Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]1[CH:22]2[CH2:23][CH:24](Br)[CH:20]([CH2:21]2)[CH2:19]1>O>[CH:20]12[CH2:21][CH:22]([CH2:23][CH2:24]1)[CH2:18][CH:19]2[O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: BrC1CC2CCC1C2
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C=O)cc1OC1CC2CCC1C2
Temperature: 80 °C
Yield: 87.2 %

Procedure:
Isovanillin (50 g, 0.328 mol) is placed in a 1 liter round bottom flask which is equipped with a stir bar and reflux condensor and is charged with 500 ml of dimethylformamimde. Potassium carbonate (45.3 g, 0.328 mol) is added to the reaction mixture which is heated to 80° C. At this temperature exo-2-bromonorbornane (12.57 g, 0.072 mol, 0.219 equivalents) is added and the reaction mixture is heated to 120° C. for 48 hours. The reaction is then cooled to room temperature and poured into 300 ml of water. The aqueous layer is extracted with ethyl ether (3×100 ml). The ethereal layer is washed with 1N sodium hydroxide solution (4×100 ml), water (3×100 ml) and saturated sodium chloride solution (3×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 15.47 g of a green/brown oil. The crude product is purified by flash chromatography using a gradient eluent system of ethyl acetate/hexane [10% ethyl acetate/hexane→20% ethyl acetate/hexane] to yield 7.76 g (14.4%) of the aldehyde as a white solid. MP: 75.5° C.-79.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])(C)(C)C.CCCCC.[B:19](OC)([O:22]C)[O:20]C>O1CCCC1>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:20][BH:19][OH:22]
Reactant: COB(OC)OC
Reactant: Cc1ccccc1Br
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1OBO

Procedure:
Following General Procedure A and using 2-bromotoluene (2 g, 7.8 mmol), 20 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (14 mL, 15.5 mmol) and trimethyl borate (2.6 mL, 15.5 mmol), the title compound was obtained after recrystallization from ethyl acetate-hexane mixture (0.8 g, 51%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:17])([F:16])[CH2:8][CH2:9][O:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:18](=O)(O)[O-:19].[Na+]>CN(C)C=O>[F:17][C:7]([F:6])([F:16])[CH2:8][CH2:9][O:10][C:11]1[S:12][C:13]([CH:18]=[O:19])=[CH:14][CH:15]=1
Reactant: FC(F)(F)CCOc1cccs1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCC(F)(F)F)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
To 8 mL dimethylformamide at room temperature was added phosphorous oxychloride (4.0 mL, 43.33 mmol) dropwise. After stirring for 10 minutes at room temperature, 2-(3,3,3-trifluoropropoxyl)thiophene (1.70 g, 8.67 mmol) as a solution in 8 mL dimethylformamide. The resulting solution was heated to 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was poured into 100 mL of ice-water and stirred vigorously for 5 minutes. Sodium bicarbonate (11 g) was added carefully and the mixture stirred until homogeneous. Organics were extracted with ether (3×100 mL), washed with water (3×50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (0-20% ethyl acetate in hexanes) to give 5-(3,3,3-trifluoropropoxyl)thiophene-2-carbaldehyde (761 mg, 39%) as an off-white solid. Used without further characterization.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[S:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:14]([CH:11]1[CH2:12][CH2:13][S:8][CH2:9][CH2:10]1)[OH:15]
Reactant: O=CC1CCSCC1
Reactant: Brc1ccccn1
Product: OC(c1ccccn1)C1CCSCC1

Procedure:
Prepared according to the method of Example 225, Step A, from 2-bromopyridine and tetrahydro-2H-thiopyran-4-carbaldehyde.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.Cl.[C:10]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.O>[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:21](=[CH:22][CH:23]=2)[NH:24][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]3=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCC(=O)C1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1CCCc2[nH]c3ccc(OCc4ccccc4)cc3c21
Yield: 38.4 %

