Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:36]([O:38][C:39](=[O:53])[CH2:40][C:41]([C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)=O)[CH3:37].C(N(CC)CC)C>ClCCCl>[CH2:36]([O:38][C:39](=[O:53])[C:40]#[C:41][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)[CH3:37]
Reactant: CCOC(=O)CC(=O)c1ccc2ccccc2c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)C#Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.7 %

Procedure:
Triflic anhydride (2.9 mL, 17 mmol) was added dropwise to a solution of triphenylphosphine oxide (4.8 g, 17 mmol) in 1,2-dichloroethane (40 mL) at 0° C. The resulting suspension was stirred for 15 minutes, followed by the dropwise addition of a solution of 3-naphthalen-2-yl-3-oxo-propionic acid ethyl ester (3.2 g, 12 mmol) in 1,2-dichloroethane (40 mL). After the addition was complete, triethylamine (4.0 mL, 29 mmol) was added and the reaction mixture was heated at reflux for 1 hr. The solution was cooled to room temperature, washed with water, and dried (MgSO4). The solvent was removed under reduced pressure, and the product was purified via column chromatography with silica eluting with hexane/ethyl acetate (9/1) to yield naphthalene-2-yl-propynoic acid ethyl ester (1.15 g, 37% yield) as a yellow oil. 1H NMR (CDCl3) δ 8.25 (s, 1H), 7.95 (m, 3H), 7.66 (m, 3H), 4.46 (m, 2H), 1.51 (t, 3H, J=8.0 Hz).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[O:12])[N:10]=1)(=[O:4])[CH3:3].[N:21]#[C:22][NH2:23]>COCCO>[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:22]([NH2:23])=[NH:21])=[CH:16][CH:15]=2)=[O:12])[N:10]=1)(=[O:4])[CH3:3]
Reactant: N#CN
Reactant: CC(=O)Nc1nc(C(=O)Nc2ccc(N)cc2)cs1
Agent: Cl
Solvent: COCCO
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(NC(=N)N)cc2)cs1
Temperature: 100 °C
Reaction time: 72 h
Yield: 63.2 %

Procedure:
A mixture of 2-(acetylamino)-N-(4-aminophenyl)-1,3-thiazole-4-carboxamide hydrochloride (70 mg), cyanamide (11 mg) and 2-methoxyethanol (2 ml) was stirred at 100° C. for 72 hours. The reaction mixture was concentrated in vacuo. To the residue was added ethyl acetate (5 ml) and saturated aqueous sodium hydrogen bicarbonate (5 ml). The precipitated solid was filtered and washed with ethyl acetate and water to give 2-(acetylamino)-N-(4-{[amino(imino)methyl]amino}phenyl)-1,3-thiazole-4-carboxamide (45 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22](O)=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:41](=[O:48])[C@@H:42]1[CH2:46][C@@H:45]([Cl:47])[CH2:44][NH:43]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:21]([OH:25])[C:22]([N:43]1[CH2:44][C@H:45]([Cl:47])[CH2:46][C@H:42]1[C:41]([NH:40][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)[C@@H]1C[C@@H](Cl)CN1)C(C)(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Yield: 24 %

Procedure:
Following a procedure similar to that described in Example 1, but using 146 mg (0.33 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid and 100 mg (0.33 mmol) of (4R)-N-t-butoxycarbonyl-4-chloro-N-t-butyl-L-prolinamide, 50 mg of the title compound were obtained as a colorless powder, melting at 103°-107° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([S:18]([CH3:21])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=1.CC(OC([N:29]([C:37]1[S:38][C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:40][N:41]=1)C(=O)OC(C)(C)C)=O)(C)C>>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]([S:18]([CH3:21])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=[C:2]([C:39]2[S:38][C:37]([NH2:29])=[N:41][CH:40]=2)[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(Cl)n1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(N)s2)n1

