Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]3=[O:31])[C@H:26]([OH:37])[C@@H:25]2[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:50]([CH2:52][CH2:53][O:54][CH2:55]Cl)#[N:51].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]3=[O:31])[C@H:26]([O:37][CH2:55][O:54][CH2:53][CH2:52][C:50]#[N:51])[C@@H:25]2[OH:38])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:39]=[CH:40][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
5′-O-(4,4′-Dimethoxytrityl)uridine (546 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added thereto, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was further added thereto. The reaction was performed at room temperature for 1 hour. Subsequently, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the reaction solution was stirred for 30 minutes. After the reaction completed, the reaction solution was added into an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride, and the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain 5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl)uridine (197 mg, yield 34%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].O[CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(n2cc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.7 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (2.0 g), tert-butyl 3-hydroxyazetidine-1-carboxylate (3.1 g) and triphenylphosphine (5.6 g) in tetrahydrofuran (20 mL) was added di-tert-butyl(E)-diazene-1,2-dicarboxylate (5.3 g) at room temperature, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.3 g).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:37])([CH:34]([CH3:36])[CH3:35])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:37])([CH:34]([CH3:35])[CH3:36])[CH3:33])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)C(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 78.5 %

Procedure:
A mixture of 2-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-3-methyl-butan-2-ol (90 mg, 0.17 mmol) in ethanol (4 mL), tetrahydrofuran (6 mL) and an aqueous sodium hydroxide solution (10%, 2 mL) was heated at 50° C. for 36 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-3-methyl-butan-2-ol (50 mg, 76%) which was used in the next step without further purification: LC/MS m/e calcd for C25H30N2O [M+H]+ 375.53, observed 375.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:17]2)[CH:3]=1.[C:32]([O-:35])(=[O:34])C.[K+]>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:29][C:28]([F:31])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([N:18]2[CH2:19][CH2:20][CH2:21][C@H:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[NH:8][C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=3)[C:32]([OH:35])=[O:34])[CH2:17]2)=[CH:23][CH:24]=1
Reactant: CC(=O)[O-]
Reactant: FC(F)(F)c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(Br)ccn3)C2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccnc(N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C(F)(F)F)cc3)C2)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
A mixture of (1R,2R)—N1-(4-bromopyridin-2-yl)-N2-((S)-1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)cyclohexane-1,2-diamine (40 mg, 0.080 mmol), potassium acetate (31.6 mg, 0.322 mmol), palladium(II) acetate (3.6 mg, 0.016 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (35.7 mg, 0.064 mmol) in DMSO (0.5 mL) was purged with carbon monoxide for 5 min, then stirred under a CO balloon at 60° C. for 14 hr. DMSO was removed by vacuum and the residue was dissolved in acetonitrile, filtered, and the filtrate was concentrated. The residue was purified by RP prep-HPLC (method C) to afford 2-(((1R,2R)-2-(((S)-1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)cyclohexyl)amino)isonicotinic acid (32 mg, 0.056 mmol, 69% yield).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[C:1]1([C:7](=[N:14][C:15]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)([CH3:29])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(N=C(c1ccccc1)c1ccccc1)c1cncnc1
Reaction time: 0.5 h

Procedure:
To a solution of 456 mg of ethyl [(diphenylmethylene)amino](pyrimidin-5-yl)acetate in 4.5 ml of DMF was added 69 mg of sodium hydride (55% mineral oil included) under ice-cooling, followed by stirring for 30 minutes. To the reaction mixture was added 0.1 ml of methyl iodide, followed by stirring at room temperature for 1.5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 224 mg of ethyl 2-[(diphenylmethylene)amino]-2-(pyrimidin-5-yl)propanoate.
Reaction SMILES: OC[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][C:16]([O:18][CH3:19])=[O:17].[O-2].[Mg+2]>>[CH2:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:17])[O:18][CH2:19][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)CCCCCCCCCCCCCCO
Agent: *CCO*
Agent: CCCCCCCCCCCCOCCCCCCCCCCCC
Agent: [Mg+2]
Product: O=C1CCCCCCCCCCCCCCO1
Reaction time: 3 h
Yield: 95 %