Procedure:
1,3-Cyclohexanedione (3.1 g) and the product of Stage (i) (5.6 g) in ethanol (196 ml) and water (39 ml) was stirred at room temperature for 3 h and then heated to reflux for 14 h. The resulting solution was allowed to cool, poured into water (500 ml) and the precipitate filtered and washed with isopropyl acetate and ether to give a solid. Recrystallisation from methanol gave the title compound as a solid (2.5 g) m.p. 235°-237°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:17][CH2:18][CH3:19])[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][N:3]=1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CC(C)([O-])C.[K+].O>COCCOC.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-]C1C(Cl)=CC=CN=1)(C)C>[CH2:18]([O:17][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:27][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)=[N:3][CH:4]=1)[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH3:19]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(CC(OCC)c1ccc(Br)nc1)OCC
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-]c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(CC(OCC)c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
2-Bromo-5-(1,3,3-triethoxypropyl)pyridine (328 mg, 0.987 mmol) produced in Example 17 (17B) and 4-trifluoromethylbenzylamine (346 mg, 1.98 mmol) were dissolved in 1,2-dimethoxyethane (10 mL), and potassium tert-butoxide (346 mg, 1.98 mmol) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (34 mg, 5 mol %) were added thereto, and then, the resulting mixture was stirred under a nitrogen atmosphere at 100° C. for 3 hours. After the reaction solution was cooled to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 50:50 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (25 mg, yield: 6%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9].[Br:13]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:13][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)c1cnccn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)c1cnccn1
Temperature: 25 °C

Procedure:
A carbon tetrachloride (150 mL) solution containing the intermediate from Step B (18 g, 108 mmol), N-bromosuccinimide (26.6 g, 150 mmol) and AIBN (0.5 g) was heated at reflux overnight. The solution was cooled to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. m/z=245.1 (M+H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12](O)[CH2:13][S:14][C@H:9]12)=[O:6].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C(C(C)=O)C(C)C>[CH3:1][O:2][N:3]=[C:4]([C:21]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)OC(C)=O
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 69.7 %

Procedure:
7-(2-Methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 5 g), acetic anhydride (4.55 ml), sodium acetate (1.45 g), and methyl isobutyl ketone (50 ml) were treated in a similar manner to that of Example 43 to give 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 3.36 g).
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22](O)=[O:23])[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:61]1[C:65]([CH2:66][CH2:67][NH2:68])=[N:64][N:63]=[N:62]1.CCN(CC)CC>CN(C=O)C>[C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22](=[O:23])[NH:68][CH2:67][CH2:66][C:65]5[N:61]=[N:62][NH:63][N:64]=5)[CH2:20][CH2:21]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: NCCc1nnn[nH]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NCCc4nn[nH]n4)CC3)n21
Temperature: 0 °C
Yield: 80.7 %

