Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Cl-].[Li+].[O:26]1[CH2:28][CH2:27]1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:28][CH2:27][OH:26])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(I)cc2C1
Reactant: C1CO1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCO)cc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1.80 g (5.00 mmol) 7-iodo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7b) in 5.0 mL THF at −20° C. is added 6.34 g (5.50 mmol) of a THF-solution of 14% isopropylmagnesium-chloride*lithiumchloride under argon. The mixture is warmed to 0° C. and stirred 1 h at 0° C. The reaction mixture is cooled to −60° C. and 0.88 g (20.0 mmol) oxirane in 2.0 mL THF is added. The cooling bath is removed and the reaction is warmed to RT. The reaction mixture is poured into 50 mL aqueous ammonium chloride solution and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with water, dried over MgSO4. After filtration and evaporation of the solvent, the residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:19])=O.N>>[Cl:19][C:6]1[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1ncc(CCc2ccccc2)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Nc1ncc(CCc2ccccc2)c(Cl)n1
Temperature: 90 °C
Yield: 40.7 %

Procedure:
A mixture of 2-amino-5-phenethylpyrimidine-4-ol (600 mg, 2.79 mmol) and phosphorous oxychloride (5 ml) was kept to warm at 90° C. for 6 hours. The reaction mixture was condensed in vacuo. Ice-water was added to the residue and an aqueous ammonia was cautiously added thereto. The solution was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate=8:2) to give the object compound (265 mg, 40.7%).
Reaction SMILES: [C:1]([O:4][CH:5]([C:22]1[CH:23]=[C:24]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:25][CH:26]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2]>C(O)(=O)C.O.O1CCCC1>[C:1]([O:4][CH:5]([C:22]1[CH:23]=[C:24]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:25][CH:26]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CCCCCCCCO[Si](C)(C)C(C)(C)C)c1coc([Si](C)(C)C)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(CCCCCCCCO)c1coc([Si](C)(C)C)c1

Procedure:
4-(1-Acetoxy-9-t-butyldimethylsiloxynonyl)-2-trimethylsilylfuran (1.00 g, 2.21 mmol) was stirred at 35° for 36 hours in a mixture of acetic acid-water-tetrahydrofuran (1:1:1). The reaction mixture was concentrated and the residue was taken up in ethyl ether, washed with 10% hydrochloric acid, saturated sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to a pale oil. Purification by flash chromatography (silica, 10% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12]P(OCC)(OCC)=O)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:34][C:35]1[O:36][CH:37]=[C:38]([CH:40]=O)[N:39]=1.O>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2/[CH:12]=[CH:40]/[C:38]2[N:39]=[C:35]([CH3:34])[O:36][CH:37]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1nc(C=O)co1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2coc(C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a suspension of N-cyclopropyl-5-(diethylphosphonomethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 321b) in THF (20 ml) was added sodium hydride (50% oil dispersion, 80 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. A solution of 2-methyl-1,3-oxazole-4-carbaldehyde (148 mg) in THF (5 ml) was added to the obtained reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column (ethyl acetate to ethyl acetate/methanol=4/1) to give the title compound as a white powder (380 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c([N+](=O)[O-])c1
Yield: 98.1 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.829 g, 3.10 mmol), 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.26 g, 4.61 mmol), KI (115 mg, 0.69 mmol), and DIPEA (1.20 mL, 6.89 mmol) in DMF (16 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 1.40 g (98%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester as a tan solid. To a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester (1.40 g, 3.03 mmol) in MeOH (15 mL) and EtOAc (15 mL) was added palladium (50% wet with water), 10 wt. % on activated carbon (0.30 g). The resultant mixture was hydrogenated at 30 psi on a Parr shaker for 3 hours. The mixture was vacuum filtered through celite and the cake was washed with MeOH and EtOAc. The solvent was removed from the filtrate under reduced pressure and the thus obtained oil was purified by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.90 g (69%) of 3-amino-4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:41][CH2:42][CH2:43][C:44]#[N:45]>C(OCC)(=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[C:10]([NH:45][CH2:44][CH2:43][C:42]#[N:41])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC#N
Reaction time: 0.08 h