Procedure:
The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidine and tert-butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(5-tributylstannyl-1,3-thiazol-2-yl)carbamate was described earlier.
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][C:17]2[C:20]([CH2:25]O)=[C:21]([Cl:24])[CH:22]=[CH:23][C:16]=2[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][C:17]2[C:20]([CH2:25][Cl:5])=[C:21]([Cl:24])[CH:22]=[CH:23][C:16]=2[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CO)c2CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add methanesulfonyl chloride (1.1 g, 9.63 mmol; alternatively 2.36 g, 20.7 mmol) to 3-tert-butoxycarbonyl-7-chloro-6-hydroxymethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.5 g, 8.03 mmol; alternatively 3.2 g, 10.3 mmol) and triethylamine (2.2 mL, 16.06 mmol; alternatively 4.3 mL, 30.8 mmol) in DCM (50 mL; alternatively 60 mL) at 0° C. Warm the mixture to room temperature and stir for 1 h., alternatively for 16 h. Dilute the reaction with DCM and wash the organic phase with water. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to afford the title compound as a clear oil that was used immediately without any further purification. MS (ES+) m/z: 274 [M-(t-Bu)+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])C=1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[C:8](=[O:12])[O:9][C:10]3[C:5]([C:6]=2[CH3:21])=[CH:4][CH:3]=[C:2]([O:1][C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])[CH:11]=3)=[CH:14][CH:15]=1
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N4CCOCC4)cc3oc2=O)cc1
Yield: 60.7 %

Procedure:
The title compound (120 mg, 61% yield, crystals) was prepared from 7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-chromen-2-one (141 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.Cl[C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)(=[O:45])=[O:44])=[CH:39][N:38]=1.C(N(CC)CC)C>ClCCl>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][C:6]2[N:7]=[N:8][N:4]([CH2:3][CH2:2][NH:1][C:37]3[CH:42]=[CH:41][C:40]([S:43]([N:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)(=[O:45])=[O:44])=[CH:39][N:38]=3)[N:5]=2)=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCOCC1
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCc2nnn(CCNc3ccc(S(=O)(=O)N4CCOCC4)cn3)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.33 g), 2-chloro-5-(4-morpholinylsulphonyl)pyridine (145 mg) and triethylamine (65 mg) in dichloromethane (15 ml) was heated under reflux for 2 hours, then stirred at room temperature for 16 hours and evaporated. The residue was purified by chromatography on silica (6 g) using dichloromethane plus from 0 to 5% by volume of methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (84 mg), m.p. 112°-114° C. Found: C,56.32; H,5.90; N,10.45. C31H36Cl2N8O8S requires: C,56.13; H,5.80; N,10.48%.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.FC1(CCCC2C=CC=CC=2)CCN(C[C@@H]2[C@@H](C3C=CC=C(F)C=3)CN([C@H](C(C)C)C(O)=O)C2)CC1.C(N(C(C)C)CC)(C)C.[CH2:76]([C:78]1[NH:88][C:81]2=[N:82][C:83]([CH3:87])=[CH:84][C:85]([CH3:86])=[C:80]2[N:79]=1)[CH3:77]>C(Cl)Cl.CCOCC>[CH2:76]([C:78]1[N:88]([CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[C:81]2=[N:82][C:83]([CH3:87])=[CH:84][C:85]([CH3:86])=[C:80]2[N:79]=1)[CH3:77]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)[C@H](C(=O)O)N1C[C@H](CN2CCC(F)(CCCc3ccccc3)CC2)[C@@H](c2cccc(F)c2)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(C)cc(C)nc2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 19.5 %

