Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.7 %

Procedure:
Orcinol monohydrate (7.10 g, 50 mmol) in N,N-dimethylformamide (20 mL) was added dropwise to NaH (2.4 g, 100 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was stirred at room temperature for 20 min. Benzyl bromide (8.55 g, 50 mmol) in N,N-dimethylformamide (20 mL) was then added, and the reaction mixture was stirred at ambient temperature for 2 hours. Water (100 mL) was added carefully followed by extraction by ethyl acetate (3×100 mL). The organic phase was washed with brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (3:1 hexane/ethyl acetate) to give the title compound as a yellow oil (3.40 g, 32%). 1H-NMR (300 MHz, CDCl3) δ 7.39 (m, 5 H), 6.40 (s, 1 H), 6.29 (s, 1 H), 6.26 (s, 1 H), 5.00 (s, 2 H), 4.89 (s, 1 H), 2.26 (s, 3 H).
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[N:26]([CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN=[N+]=[N-])C1

Procedure:
A solution of EXAMPLE 258A (1.66 g) and sodium azide (0.581 g) in anhydrous N,N-dimethylformamide (10 mL) was stirred at 90° C. for 4 hours. The mixture was cooled and concentrated to dryness. The residue was taken up in 5% aqueous sodium carbonate solution and extracted with methylene chloride. The organic solution was dried (MgSO4), filtered and concentrated to give a solid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([OH:14])(=[O:13])[CH3:12].C(N(CC)CC)C>CC(O)CC>[C:11]([O:14][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)COC(C)=O

Procedure:
71 ml of ethyl 4-chloro-3-oxobutyrate are reacted with 57 ml of acetic acid and 132 ml of triethylamine in 1 l of 2-butanol by the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.ClCCl.ClC1C=C(C=CC=1)C(O)=O.[Br:25]Br>CC(C)=O>[Br:25][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(Cl)cc1

Procedure:
A 6.6 g. portion of p-chloropropiophenone is dissolved in 150 ml. of dichloromethane and 100 mg. of m-chlorobenzoic acid are added. The solution is stirred as a mixture of 6.0 g. of bromine in 50 ml. of dichloromethane is added dropwise. The solution is stirred for 2 hours, taken to dryness in vacuo and the oil is dissolved in 100 ml. of acetone and clarified, providing an acetone solution of 2-bromo-4'-chloropropiophenone. A 50 ml. portion of this acetone solution is added to a stirred solution of 3.0 g. of hexahydro-1,3-diazocine-2(1H)-thione in 500 ml. of acetone. The mixture is stirred for 18 hours, the solid is collected, washed with 100 ml. of acetone and dried in vacuo, giving 1.6 g. of the desired product, m.p. 212°-213° C. (dec.).
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19]C(=O)C)(=O)[CH3:17].Cl>C(#N)C>[C:16]([N:2]([CH3:1])[C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5])(=[O:19])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(C)C(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.6 %