Procedure:
1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid (50 mg, 0.09 mmol) and HATU (57 mg, 0.15 mmol), were combined with a heterogeneous solution of 2-(1H-tetrazol-5-yl)-ethylamine formiate (45 mg, 0.26 mmol) in anhydrous DMF (1 mL) and cooled to 0° C. Et3N (0.043 mL, 0.3 mmol) was added to the reaction. After 18 h the reaction slowly warmed to room temperature. The crude reaction solution was filtered and purified via reverse HPLC to yield 45 mg of the title compound as a white solid, m/z 619.5 [M+1]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([Cl:15])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2cccc(Cl)c2)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonylchloride (1g, 3.9 mmol), 3-chloroaniline (0.5 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2Cl2 (2 mL) was stirred at room temperature. The reaction was quenched with NaHCO3 (sat aq solution, 30 mL×3). The organic phase was separated, dried (MgSO4), and filtered. The volatiles were evaporated and the residue was purified by column chromatography (SiO2, pentane:EtOAc, 4:1) to give 4-chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide; MS (posESI) m/z=349.2 (M+H+). 1H NMR (CDCl3) δ 7.00-7.40 (m, 3H), 7.60-7.90 (m, 3H), 8.70 (bs, 1H). 4-Chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide (0.45 g, 1.3 mmol), N-methylpiperazine (0.191 mL, 1.73 mmol) and K2CO3 (359 mg, 2.6 mmol) in CH3CN (2.5 mL) as the filtrated was concentrated to give a residue which was purified by column (SiO2, CHCl3:MeOH: NH3 9:1:0.4%) to give 420 mg of N-(3-chlorophenyl)-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide (85%). Purity>95% according to HPLC analysis. The compound was dissolved in THF (1 mL) and ethanol (5 mL) was added. The solution was treated with Raney-Ni (50 mg) and hydrazine monohydrate (0.05 mL) overnight. The Raney-Ni was filtered (celite pad), the volatiles were evaporated and the residue was purified by column chromatography (SiO2, CHCl3:MeOH: NH3 9:1:0.4%). The product was isolated as hydrochloride salt by treatment with HCl gas in diethyl ether to yield 170 mg of final product (32%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([S:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[C:12]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:11]=2)=[N:5][N:4]=1)[CH3:2].[H-].[Na+].CS(O[CH2:37][C:38]1[CH:43]=[C:42]([N+:44]([O-:46])=[O:45])[CH:41]=[C:40]([CH3:47])[CH:39]=1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[C:19]([O:18][C:17]([N:16]([C:14]1[CH:13]=[C:12]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:11]=[C:10]([CH2:9][S:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[N:15]=1)[CH2:37][C:38]1[CH:43]=[C:42]([N+:44]([O-:46])=[O:45])[CH:41]=[C:40]([CH3:47])[CH:39]=1)=[O:23])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCc1nnc(SCc2cc(N3CCOCC3)cc(NC(=O)OC(C)(C)C)n2)s1
Reactant: Cc1cc(COS(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nnc(SCc2cc(N3CCOCC3)cc(N(Cc3cc(C)cc([N+](=O)[O-])c3)C(=O)OC(C)(C)C)n2)s1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholino-2-pyridyl]carbamate (200 mg) obtained in Example 1-(5) in dimethylformamide (2 ml), 60% sodium hydride (30 mg) was added under cooling with ice, followed by stirring at the same temperature for 30 minutes. A solution of 3-methyl-5-nitrobenzyl methanesulfonate (283 mg) in dimethylformamide (1 ml), was added to the reaction solution, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and a saturated sodium hydrogen carbonate aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=1:1) to obtain the above identified compound (314 mg) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[S:13][C:12]([CH:14](O)[C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]1[S:13][C:12]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccc(C(O)c2cc(OC(C)C)cc(C(=O)O)c2)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)c1ccc(Cc2cc(OC(C)C)cc(C(=O)O)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{[5-(diethoxy-phosphoryl)-thiophen-2-yl]-hydroxy-methyl}-5-isopropoxy-benzoic acid (700 mg, 1.64 mmol) in CH2Cl2 (10 ml) was added TFA (1.1 ml), followed by triethylsilane (0.92 ml, 5.72 mmol). The reaction mixture was then stirred at r.t. for 30 min, concentrated down, re-dissolved in water, extracted with EtOAc. The EtOAc layer was separated, dried over MgSO4, filtrated, and concentrated to afford the crude product 3-[5-(diethoxy-phosphoryl)-thiophen-2-ylmethyl]-5-isopropoxy-benzoic acid.
Reaction SMILES: Cl.C[O:3][CH:4](OC)[CH2:5][NH:6][C:7]([C:9]1[NH:10][N:11]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:8]>O.CC(C)=O>[OH:3][CH:4]1[N:10]2[N:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[C:9]2[C:7](=[O:8])[NH:6][CH2:5]1
Reactant: COC(CNC(=O)c1cc(COc2ccccc2)n[nH]1)OC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1NCC(O)n2nc(COc3ccccc3)cc21
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
A 2M solution of HCl in H2O was added to a solution of 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid (2,2-dimethoxy-ethyl)-amide (1.25 g, 4.09 mmol) in acetone (7 mL). The mixture was stirred at 100° C. for 5 minutes under microwave irradiation. The solvent was evaporated in vacuo and the residue was supported on silica gel and purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0, then MeOH in AcOEt 0/100 to 10/90). Desired fractions were collected and the solvents evaporated in vacuo. The residue was triturated with diethyl ether to yield (rac)-7-hydroxy-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (286 mg, 30% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:23]([Cu])#[N:24]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:23]#[N:24])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Solvent: c1ccncc1
Product: N#Cc1cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2s1
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (0.500 g) in pyridine (5 mL) is added CuCN (0.201 g). The reaction is heated to reflux and stirred for 18 h. The reaction mixture is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yellow solid which is recrystallized from methanol to yield 0.100 g (26%) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](=O)([O-])[O-].[K+].[K+].IC.Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(Br)cccc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a solution of 3-bromo-2-hydroxy-benzaldehyde (2.72 g, 13.53 mmol) in DMF (70 mL) were added potassium carbonate (5.61 g, 40.59 mmol) and iodomethane (1.01 mL, 16.24 mmol). The reaction mixture was stirred at RT. After 18 h, the mixture was acidified with cooling using 1 M HCl (aq), extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as an oil (2.73 g, 94%). 1H NMR (300 MHz, CDCl3): δ 10.36 (s, 1H), 7.85-7.79 (m, 2H), 7.15 (dt, J=7.7 and 0.7 Hz, 1H), 4.00 (s, 3H).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[O:17][C@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]([F:38])[F:37])=[CH:30][CH:29]=3)[CH:21]=2)([O:18][CH3:19])[C@H:15]([OH:39])[C@@H:14]([OH:40])[C@@H:13]1[OH:41])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1.CN(C)C=O>[CH2:42]([O:41][C@H:13]1[C@H:14]([O:40][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:15]([O:39][CH2:16][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH:36]([F:38])[F:37])=[CH:32][CH:33]=3)[CH:21]=2)([O:18][CH3:19])[O:17][C@@H:12]1[CH2:11][O:10][Si:3]([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: BrCc1ccccc1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 200.1 %

