.74-2.65 (m, 2H), 2.06-1.94 (m, 2H), 1.27 (t, 3H); MS (ES+) m/z 350 (M−17), 390 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][OH:11])[C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CC(C)=O>[CH2:20]([O:12][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1cc(F)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OCCc1cc(F)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a solution of 2,4-difluoro-6-(2-hydroxyethyl)phenol (450 mg, 2.58 mmol) in Acetone (10 mL) was added K2CO3 (714 mg, 5.17 mmol) followed by (bromomethyl)benzene (0.461 mL, 3.88 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford 2-(2-(benzyloxy)-3,5-difluorophenyl)ethanol (540 mg, 2.043 mmol, 79% yield) as viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.48-7.36 (m, 5H), 6.84-6.72 (m, 2H), 5.07 (s, 2H), 3.78 (q, J=6.3 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H), 1.53 (t, J=5.5 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[O:31])[NH:10]2)=[C:5]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:4]=1)#[N:2].[Br:36]Br>C(Cl)(Cl)Cl>[Br:36][CH2:20][C:13]1[N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:11](=[O:31])[NH:10][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[S:32]([CH3:35])(=[O:33])=[O:34])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(rac)-Ethyl 4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 115; 3.00 g, 5.62 mmol) was dissolved in chloroform (49.9 ml), and the solution was cooled to 0° C. on an ice bath. Bromine (987 mg, 6.18 mmol) was then added dropwise. Subsequently, the ice bath was removed and the reaction mixture was stirred at RT for 1 h. Sodium thiosulfate solution (50 ml) was then added, and the organic phase was separated off, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether, and the solid was filtered off with suction and washed with diethyl ether. This gave 2.96 g (90% of theory) of the target compound as a yellow crystalline solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(O[CH:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)(=O)C>C1(C)C=CC=CC=1>[C:8]1([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][CH:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[O:25][C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:3]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: NC1CCCN(c2ccccc2)C1
Solvent: Cc1ccccc1
Product: c1ccc(N2CCCC(NC3c4ccccc4Oc4ccccc43)C2)cc1

Procedure:
Refluxing 3-amino-1-phenylpiperidine with 9-acetoxyxanthene in dry toluene by the procedure of Example 1 gives N-(N-phenyl-3-piperidinyl)-9-xanthenylamine.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18].CSC.B.O>C1COCC1>[SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCS
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: OCCCCCCCCCCCCCCCCS
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16-mercaptohexadecanoic acid (N) (0.2 g, 0.7 mmol) was dissolved in dry THF (20 mL) and borane dimethyl sulphide (1 mL, 1.1 equiv.) was slowly added under N2 atmosphere. The mixture was stirred at room temperature for 4 hr. Water was added to the solution was extracted using ethyl acetate. The organic extract was washed with 1N HCl, water and saturated sodium bicarbonate solution successively. After drying (MgSO4), the solvent was evaporated to give a white powder. Yield: 87 mg (46%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[CH2:6][CH2:5]1.Br[CH2:28][CH:29]([O:32][CH3:33])[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O1CCOCC1>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:29]([O:32][CH3:33])([O:30][CH3:31])[CH3:28])[CH2:5][CH2:6]3)=[CH:11][N:12]2[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[CH:17][CH:16]=1
Reactant: COC(CBr)OC
Reactant: NCCN1CCC(c2cn(-c3ccc(F)cc3)c3cc(Cl)ccc23)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(C)(NCCN1CCC(c2cn(-c3ccc(F)cc3)c3cc(Cl)ccc23)CC1)OC