Procedure:
To a mixture of N,S-dimethyl-N'-nitroisothiourea (500 mg), potassium carbonate (695 mg) and acetonitrile (10 ml) was added 376 mg of acetic anhydride at room temperature. After stirring at room temperature for 5 hours, 10 ml of 2N hydrochloric acid was added to the mixture which was then extracted with 40 ml of dichloromethane. The resultant organic layers were washed with aqueous saturated sodium bicarbonate, then dried over anhydrous magnesium sulfate and concentrated to afford 600 mg of N-acetyl-N,S-dimethyl-N'-nitroisothiourea as a white crystal, mp 40-41° C.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[CH2:2]1[O:3][C:4]2([CH2:5][CH2:6][C:7]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)([OH:10])[CH2:8][CH2:9]2)[O:11][CH2:1]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
1,4-Cyclohexanedione mono-ethylene ketal (10.1 g, 64.7 mmol) was dissolved in anhydrous THF (100 mL), and the solution was cooled to −78° C. 4-Fluorophenylmagnesium bromide (78 mL of a 1.0 M solution in THF, 78 mmol) was added slowly over 10 minutes. After 20 minutes, saturated NH4Cl (10 mL) was added and the mixture allowed to warm to room temperature. The mixture was partitioned between CHCl3 and saturated NH4Cl. The organic layer was dried (Na2SO4), filtered through CELITE, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 1:9 to 3:7 EtOAc: hexanes, loaded in a minimum of CH2Cl2) gave 4-(4-fluoro-phenyl)-4-hydroxy-cyclohexanone ethylene ketal (10.9 g, 67%); 1H NMR (300 MHz, CDCl3) δ 7.5 (dd, J=8, 8 Hz, 2H), 7.05 (dd, J=8, 8 Hz, 2H), 4.00-3.91 (m, 5H), 2.25-2.08 (m, 4H), 1.85 (d, J=8 Hz, 2H), 1.65 (d, J=8 Hz, 2H).
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].S(=O)(=O)(O)O.[C:11]([OH:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.S(Cl)(Cl)=O>S(=O)(=O)(O)N>[Cl:5][S:1]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([OH:19])=[O:18])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: NS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
349.5 g=199.7 ml (3.0 mol) of chlorosulfuric acid and 20.0 g of 96% strength sulfuric acid are placed in a 2 l four-neck flask fitted with stirrer, internal thermometer, reflux condenser with gas outlet and dropping-funnel, at 25° C., and 1.0 g of sulfamic acid is added. Subsequently 122.1 g (1.0 mol) of benzoic acid are introduced into this mixture. The reaction mixture is heated to 120° C. over 3 hours and stirred further until evolution of HCl has ended (about 30 minutes). Then it is cooled to 70° C. and 119.0 g (1.0 mol) of thionyl chloride are added dropwise over 2 hours. The reaction solution is then heated to 80° C. and stirred further for about 30 minutes until gas evolution has ended. The mixture is added dropwise to 1000 g of ice-water at 10° C. over 2 hours. The precipitated product is filtered off with suction and washed with 500 g of ice-water. 321.2 g of crude 3-(chlorosulfonyl)benzoic acid (water content: 33.9%; chlorine: 10.8%) are obtained, corresponding to 212.3 g (0.96 mol) of 100% 3-(chlorosulfonyl)benzoic acid. 1115 g of mother liquor and 538 g of wash-water are produced.
Reaction SMILES: [C:1]1([NH:7][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.[N:14]([O-])=[O:15]>>[N:14]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:15]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=N[O-]
Product: O=NN(c1ccccc1)c1ccccc1

Procedure:
diphenylamine method, where diphenylamine as raw material is nitrosated using a nitrite in an organic solvent to produce N-nitrosodiphenylamine, which is rearranged to 4-nitrosodiphenylamine hydrochloride under the action of anhydrous hydrogen chloride, and then, 4-nitrosodiphenylamine hydrochloride is neutralized with a base to give 4-nitrosodiphenylamine which is finally reduced to 4-aminodiphenylamine by sodium sulfide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:25])[CH2:15][O:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([OH:25])[CH2:15][O:16][C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CO[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-((R)-1-phenyl-ethoxy)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([Cl:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: Cc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Temperature: 25 °C
Yield: 57.2 %

Procedure:
4-Bromo-2-chloro-1-methyl-benzene (2.5 mL, 18.7 mmoles) and N-bromosuccinimide (4.0 g, 22.5 mmoles) were dissolved into 50 mL of CCl4. To this stirring mix was added benzoyl peroxide (0.5 g, 2.1 mmoles) and the solution was irradiated using white light. Enough light intensity was utilized to affect gentle reflux for 2 hours. After this period the mixture was cooled to ambient temperature and benzoyl peroxide (0.5 g, 2.1 mmoles) was added. Again, the mix was irridiated to reflux for a period of 2 hours. After this period the reaction mix was chilled to ambient temperature and was gravity filtered. The filtrate was evaporated in vacuo and the resulting crude residue was purified using flash silica chromatography (0-1% EtOAc/Hexane) to yield 4-bromo-1-bromomethyl-2-chloro-benzene (3.04 g, 60%) as a clear liquid. 1H-NMR (CDCl3): δ 7.57 (d, J=2.0 Hz, 1H), 7.39 (dd, J′=8.3 Hz, J″=1.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 4.53 (s, 2H).
Reaction SMILES: [N+](C)([O-])=O.C[C:6]([O:8][CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.CO.C(=O)(O)[O-].[Na+]>O>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][O:8][CH3:6])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of nitromethane were added 2.72 g of 7-ACA, 6 g of stannic chloride and 1.0 g of methanol The mixture was heated at 30° C. for 60 min while stirring to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 100 ml of water. Then, the mixture was adjusted to pH 8.0 with sodium bicarbonate at a temperature of from 0° C. to 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid, and then concentrated by evaporation under reduced pressure so that a precipitate was formed. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 5 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.49 g. The yield of the desired product was 20 %.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.CCOCC.FS(O)(=O)=O.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: FB(F)F
Agent: O=S(=O)(O)F
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 25 °C