Procedure:
(S)-2-t-Butoxycarbonylamino-3-biphenyl-4-yl-propionic acid (J. Org. Chem., 1992, 57, 379; 20 g, 58 mmol) in ethyl acetate (300 mL) and methylene chloride (75 mL) is cooled under nitrogen to 0° with an ice bath and treated with N-methylmorpholine (6.5 mL, 58 mmol). Isobutyl chloroformate (7.6 mL, 58 mmol) is added dropwise. After 5 minutes of stirring, 3-aminopropionitrile (4.52 g, 64 mmol) in methylene chloride (50 mL) is added over 4 minutes. Stirring is continued for 1 hour at 0° then for 4 hours at room temperature. Ethyl acetate (300 mL) is added and the solution is successively washed with cold water (100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is triturated with ether (150 mL). The solid is filtered off, washed with cold ether and dried under high vacuum to give (S)-2-t-butoxycarbonylamino-3-biphenyl-4-yl-N-(2-cyanoethyl)-propionamide as a colorless crystalline solid, m.p. 163°-164°; [α]D =+3.58° (c 1, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:12]([C:13](=[O:19])[C:14]=1[CH2:15][N:16]=[N+]=[N-])=[CH:11][CH:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=2)=[O:4].[ClH:30].C(OCC)(=O)C>O1CCOCC1.CO.[Pt](=O)=O>[ClH:30].[CH3:1][O:2][C:3]([C:5]1[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:12]([C:13](=[O:19])[C:14]=1[CH2:15][NH2:16])=[CH:11][CH:10]=[C:9]([C:20]([F:21])([F:23])[F:22])[N:8]=2)=[O:4]
Reactant: COC(=O)c1c(CN=[N+]=[N-])c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
In a 100 mL pear-shaped flask, 3-azidomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (490 mg, 1.21 mmol), platinum (IV) oxide (100 mg, 0.440 mmol) and a 4N HCl in 1,4-dioxane (2.4 g, 2 mL) were combined with ethyl acetate (12 mL) to give a brown suspension which was hydrogenated at atmospheric pressure at 25° C. for 11 hr. The reaction mixture was diluted with methanol (200 mL), stirred for 1 hr at room temperature, filtered through a small celite pad, and concentrated under vacuum to give 3-aminomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester hydrochloride (0.54 g, 107% crude yield) as a light brown solid. Material was used without any further purification. 1H NMR (DMSO-d6) δ ppm 8.93 (d, J=8.2 Hz, 1H) 8.21 (br. s., 2H) 8.04 (d, J=8.2 Hz, 1H) 6.80-7.72 (m, 4H) 3.88 (br. s., 2H) 3.54 (s, 3H). MS calcd. for C18H14F3N3O3 [(M+H)+] 378.0, obsd. 378.0, [(M+H-NH3)+] 361.0, obsd. 361.0, [(M+H-NH3+CH3CN)+] 402.0, obsd. 402.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([C:8](=[O:13])[CH2:9]S(C)=O)[CH:7]=1.[C:15]([C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=O)=[CH:19][CH:18]=1)#[N:16].N1CCCCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:23]([CH:22]=[CH:21][C:20]3[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:26][CH:25]=3)=[CH:9][C:8](=[O:13])[C:6]=2[CH:7]=1
Reactant: CS(=O)CC(=O)c1cc(Br)ccc1O
Reactant: N#Cc1ccc(C=CC=O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C=Cc2cc(=O)c3cc(Br)ccc3o2)cc1

Procedure:
A mixture of 3.9 g of 5'-bromo-2'-hydroxy-2-(methylsulfinyl)acetophenone, 2.2 g of p-cyanocinnamaldehyde, 50 ml of toluene and 0.1 ml of piperidine was refluxed for 4 hrs. The mixture was chilled, and the precipitate was filtered and recystallized from DMF, mp 275°-76° ; yield 1 g (20%); λ max mμ (ε) 223 (22,700), 273 (12,900), 330 (41,000); ν max 840 (m), 980 (m), 1280 (m), 1640 (m), 1660 (ms), 2240 (m) cm-1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl.CO>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:24][CH2:25]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(S(C)(=O)=O)CC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]-triazolo[4,5-c]pyridine-4-carbonitrile (50 mg), triethylamine (0.019 ml), and methanesulfonyl chloride (8.99 μl) were combined in dichloromethane (1 ml) and the reaction mixture stirred at room temperature for 3 hours. Washed with water, the organic layer was separated, dried, and blown down to afford crude product. Solid was suspended in methanol and filtered off to afford the title compound (32.5 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:15]I.OO.O>CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([I:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: OO
Solvent: O
Solvent: CO
Product: Nc1ccc(Cc2ccccc2)cc1I
Reaction time: 8 h