Procedure:
To a solution of 3-[1-(2-aminoethyl)-4-piperidyl]-6-chloro-1-(4-fluorophenyl)-1H-indole 7b (11 g) in dioxan (100 ml) were added 2-bromo-1,1-dimethoxyethane (5.6 g), potassium carbonate (5 g) and a potassium iodide crystal. The mixture was refluxed for 16 hours. After cooling inorganic salts were filtered off and dioxan evaporated leaving crude 6-chloro-3-[1-[N-(1,1-dimethoxyethyl)-aminoethyl]-4-piperidyl]-1-(4-fluorophenyl)-1H-indole as an oil. The crude product was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol 1:1). Yield: 6 g as an oil. The thus obtained alkylated aminoderivative (6 g) was dissolved in dichloromethane (100 ml) and 2-propylisocyanate (1.1 g) was added. After refluxing for 2 hours dichloromethane was evaporated and the title compound 16a was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol 1:1). Yield: 4.9 g as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:24]1([S:30]([NH:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]2[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
224.5 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 207 mg of benzenesulfonyl chloride and 303 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 98 mg. MS (ES+): m/e=464.1 (M+H)+; 408.1.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:14]1[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:10][CH2:9][C:8]=2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=1[O:17][CH3:18]
Reactant: Oc1cccnc1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.9 %

Procedure:
A mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.20 g), 3-hydroxypyridine (816 mg), and potassium carbonate (2.38 g) in DMF (12 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (ethyl acetate) and then with recrystallization from hexane-ethyl acetate to obtain the entitled compound (430 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]([NH:24][NH2:25])=[O:23])[N:6]=1)([CH3:4])[CH3:3].[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27].C(N(CC)CC)C>C1COCC1>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:19])([CH3:20])[CH3:21])[N:8]=[C:7]([C:22]2[O:23][C:26](=[O:27])[NH:25][N:24]=2)[N:6]=1)([CH3:4])[CH3:1]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C(=O)NN)nc1C(C)(C)C
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(-c2n[nH]c(=O)o2)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 64 h

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy) methoxy]-2-pyrimidine carboxylic acid hydrazide (1.0 g, 2.8 mmoles), carbonyl diimidazole (0.7 g, 4.2 mmoles), and triethylamine (0.6 g, 5.9 mmoles) are combined in 20 mL of THF and the reaction mixture is stirred at room temperature under argon for 64 hours. The reaction is quenched with 50 mL of 10% HOAc/H2O. The organics are extracted into ether (3×30 mL) and washed with 50 nil of brine. The solvent is evaporated and the residue is taken up in 20 mL of acetic acid. The reaction mixture is warmed to reflux for 18 hours. It is cooled to room temperature and diluted with 150 mL of H2O. The organics are extracted into EtOAc (3×100 mL) and washed with H2O (3×100 mL) followed by brine (3×100 mL). The solvent is evaporated, and the remaining oil is purified by flash chromatography (50% EtOAc|Hexane). Yield of 5-[4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]-1,3,4-oxadiazole-2 (3H)-one=0.11 g (13%), mp 230°-232° C.
Reaction SMILES: F[C:2]1[C:3](=[CH:17][C:18]([F:24])(C)[CH:19]([F:22])[C:20]=1[F:21])[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:25]C(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:14]1([N:13]2[C:2]3[C:3](=[C:17]([CH3:25])[C:18]([F:24])=[C:19]([F:22])[C:20]=3[F:21])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)C1=CC(C)(F)C(F)C(F)=C1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C)c2c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
To a mixture of 9.05 g (26.3 mmol) of ethyl 2-(2,3,4,5-tetrafluoro-5-methylbenzoyl)-3-cyclopropylaminoacrylate in 100 mL of dry t-butanol was added a slurry of 3.25 g (29.0 mmol) of potassium t-butoxide in 20 mL of dry t-butanol, and the mixture was stirred at 60° C. for 4 hours. The suspension was cooled to room temperature and concentrated to a paste which was partitioned between dichloromethane and 1N hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, and concentrated. Recrystallization from ethyl acetate:hexane gave 4.70 g of the title compound, mp 176°-177° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@H:28]([C:30]([N:32]2[C@H:39]([C:40]([O:42]CC3C=CC=CC=3)=[O:41])[CH2:38][C@H:37]3[C@@H:33]2[CH2:34][CH2:35][CH2:36]3)=[O:31])[CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@H:28]([C:30]([N:32]2[C@H:39]([C:40]([OH:42])=[O:41])[CH2:38][C@H:37]3[C@@H:33]2[CH2:34][CH2:35][CH2:36]3)=[O:31])[CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:16]1
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Reaction time: 4 h