Procedure:
A 13.1 g (48.1 mmol) portion of methyl 15-hydroxypentadecanoate, 45.1 g (100 mmol) of polyoxyethylene lauryl ether {average addition mol number 6} and 1.0 g of magnesium oxide were put into the same apparatus of Inventive Example 1, and the reaction was carried out under ambient pressure to 1.3 kPa and at 190 to 245° C. for 3 hours, while distilling out methanol, and then under 53 Pa and at 160 to 260° C. to obtain 19.5 g of a colorless to light yellow liquid. This distillate contained 11.0 g of cyclopentadecanolide (yield 95%).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:6][CH2:5]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>C(Cl)Cl>[CH:26]([S:29]([N:2]1[CH2:3][C:4]2([CH2:5][CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:8]2)[CH2:1]1)(=[O:31])=[O:30])([CH3:28])[CH3:27]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC2(CNC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CC2(CCN(C(=O)OCc3ccccc3)C2)C1
Reaction time: 0.33 h
Yield: 96 %

Procedure:
A solution of benzyl 2,7-diazaspiro[3.4]octane-7-carboxylate (192 mg, 0.68 mmol) in DCM (1 mL) was treated with triethylamine (137 mg, 189 μL, 1.36 mmol) and isopropylsulfonyl chloride (107 mg, 84 μL, 0.75 mmol) at 0° C. The reaction mixture was stirred for 20 minutes. The reaction mixture was diluted with DCM and washed with 1N HCl and brine. The organic layer was dried over Na2SO4 filtered and concentrated under reduced pressure to obtain benzyl 2-isopropylsulfonyl-2,6-diazaspiro[3.4]octane-6-carboxylate (230 mg, 96%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:23])[CH2:21][CH3:22].Cl>C(=S)=S>[C:20]([C:10]1[CH:9]=[CH:8][C:7]2[C:6]3[C:14](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[CH2:13][C:12]=2[C:11]=1[F:15])(=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: Fc1cccc2c1Cc1c(F)cccc1-2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc2c(c1F)Cc1c(F)cccc1-2
Reaction time: 2 h
Yield: 31.8 %

Procedure:
50.5 g of 1,8-difluorofluorene (K-1) was dissolved in 150 ml of carbon disulfide, and the temperature was lowered to −10° C. With the temperature maintained at this level, 30 g of anhydrous aluminum chloride was added, and with the temperature still held at −10° C., 25.4 g of propionyl chloride was added dropwise over a period of 30 minutes, and the mixture was then stirred at the same temperature for 2 hours. Following completion of the stirring, the reaction mixture was poured into 200 ml of cooled 1N dilute hydrochloric acid, and was then extracted with 250 ml of toluene. The thus obtained organic layer was washed twice with 100 ml portions of water. Following drying, the solvent was removed by evaporation and the product purified by silica gel chromatography (toluene) to yield 20.5 g of 2-propionyl-1,8-difluorofluorene (K-2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[O:25][CH:26]([CH2:29][F:30])[CH2:27][F:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([NH:16][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:18]([O:25][CH:26]([CH2:27][F:28])[CH2:29][F:30])[CH:19]=1)#[N:22]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: N#Cc1ccc(N)c(OC(CF)CF)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(C#N)cc3OC(CF)CF)c2c1C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.2 g), 4-amino-3-(2-fluoro-1-fluoromethyl-ethoxy)-benzonitrile (0.17 g), p-toluenesulfonic acid monohydrate (0.16 g) and isopropanol (3.0 ml) were stirred at 90° C. for 2 hours. Then the mixture was poured in water and filtrated. The solid was washed with water and dried in an oven at 70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[N:8]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ccnc(C(F)(F)F)c4)cc3)C2=N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of 5-chloro-3-(4-(2-(trifluoromethyl)pyridin-4-yloxy)phenyl)pyridin-2-amine (220 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 120 mg) and 2-chloroethanesulfonyl chloride (294 mg) in THF (dry) (10 mL) at room temperature. The mixture was stirred at 70° C. for 1 hr. MeOH and NH silica gel were added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the titled compound (253 mg) as a white solid. The solid was crystallized from CH3CN-IPE to give a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:20])[C:10]=2[C:16]([F:19])([F:18])[F:17])[N:5]=1.C(C1C(C)=C([O:34][C:35]([CH:37]2[CH2:39][CH2:38]2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C>CN(C)C=O.O>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([O:15][C:35]([CH:37]2[CH2:39][CH2:38]2)=[O:34])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:20])[C:10]=2[C:16]([F:17])([F:19])[F:18])[N:5]=1
Reactant: Cc1nc2ccc(F)c(C(F)(F)F)c2c(O)c1C
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(F)c(C(F)(F)F)c2c(OC(=O)C2CC2)c1C
Reaction time: 1 h