Procedure:
To a solution of 4-benzylbenzenamine (3.00 g, 16.4 mmol) in 16 mL MeOH was added iodine (2.49 g, 9.82 mmol) followed by hydrogen peroxide, 30% in water (1.67 mL, 16.4 mmol). The dark solution was allowed to stir overnight. The reaction was partitioned between water/brine and EtOAc. The organic layer was washed 1× brine, dried over MgSO4, filtered, and concentrated. The resulting oil was purified by ISCO (120 g, 0-10% EtOAc/hexanes) to give 4-benzyl-2-iodobenzenamine as a red oil which slowly solidified to a red solid. MS (ESI) m/z: Calculated: 309.0; Observed: 310.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]#[N:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>FC(F)(F)C(O)C(F)(F)F>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:26][CH2:25][C:24]4[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=4)=[NH:19])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: N#CN1CCN(c2ccnc3cc(Cl)ccc23)CC1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: N=C(NCc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(4-cyanopiperazin-1-yl)quinoline (219 mg, 0.8 mmol) and 4-fluorobenzylamine (114 μL, 1.0 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (5 mL) are heated at 130° C. in a sealed tube for 44 h. The reaction mixture is concentrated, and the residue is purified by column chromatography with CH2Cl2—NH3-MeOH to give the title product as a yellow foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])/[C:7](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:26])/[C:7](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:8][CH2:9][N:50]1[C:46](=[O:56])[C:47]2[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:49]1=[O:51])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(/C=C(\CCO)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(/C=C(\CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Yield: 87.5 %

Procedure:
To an anhydrous THF (3.0 mL) solution of (E)-4-hydroxy-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid tert-butyl ester (100 mg), triphenylphosphine (87.8 mg), phthalimide (49.3 mg) and diisopropyl azodicarboxylate (77.0 μL) were added one by one. After agitating reaction solution at room temperature for 1.5 hours, reaction solution was concentrated under reduced pressure as it was, the residue was purified by silica gel chromatography (elution solvent: ethyl acetate), and 119 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1I.[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[S:28][C:25]1[S:26][CH:27]=[C:23]([C:16]2([OH:15])[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]2)[CH:24]=1
Reactant: CN1C(=O)CCc2cc(I)c(F)cc21
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Product: CC1CC(O)(c2csc(Sc3cc4c(cc3F)N(C)C(=O)CC4)c2)CCO1
Yield: 85 %