Procedure:
To a solution of 0.216 g of 4-hydroxymethyl-piperidine-1-carboxylic acid, tert-butyl ester (from Step B) in 6 mL of CH2Cl2 at −78° C. was added 0.202 mL of triflic anhydride. After stirring at −78° C. for 5 minutes, 0.151 mL of 2, 6-lutidine was added dropwise. The temperature was maintained below −70° C. throughout the reaction. After stirring for 15 minutes, 0.35 mL of diisopropylethylamine was added dropwise. After 15 minutes, a solution of 0.35 g 2-ethyl-5,7-dimethyl-3-H-imidazo[4,5-b]pyridine (prepared as described by Mantlo et al. U.S. Pat. No. 5, 412,097 and J. Med. Chem. 1991, 34, 2919 ) in 4 mL of CH2Cl2 was added dropwise. After warming to 0° C., the reaction was stirred at rt for 5 hr. The reaction was diluted with Et2O, then washed with H2O. The aqueous phase was extracted with 2×25 mL Et2O. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 50% EtOAc in hexane to give 73 mg of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1.[O-]C1C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.O>[CH3:24][C:19]1[CH:20]=[C:21]([CH3:23])[N:22]=[C:17]([NH:16][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[N:18]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cn(-c2ccc(Nc3nc(C)cc(C)n3)cc2C#N)cn1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile (200 mg, 0.76 mmol), 2-amino-4,6-dimethyl-pyrimidine (141 mg, 1.14 mmol), sodium phenoxide (266 mg, 2.29 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (21 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene=xanthphos (26 mg, 0.04 mmol) in 5 mL of dioxane was heated to 80° C. under argon for 2 hours. The mixture was diluted with water, extracted with ethyl acetate and the product purified by by chromatography on silica gel using dichloromethane/methanol 9:1 v/v as an eluent. The title compound was obtained as a colorless solid (144 mg, 62%). MS ISP (m/e): 305.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): 8 (ppm)=10.08 (s, 1H), 8.44 (s, 1H), 8.15 (d, 1H), 7.89 (s, 1H), 7.55 (d, 1H), 7.25 (s, 1H), 6.76 (s, 1H), 2.36 (s, 6H), 2.18 (s, 3H).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[CH:11]([C:15]([O:17]CC)=[O:16])[N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:8][C:7]=2[N:6]=1.CCO.Cl>O.C1COCC1>[C:23]([O:22][C:20]([N:10]1[CH2:9][CH2:8][C:7]2[N:6]=[C:5]([O:4][CH3:3])[CH:14]=[CH:13][C:12]=2[CH:11]1[C:15]([OH:17])=[O:16])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C1c2ccc(OC)nc2CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
2N Aqueous lithium hydroxide solution (61.8 mL, 123.61 mmol) was added to a solution of 5-ethyl 6-tert-butyl 2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (6.93 g, 20.60 mmol) in a mixed solvent of EtOH (30 mL) and THF (30 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into ice-cooled water, and the pH of the mixture was adjusted to 4 with 6N hydrochloric acid. Then, the mixture was extracted with a mixed solvent of mixed ethyl acetate/THF (3:1) (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylic acid (6.37 g, 20.66 mmol, 100%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:40][CH2:41][CH3:42])([C:6]([F:39])([F:38])[C:7]1([O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)O)=[O:5])[CH3:2].S(Cl)([Cl:45])=O>ClCCl.CN(C)C=O.CCOCC>[CH2:1]([O:3][P:4]([O:40][CH2:41][CH3:42])([C:6]([F:39])([F:38])[C:7]1([Cl:45])[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOP(=O)(OCC)C(F)(F)C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)C1(Cl)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 14.4 g of 1-deoxy-1-(diethoxyphosphinyl)-1,1-difluoro-3,4,6-tris-O-(phenylmethyl)-D-fructofuranose in 50 ml of dichloromethane was added 7.3 ml of thionyl chloride and several drops of dimethylformamide. The solution was stirred at 25° C. for 16 hours, then diluted with ether and treated with icewater. The ether layer was washed with sodium bicarbonate solution, water and brine, dried and concentrated. The residue was subjected to column chromatography on silica gel, giving the desired compound as an oil, CMR δ 105.1 (multiplet, anomeric carbon atom).
Reaction SMILES: [CH:1]([NH:4][C:5](=[NH:7])[CH3:6])([CH3:3])[CH3:2].Br[C:9](=[CH:13]OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: COC=C(Br)C(C)=O
Reactant: CC(=N)NC(C)C
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(C)n1C(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 16.2 g (0.162 mol) of N-isopropylacetamidine (which was prepared in the above-mentioned Reference Example 1), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours, for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was distilled under reduced pressure (0.4 kPa, 85° C.) to give 10.9 g (yield: 61%) of 5-acetyl-1-iso-propyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH:8]1[O:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[CH3:2].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][O:13]1)[CH3:2]
Reactant: CCOCCOCC1CCC(O)CO1
Reactant: ClCc1ccccc1
Product: CCOCCOCC1CCC(OCc2ccccc2)CO1

Procedure:
5 was prepared as a liquid, boiling point not determined, by treating 5B with benzyl chloride according to the procedure described in the last paragraph of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([NH2:13])=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][CH3:7].[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]2[CH2:20][CH2:21][CH:22]=[CH:23][CH:15]12>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH2:4][O:5][CH2:6][CH3:7])=[CH:8][C:9]([N:13]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:10]([F:12])[CH:11]=1
Reactant: CCOCc1cc(N)c(F)cc1Br
Reactant: O=C1OC(=O)C2CCC=CC12
Solvent: CC(=O)O
Product: CCOCc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Br
Yield: 40.7 %

Procedure:
By the method of Example 2, Step H, 1.61 g (0.00649 mole) of ethyl 2-bromo-4-fluoro-5-aminobenzyl ether and 1.08 g (0.0071 mole) of tetrahydrophthalic anhydride were reacted in 30 ml of glacial acetic acid, yielding 1.01 g of N-(4-bromo-2-fluoro-5-ethoxymethylphenyl)-3,4,5,6-tetrahydrophthalimide as a yellow solid, m.p. 104°-106° C. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:14]([NH2:22])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=C[CH:16]=1.Cl.C(Cl)C1C=CC=NC=1>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:16]([C:15]3[CH:14]=[N:22][CH:18]=[CH:19][CH:20]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Reactant: NC(=O)c1ccccc1
Agent: Cl
Agent: ClCc1cccnc1
Product: COc1ccc2c(O)nc(-c3cccnc3)nc2c1C
Yield: 92 %