Procedure:
In 3 ml dimethyl formamide was suspended 18.8 mg of 60% sodium hydride. The mixture of 2,3-dimethyl-4-hydroxy-5-trifluoromethyl-6-fluoroquinoline with 2,3-dimethyl-4-hydroxy-6-fluoro-7-trifluoromethylquinoline (starting material 1) (100 mg) was suspended in 3 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 40.8 mg of cyclopropanecarbonyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on a silica gel packed column (Varian) (20 g; elution solvent=n-hexane-ethyl acetate (40:1) to (20:1)) to give 27.9 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-5-trifluoromethyl-6-fluoroquinoline (compound 61) and 51.3 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-6-fluoro-7-trifluoro -methylquinoline (compound 63). 1H-NMR data are shown in Table 3.
Reaction SMILES: [CH2:1]=[C:2]1[C@H:7]([C:8]([O:10]C(C)(C)C)=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:5]2[S:4][CH2:3]1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]=[C:2]1[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: C=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
A stirred solution of tert-butyl (4R, 6R, 7R) -3-methylene-7-phenylacetamido-cepham-4-carboxylate (0.83 g, purity 93.7%, 2.0 mmol) in dichloromethane (80 ml) was cooled to 0° C. Titanium tetrachloride (0.66 ml, 6.0 mmol) was added in 1 min. After stirring for 4 h at 0° C., the suspension was mixed with a chilled 2M solution of hydrochloric acid in water (40 ml). The organic phase was separated and washed with a 1M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was dried over magnesium sulphate and evaporated to give 0.40 g of (4R,6R,7R)-3-methylene-7-phenylacetamido-cepham-4-carboxylic acid (purity 75%, yield 45.1%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([Cl:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:26][C:27]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:28]=1[CH2:29]Cl.CC(C)=O>C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH2:29][C:28]4[C:31]([CH3:36])=[CH:32][C:33]([CH3:35])=[CH:34][C:27]=4[CH3:26])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([Cl:19])=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(O)c2C(=O)c2c(Cl)ccc(Cl)c21
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc(Cl)c2C3=O)c(C)c1
Temperature: 10 °C
Yield: 77.7 %

Procedure:
A mechanically stirred mixture of 550.6 g (1.88 mol) of 1,4-dichloro-5-hydroxy-9,10-anthracenedione (1), 413.4 g (2.14 mol) of anhydrous cesium carbonate, 444 g, (2.4 mol) of 2,4,6-trimethylbenzyl chloride, 7.06 l of acetone, and 2.31 l of N,N-dimethylformamide was heated at reflux for 23 hr. During this period, additional portions of 2,4,6-trimethylbenzyl chloride (2.5 hr, 31.7 g; 6.5 hr, 63.4 g; 20 hr, 31.7 g) and one portion of cesium carbonate (20 hr, 4.8 g) were added. The mixture was cooled to 10° C. The precipitate was collected by filtration, washed successively with hot water and methanol, then dried at 7-9 mm/50° C./20 hr to leave 621 g (78%) of 11, mp 216°-218° C., 97.9% pure by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=C)[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:28]=[CH:27][N:26]=[C:25]5[CH2:29][N:30]([CH3:41])C(=O)OCC5C=CC=CC=5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:43]([F:46])([F:45])[F:44])=[N:10]2)=[CH:5][CH:4]=1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[C:14](=[O:48])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH:28]=[CH:27][N:26]=[C:25]5[CH2:29][NH:30][CH3:41])=[CH:22][CH:23]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:43]([F:46])([F:45])[F:44])=[N:10]2)=[CH:7][CH:8]=1
Reactant: C=C1c2c(c(C(F)(F)F)nn2-c2ccc(OC)cc2)CCN1c1ccc(-n2ccnc2CN(C)C(=O)OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNCc1nccn1-c1ccc(N2CCc3c(C(F)(F)F)nn(-c4ccc(OC)cc4)c3C2=O)cc1