Procedure:
60% NaH (1.9 g, 47.21 mmol) and 15 mL THF were added into a 100 mL reaction flask and cooled to 0° C., followed by dropwise addition of (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 12f (4.96 g, 8.43 mmol) in THF (18 mL) within 10 minutes at 0° C. The reaction mixture was stirred for 30 minutes. Then a solution of benzyl bromide (7.21 g, 42.15 mmol) in N,N-dimethyl formamide (10 mL) was dropwise added before the reaction mixture was warmed and stirred for 16 hours at room temperature. Thereafter, the reaction mixture was partitioned after 200 mL ethyl acetate, saturated sodium bicarbonate (70 mL) and water (50 mL) were added. The organic extract was washed with 0.01 N hydrochloric acid (60 mL) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 12g (7.25 g, pale yellow liquid), which was used directly in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:39][N:40]([CH:57]([C:65](=[O:68])[NH:66][CH3:67])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:41](=[O:56])[CH:42]([NH:54][CH3:55])[CH2:43][C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10](/[CH:12]=[CH:13]/[C:14](=[O:16])[N:54]([CH3:55])[C@@H:42]([C:41](=[O:56])[N:40]([CH3:39])[C@@H:57]([C:65](=[O:68])[NH:66][CH3:67])[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(/C=C/C(=O)O)C1
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
3-((E)-2-Carboxyvinyl)azetidine-1-carboxylic acid tert-butyl ester (0.28 g; 1.24 mmol) was dissolved in methylene chloride (3 mL). 1-Hydroxy-7-azabenzotriazole (0.17 g; 1.24 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. N-Methyl-2-methylamino-N-(1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.50 g; 1.24 mmol) (prepared as in example 1) was dissolved in methylene chloride (3 mL) and added to the reaction mixture. Ethyldiisopropylamine (0.21 mL; 1.24 mmol) was added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (20 mL) was added and the reaction mixture was washed with water (10 mL), an aqueous solution of sodium hydrogen sulfate (10 mL; 10%), an aqueous solution of sodium hydrogen carbonate (10 mL; sat.) and water (10 mL). The organic phase was dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2,5×20 cm) using 2.5%(7% ammonia in ethanol) in methylene chloride as eluent to afford 0.49 g of 3-((E)-2-(methyl((1R)-1-(methyl((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)vinyl)azetidine-1-carboxylic acid tert-butyl ester.