Procedure:
The general procedure described in Example 8 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative and nicotinyl chloride hydrochloride as acid chloride, which gave the title compound (2.5 g, 92%), [M+H]=268.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([CH3:20])[C:17]=3[CH3:19])[CH2:12][C:11]3([CH2:24][CH2:23][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:27](Br)/[CH:28]=[C:29](/[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])\[CH3:30].[NH4+].[Cl-]>CC(O)(C)C>[CH3:30][C:29]([CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:28][CH2:27][C:14]1[C:15]([OH:21])=[C:16]([CH3:20])[C:17]([CH3:19])=[C:18]2[C:13]=1[CH2:12][C:11]1([CH2:22][CH2:23][CH2:24]1)[CH2:10][N:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(N2CC3(CCC3)Cc3cc(O)c(C)c(C)c32)cc1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(N2CC3(CCC3)Cc3c(CC=C(C)CCC=C(C)C)c(O)c(C)c(C)c32)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 1′-(4-methoxyphenyl)-7′,8′-dimethyl-1′,4′-dihydro-2′H-spiro[cyclobutane-1,3′-quinolin]-6′-ol (112 mg) in 3.2 mL t-BuOH was added NaOH (224 μL) and geranyl bromide (133 μL). After 20 minutes, saturated NH4Cl was added and the mixture was extracted with dichloromethane. The organic phase was then washed with brine, dried and evaporated. The residue was passed through a column (Hexane:EtOAc=10:1.2-10:2) to give 5′-(3,7-dimethylocta-2,6-dienyl)-1′-(4-methoxyphenyl)-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-6′ol (14.7 mg) as a semi white solid. 1H-NMR (300 MHz, CDCl3) δ=6.79-6.62 (m, 4H); 5.26-5.13 (m, 1H); 5.13-5.01 (m, 1H); 4.93 (s, 1H); 3.76 (s, 3H); 3.61 (s, 2H); 2.79 (s, 2H); 2.17-2.02 (m, 7H); 1.82-1.28 (m, 18H). 13C-NMR (75 MHz, CDCl3) δ=152.74, 148.42, 146.18, 138.01, 135.33, 131.98, 129.67, 126.73, 123.86, 122.39, 122.12, 121.95, 119.93, 113.99, 76.63, 61.49, 55.51, 40.16, 39.75, 38.33, 32.89, 26.46, 25.75, 25.53, 17.77, 16.27, 15.76, 15.61, 12.39 ppm.
Reaction SMILES: C(N(CC)C(C)C)(C)C.C([Li])CCC.[C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH3:16].[CH3:23][C:24]1[C:32]([C:33](OCC)=[O:34])=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]2[N:25]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[CH3:23][C:24]1[C:32]([C:33](=[O:34])[CH2:16][C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]2[N:25]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(C)nn2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nn2ccccc2c1C(=O)CC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
To a solution of N,N-diisopropylethylamine (6.6 mL, 38 mmol) in THF (50 mL), n-butyllithium (1.6 mol/L in hexane solution: 24 mL, 38 mmol) was added at −40° C. After being stirred for 30 min, the mixture was cooled to −78° C. To the mixture, was added 1,1-dimethylethyl acetate (5.28 mL, 62.8 mmol) and the mixture was stirred for 40 min at −78° C. To the mixture, was added ethyl 2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (3.64 g, 17.8 mmol) and the mixture was stirred for 1 h at rt. To the mixture, were added a saturated aqueous solution of ammonium chloride (300 mL) and EtOAc (300 mL) and the resulting biphasic mixture was vigorously stirred for 30 min. The organic phase was washed with brine and then dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. Column chromatography was performed to yield the title compound (1.58 g, 32%) as a pale yellow syrup. 1H NMR (300 MHz, d6-DMSO) δ: 8.78 (d, J=7.0 Hz, 1H), 8.19-8.10 (m, 1H), 7.61 (ddd, J=8.7, 7.2 and 1.1 Hz, 1H), 7.15 (td, J=7.0, 1.1 Hz, 1H), 3.91 (s, 2H), 2.61 (s, 3H), 1.42 (s, 9H).