Procedure:
Using an analogous procedure to that described in Example 5, 7-fluoro-6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give 4-[2-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]-4-hydroxy-2-methyltetrahydropyran in 85% yield as a gum;
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][OH:24])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[OH:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[O:33][S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)(=[O:42])=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 1-(3,5-di-O-benzyl-4-C-hydroxymethyl-(3-D-ribofuranosyl)uracil 41 (3.55 g, 7.81 mmol) in dichloromethane (50 cm3) were added DMAP (3.82 g) and p-toluenesulphonyl chloride (4.47 g, 23.5 mmol) at room temperature. Stirring was continued for 2 h, and dichloromethane (100 cm3) was added. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (2×75 cm3) and dried (Na2SO4). The organic phase was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99.5:0.5, v/v) as eluent to give nucleoside 75 (4.65 g, 78%) as a white solid material. δH (CDCl3) 8.49 (1H, br s, NH), 7.67 (1H, d, J 8.3, 6-H), 7.51-7.03 (18H, m, Bn, Ts), 6.0 (1H, d, J 7.6, 1′-H), 5.05 (1H, m, 2′-H), 4.91 (2H, m, 5-H, Bn), 4.56 (2H, m, Bn), 4.42 (1H, d, J 10.4, Bn), 4.31 (1H, d, J 4.9, 3′-H), 4.05 (2H, m, 1″-H), 3.75-3.64 (2H, m, 5′-H), 2.41 (3H, s, CH3), 2.34 (3H, s, CH3). δC (CDCl3) 162.2 (C-4), 149.5 (C-2), 146.0, 145.3 (Ts), 139.0 (C-6), 136.7, 131.9, 130.0, 129.9, 128.9, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.6 (Bn, Ts) 102.7 (C-5), 85.5 (1′-C), 84.4 (4′-C), 79.2, 78.3, 75.1, 74.3, 72.4, 69.1 (Bn, 3′-C, 2′-C, 5′-C, 1″-C), 21.7, 21.6 (Ts). FAB-MS m/z 763. Found: C, 61.2; H, 4.4; N, 3.3; C38H38N2O11S2 requires C, 59.8; H, 5.0; N, 3.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([F:23])([F:22])[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([F:21])=[CH:13][CH:12]=2)=[C:4]([F:25])[C:3]=1[CH2:26][CH2:27][OH:28].B.C1COCC1.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:23][C:10]([F:22])([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([F:21])=[CH:13][CH:12]=1)[CH2:9][NH:8][C:5]1[C:4]([F:25])=[C:3]([CH2:26][CH2:27][OH:28])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Cl)c(CCO)c1F)C(F)(F)c1ccc(F)c2ccccc12
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of N- [4-chloro-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-(4-fluoronaphthyl)acetamide (1.9 g, 4.6 mmol), as prepared in the preceding step, in THF (19 mL) at 0° C. was added dropwise a solution of BH3.THF complex (19.4 mL, 19.4 mmol, 1.0 M in THF) over a period of 20 minutes, and the reaction mixture continued to stir until the ice bath expired. The mixture was then heated at reflux in an oil bath at 75° to 80° C. for 3 hours, and continued to stir at ambient temperature overnight. A solution of NaHCO3 (1.63 g, 19.4 mmol) in H2O (20 mL) was added, the THF was evaporated, and the resulting mixture was extracted with DCM twice. The extracts were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 1, 1.5%) to give the title compound (805 mg, 44% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.24-8.19 (m, 2H), 7.70-7.61 (m, 3H), 7.14 (t, J=9.3 Hz, 1H), 6.90 (dd, J=8.7, 1.6 Hz, 1H), 6.42 (t, J=8.9 Hz, 1H), 4.22-4.16 (m, 1H), 4.00 (dt,J=13.4, 6.8 Hz, 2H), 3.82 (dd, J=12.1, 6.4 Hz, 2H), 3.02 (dt, J=6.8, 2.3 Hz, 2H), 1.39 (br s, 1H). Mass spectrum (LCMS, ESI) calc'd for C20H17ClF4NO (M+H): 398.1. Found: 398.3.
Reaction SMILES: Cl[CH:2]1[N:7]=[C:6](C2CC2)[N:5]=[C:4](C2CC2)[N:3]1N.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>O1CCOCC1>[CH:15]1([NH:18][C:2]2[N:3]=[C:4]([NH:18][CH:15]3[CH2:17][CH2:16]3)[N:5]=[C:6]([NH:18][CH:15]3[CH2:17][CH2:16]3)[N:7]=2)[CH2:17][CH2:16]1
Reactant: NN1C(C2CC2)=NC(C2CC2)=NC1Cl
Reactant: NC1CC1
Solvent: C1COCCO1
Product: C1CC1Nc1nc(NC2CC2)nc(NC2CC2)n1
Temperature: 140 °C

Procedure:
A mixture of 20 g of 2-chloro-4,6-bis-cyclopropyl-amino-s-triazine, 10.1 g of cyclopropylamine and 80 ml of dioxan is heated at 140° C. in an autoclave for 22 hours. The reaction mixture is concentrated in vacuo to half its volume and 300 ml of water are added. The mixture is extracted with ethyl acetate, the product phase is dried over sodium sulfate and the solvents are removed in vacuo. The residue is recrystallised from dioxan/petroleum ether; melting point 75°-77° C.