Procedure:
To 20 ml of sulfolane were added 1.41 g of 7-ACA, 8.2 ml of boron trifluoride ethyl ether, 1.9 ml of fluorosulfonic acid and 6.12 ml of trimethyl borate. The mixture was heated at 25° C. for 20 minutes to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.76 g. The yield of the desired product was 60%.
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.C(OC)(=O)C.C[C:20]([O:22][CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[C@H:28]([NH2:31])[C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=O>S1(CCCC1)(=O)=O>[NH2:31][CH:28]1[C:29](=[O:30])[N:26]2[C:25]([C:34]([OH:36])=[O:35])=[C:24]([CH2:23][O:22][CH3:20])[CH2:33][S:32][C@H:27]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: COC(C)=O
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
11.9 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2) and 2.10 g of trimethyl borate were added to a solution containing 10 ml of sulfolane and 5 ml of methyl acetate. The mixture was cooled to 20° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 20° C. for 1 hour. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.11 g (yield 86%) of the desired compound with a high purity.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 47.9 %

Procedure:
4-Hydroxybenzaldehyde (300 g) and 2-chloroethyl methyl ether (279 g) were dissolved in DMF (3 L) and potassium carbonate (408 g) was added. The mixture was stirred with heating at 60° C. for 16 hr. After the reaction, the reaction mixture was poured into water and liberated oil was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. After drying, the residue was concentrated under reduced pressure to give 4-(2-methoxyethoxy)benzaldehyde as an oil (212 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[N+:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Product: O=[N+]([O-])c1ccccc1

Procedure:
feeding fresh benzene and nitric acid in about stoichiometric proportions to produce nitrobenzene into a first-stage reaction vessel containing nitrobenzene, benzene and sulfuric acid;
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccccc1

Procedure:
Aniline (C6H5NH2) is mainly produced in industry in two steps from benzene. First, benzene is nitrated using a concentrated mixture of nitric acid and sulfuric acid at 50 to 60° C., which gives nitrobenzene. In the second step, the nitrobenzene is hydrogenated, typically at 200-300° C. in presence of various metal catalysts.
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:20]=[CH:19][N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[CH:21]=[CH2:22])=[CH:7][CH:6]=1)([CH3:4])=[O:3].[Cl:23][C:24]1[C:29](I)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:24]1[C:29](/[CH:22]=[CH:21]/[N:16]2[CH:15]=[N:14][C:13]3[C:17]2=[N:18][CH:19]=[N:20][C:12]=3[NH:11][C:8]2[CH:9]=[CH:10][C:5]([P:2]([CH3:1])([CH3:4])=[O:3])=[CH:6][CH:7]=2)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1
Reactant: Cc1ccnc(Cl)c1I
Reactant: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(Cl)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Temperature: 120 °C

Procedure:
N-(4-(Dimethylphosphoryl)phenyl)-9-vinyl-9H-purin-6-amine (Example 3, 1 mmol), 2-chloro-3-iodo-4-methylpyridine compound (1.3 mmol), diisopropylethyl amine (3 mmol), palladium acetate (0.05 mmol), tri-o-tolylphosphine (0.1 mmol) in DMF (5 mL) was thoroughly purged with argon for 10-15 min. and sealed and heated for 120° C. for 18 h. until the starting materials disappeared. The reaction mix. was passed through celite, and washed with dichloromethane containing 30% methanol. The filtrate was concentrated in vacuo. The residue was purified by Biotage-S column chromatography using 1/1 hexane ethyl acetate, ethyl acetate and 1-10% methanol containing ethyl acetate: MS [M+H]+ 439.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[S:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[CH2:3]1.O.[OH-].[Li+]>CC(O)C.O1CCCC1>[CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: CCOC(=O)c1cc2c(s1)CC(C)(C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC1(C)Cc2cc(C(=O)O)sc2C1
Temperature: 65 °C
Yield: 86.1 %