Procedure:
In 50 ml of ethanol is dissolved 0.26 g of benzyl (S,S,S)-2-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylate, and a catalytic reduction is carried out at ambient temperature and under atmospheric pressure using 0.2 g of 10% palladium-carbon (50% wet) as a catalyst. After the reaction is allowed to proceed for 4 hours, the catalyst is filtered off, and the filtrate is concentrated under reduced pressure to give (S,S,S)-2-[N-[(S)-5-(4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylic acid as a colorless oil. This product is dissolved in 5 ml of 1N aqueous sodium hydroxide, and the solution is allowed to stand at room temperature for 1 hour, made weakly acidic with 1 ml of acetic acid and purified by XAD-2 column chromatoraphy (0.15M aqueous ammonia-5% acetonitrile). The effluent is concentrated under reduced pressure, and the concentrate is lyophilized to give 0.15 g of (S,S,S)-2-[N-[(S)-5-(4-piperidyl)-1-carboxypentyl]-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylic acid as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH3:19][C:20](CCC=C(C)COC(=O)C1C=CC=CC=1)=CCCC(=O)C>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:19]#[CH:20]
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC(=O)c1ccccc1
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC(C)=O
Product: C#CC(C)(O)CCC=C(C)CCC=C(C)COC(C)=O

Procedure:
The procedure described in Example 9 was repeated except that 6,10-dimethyl-11-acetoxy-5,9-undecadien-2-on or 6,10-dimethyl-11-(benzoyl)oxy-5,9-undecadien-2-one was employed as a starting material to give 3,7,11-trimethyl-12-acetoxy-6,10-dodecadien-1-in-3-ol and 3,7,11-trimethyl-12-(benzoyl)oxy-6,10-dodecadien-l-in-3-ol.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.O1[CH2:16][CH2:15][CH2:14]C1.C([O-])(=O)C.N12CCCN=C1CC[CH2:24][CH2:23][CH2:22]2>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.CCOCC>[CH2:14]([C:2]1([CH2:24][CH:23]=[CH2:22])[C:1](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:10])[CH:15]=[CH2:16]
Reactant: O=C1CC(=O)c2ccccc21
Reactant: C1CCOC1
Reactant: C1CCC2=NCCCN2CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: C=CCC1(CC=C)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
There were put 2.06 g of indan-1,3-dione manufactured by Tokyo Chemical Industry Co., Ltd., and 30 mL of dry tetrahydrofuran manufactured by Kanto Chemical Co., Inc. in a 100 mL round-bottom flask. To the resultant mixture, 4.6 mL of ally acetate manufactured by Tokyo Chemical Industry Co., Ltd., 5 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene manufactured by Tokyo Chemical Industry Co., Ltd., and 76 mg of tetrakis(triphenylphosphine)palladium prepared according to Supporting Information disclosed in The Journal of Organic Chemistry, Vol. 121, page 8728 (1999) were added. The mixture was stirred for 36 hours at a room temperature under a nitrogen atmosphere. There was added 30 mL of ether to the reaction mixture, and the resultant mixture was washed twice with each 30 mL of saturated aqueous ammonium chloride. The washed mixture was further washed with 30 mL of water, and was further washed with 30 mL of a saturated sodium chloride solution. The washed mixture was dried over magnesium sulfate. The dried mixture was subjected to evaporation to remove the solvents contained therein. The obtained liquid was distilled in vacuo, thereby obtaining 3.17 g of 2,2-diallylindan-1,3-dione as a red-tinged crystal fraction at 130° C. under a pressure of 4 mmHg.
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC(C)=CC=1C(O)=O.CC1C=CC(C)=CC=1C(Cl)=O.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[C:35]([N:37]=[C:38]=[S:39])=[O:36].[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1)[NH2:44]>C(O)C.C1(C)C=CC=CC=1>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:38]([NH:37][C:35](=[O:36])[C:29]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=2[CH3:27])=[S:39])[CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Cc1ccc(C)c(C(=O)N=C=S)c1
Agent: Cc1ccc(C)c(C(=O)Cl)c1
Agent: Cc1ccc(C)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)ccc4C)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,5-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,4-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,5-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 2,5-Dimethyl-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (74 mg, yield 94%).