Procedure:
Benzyl (1-{4-[1-(4-methoxyphenyl)-7-methylene-3-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]phenyl}-1H-imidazol-2-yl)methyl(methyl)carbamate (100 mg) was heated with 5 mL of TFA at 80° C. for 1 h. The solvent was removed and dried under vacuum. The crude product was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 20.0 mg of the desired product as the bis-TFA salt. MS (ES+): 497.5, (M+H)+. 1HNMR (CDCl3): δ 7.53-7.39 (m, 6H), 7.27 (s, 1H), 7.20 (s, 1H), 6.95 (d, 2H), 4.25 (s, 2H), 4.23 (t, 2H), 3.84 (s, 3H), 3.22 (t, 2H), 2.74 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].C(OCC)C>ClCCl>[CH2:18]([S:17][CH2:16][C:10]([CH2:9][S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:13][CH2:14][CH3:15])[CH:11]=[O:12])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCC(CO)(CSCc1ccccc1)CSCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC(C=O)(CSCc1ccccc1)CSCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 2,2-di-(benzylthiomethyl)pentan-1-ol (1.0 g Example XI) in dry dichloromethane (10 ml) was added to a stirred suspension of pyridinium chlorochromate (1.8 g) and anhydrous sodium acetate (0.11 g) in dry dichloromethane (25 ml) at 0° C., under a current of nitrogen. The reaction mixture was allowed to warm to 20° C. and then stirred for 2 hours. Dry diethyl ether was added and the mixture stirred for 30 minutes. The ethereal extracts were decanted off and the residue was washed with further portions of diethyl ether. The combined ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on a mixture of silica and charcoal, eluting with diethyl ether. 2,2-Di(benzylthiomethyl)pentanal was obtained as a pale yellow oil (0.27 g).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.Cl[C@@H:18]1[C@@H](CO)O[C@@H](N2C=CC(=O)NC2=O)[CH2:19]1.[N-]=[N+]=[N-].[Li+]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:18]([C:15]1[C:13](=[O:14])[NH:12][C:10](=[O:11])[N:9]([CH:16]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1)[CH3:19]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: O=c1ccn([C@H]2C[C@H](Cl)[C@@H](CO)O2)c(=O)[nH]1
Agent: [Li+]
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5-Chloromercuri-2'-deoxyuridine was prepared from 2'-deoxyuridine (10 g, 0.044 moles) by the procedure of Bergstron and Ruth (J. Carb. Nucl, and Nucl., 4,257, (1977)). 2'-Deoxy-5-ethyluridine was prepared by the method of Berstrom et al., (J. Am. Chem. Soc., 100, 8106, (1978)). The 5'-hydroxyl group was protected by the method of Example 62. The 3'-hydroxyl group was chlorinated and the 5'-hydroxyl was deprotected by the method of Example 64. The 3'-chloro of threo 3'-chloro-2',3'-dideoxyuridine was displaced with inversion of configuration by heating in HMPA with lithium azide (5 eq.) at 55° C. for one hour. The title compound was purified by chromatography on silica gel eluted with ethyl acetate. Removal of solvent from the appropriate fractions gave the desired compound; mp=112.5°-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH:9]=[CH:10][C:5]=2[NH:4][N:3]=1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH:9]=[C:10]([Br:19])[C:5]=2[NH:4][N:3]=1
Reactant: Cc1ccccc1-n1ccc2[nH]nc(N)c2c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1ccccc1-n1cc(Br)c2[nH]nc(N)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a mixture of 3-amino-5-(2-methylphenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step E (200 mg) and acetonitrile (6 mL) was slowly added a solution of N-bromosuccinimide (163 mg) in acetonitrile (2 mL) under ice-cooling. The reaction mixture was stirred overnight at room temperature, and the resulting solid was collected by filtration, and washed with acetonitrile. The obtained solid was purified by silica gel chromatography (methanol/dichloromethane) to give the title compound (127 mg).