Procedure:
To the solution of 282c (16.0 g, 71.0 mmol) in propan-2-ol (200 mL), tetrahydrofuran (200 mL), and water (200 mL) was added lithium hydroxide (6.82 g, 284 mmol). The reaction mixture was heated at 65° C. for 5 h. The organic solvents were removed under reduced pressure. The pH of the residue was adjusted to 1.0 with hydrochloride acid (12M). The precipitate was collected by filtration and dried in vacuo to afford 282d (12.0 g, 86%) as white solid. MS-ESI: [M+H]+ 196.9
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.C([BH3-])#N.[Na+]>CO>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH2:12][N:24]3[CH2:25][CH2:26][CH:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=Cc1ccn(-c2ccccc2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CC2CCN(Cc3ccn(-c4ccccc4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 171 mg of 1-phenyl pyrrole-3-carboxaldehyde in 1 mL of methanol was added 525 mg of 4-benzylpiperidine, 175 mg of 4-benzylpiperidine.HCl and 63 mg of sodium cyanoborohydride. The reaction mixture was stirred overnight at room temperature under an atmosphere of nitrogen. The methanol was removed by evaporation under reduced pressure and the residue was extracted into 50 mL of ethyl acetate, then washed successively with 50 mL aliquots of 10% sodium hydroxide and water. The ethyl acetate extract was dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield 1-phenyl-3[(4-benzyl-piperidin-1-yl)methyl]pyrrole, which was purified by chromatography on silica gel using 5% methanol in dichloromethane as elvent. On evaporation of the solvent. the free base was dissolved in ethanol and treated with 1 equivalent of maleic acid. The 1-phenyl-3[(4benzyl-piperidin-1-yl)methyl]pyrrole maleate salt (compound 7) had a melting point of 159-161° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)C>[Si:13]([O:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1OCC[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCOC1=O
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (S)-3-hydroxydihydrofuran-2(3H)-one (91a, 5 g, 49 mmol) in anhydrous DMF (40 mL) was added imidazole (6.7 g, 98 mmol) and TBDMS-chloride (8.1 g, 54 mmol) and the reaction is stirred for 3 h. The reaction was diluted with diethyl ether and washed with 1N HCl×3. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (S)-3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (91b) as a clear oil (10.6 g, 49 mmol). 1H NMR (400 MHz, CHLOROFORM-d) δ 0.15 (s, 3H), 0.18 (s, 3H), 0.86-0.99 (m, 9H), 2.23 (dq, J=12.63, 8.67 Hz, 1H), 2.46 (dddd, J=12.63, 7.58, 6.57, 3.28 Hz, 1H), 2.84-3.01 (m, 1H), 4.20 (td, J=9.16, 6.44 Hz, 1H), 4.33-4.47 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[CH:15]=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C=O
Reaction time: 3 h
Yield: 66.9 %

Procedure:
To a stirred mixture of 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethanol (2.11 g, 8.89 mmol), Et3N (6.2 ml, 44.5 mmol), DMSO (6.3 ml, 88.9 mmol) in CH2Cl2 (20 ml) was added SO3-pyridine (4.25 g, 26.7 mmol). After 3 h stirring, the mixture was concentrated in vacuo and diluted with Et2O (200 ml). The resulting mixture was washed with 1 N HCl (100 ml) and brine (100 ml), dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinecarbaldehyde (1.40 g, 67%) as a yellow oil. 1H-NMR (CDCl3) δ1.45-1.52 (m, 9 H), 2.49 (m, 2 H), 3.75-3.88 (m, 2 H), 4.29-4.42 (m, 1 H), 9.54 and 9.60 (s, each, total 1 H).