Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CCCCC.[C:8]([C:13]1[CH:27]=[CH:26][C:16]([CH2:17]P(=O)(OCC)OCC)=[CH:15][CH:14]=1)([O:10][CH2:11][CH3:12])=[O:9].[CH3:28][C:29]([C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:43])([CH3:42])[CH2:36][CH2:37][N:38]2[CH3:41])=[CH:33][CH:32]=1)=O>CN(C)C=O>[CH3:41][N:38]1[C:39]2[C:34](=[CH:33][CH:32]=[C:31]([C:29]([CH3:28])=[CH:17][C:16]3[CH:15]=[CH:14][C:13]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:27][CH:26]=3)[CH:40]=2)[C:35]([CH3:42])([CH3:43])[CH2:36][CH2:37]1
Reactant: CC(=O)c1ccc2c(c1)N(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C=C(C)c2ccc3c(c2)N(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
2.9 g of a 50% suspension of sodium hydride in mineral oil were suspended in 30 ml of dimethylformamide after two-fold Washing with pentane and treated dropwise at room temperature with a solution of 17.3 g of diethyl (4-carbethoxybenzyl)phosphonate in 50 ml of dimethylformamide. After stirring at room temperature for 1 hour, a solution of 5 g of 1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl methyl ketone in 50 ml of dimethylformamide was added dropwise thereto. The reaction mixture was heated to 50° C. for 1 hour, poured on to ice/water and extracted with ethyl acetate. The brownish oil obtained after drying and evaporation of the organic phase was chromatographed (silica gel, eluting agent hexane/ethyl acetate=9:1) and gave 4.2 g of ethyl p-[2-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl)propenyl]benzoate as a slightly yellow, viscous oil.
Reaction SMILES: Cl.C(OC([NH:9][C@@H:10]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>C(Cl)Cl>[NH2:9][C@@H:10]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C[C@@H](N)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 115.1 %

Procedure:
Hydrochloric acid (4.0M in dioxane) (7.89 mL, 31.55 mmol) was added in one portion to (R)-methyl 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoate (Intermediate 39) (990 mg, 3.16 mmol) in DCM (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 3 hours. The reaction mixture was evaporated to afford (R)-methyl 3-amino-3-(4-chlorophenyl)propanoate (hydrochloride) (777 mg, 98%) as a yellow solid.
Reaction SMILES: [O-:1][S:2]([O-:4])=[O:3].[Na+].[Na+].Cl[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O.CCO>[CH2:12]([O:11][C:9]([CH2:8][S:2]([OH:4])(=[O:1])=[O:3])=[O:10])[CH3:13]
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)CCl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CS(=O)(=O)O
Yield: 100.1 %

Procedure:
To a solution of Na2SO3 (10 g, 79 mmol.) in 50 mL of H2O was added a solution of ethyl 2-chloroacetate (12.7 mL, 119 mmol.) in 55 mL of EtOH. The mixture was heated at reflux for 6 h, after which time all the volatiles were removed by evaporation under reduced pressure. The concentrated materials were dried to afford crude (ethoxycarbonyl)methanesulfonic acid (13.3 g, 100%) used directly without purification.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[C:39]([N:46]1[CH2:51][CH2:50][CH:49]([CH2:52][C:53](O)=[O:54])[CH2:48][CH2:47]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:53]([CH2:52][CH:49]2[CH2:48][CH2:47][N:46]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:51][CH2:50]2)=[O:54])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)CC1
Yield: 66.7 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)propan-1-one (Example 1, Step g) (471 mg, 1.0 mmol), DIEA (Aldrich) (0.20 mL, 1.0 mmol), N-Boc-4-piperidineacetic acid (AstaTech, Inc.) (365 mg, 1.5 mmol), HOAT (Aldrich) (232 mg, 1.70 mmol) and EDC (Aldrich) (544 mg, 2.84 mmol) in DMF (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (441 mg). MS (ESI, pos. ion) m/z: 661 (M+1); (ESI, neg. ion) m/z: 590 (M−1). Calc'd for C33H45ClN4O6S: 661.25.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:52][C:53]1[CH:58]=[C:57]([CH2:59][NH:60][CH:61]2[CH2:64][CH2:63][CH2:62]2)[CH:56]=[CH:55][N:54]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Br:52][C:53]1[CH:58]=[C:57]([CH2:59][N:60]([CH:61]2[CH2:62][CH2:63][CH2:64]2)[C:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[O:9])[CH:56]=[CH:55][N:54]=1
Reactant: Brc1cc(CNC2CCC2)ccn1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1cnc(C(=O)N(Cc2ccnc(Br)c2)C2CCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 175.7 %

Procedure:
After a solution of methyl-1H-imidazole-4-carboxylic acid (300 mg), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (1.27 g) and diisopropylethylamine (431 mg) in dimethylformamide (7 mL) was stirred at room temperature for 15 min, N-[(2-bromopyridin-4-yl)methyl]cyclobutanamine (574 mg) was added thereto and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform, and washed with saturated aqueous sodium hydrogen carbonate solution. After extraction with chloroform, the organic phase was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20-50:50) to afford the title compound (1.46 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:28])[NH:22]2>>[Cl:27][C:26]1[C:18]([CH3:17])=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:28])[C:20]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(Cl)c(C)c32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 4-methyl-5-chloro-2-oxindole to give 0.4 g of 5-chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.O.C1(C)C=CC(S(O)(=O)=[O:20])=CC=1>CC(CC)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:20])[CH2:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Solvent: CCC(C)=O
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A solution of 5.0 g. of acetonine in 33.8 g. of methylethyl ketone was added with 6.2 g. of p-toluenesulfonic acid monohydrate under stirring. The mixture was stirred at room temperature for 8 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 8 to obtain triacetonamine in a yield of 91.7%.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Cl[C:39]1[CH:44]=[N:43][CH:42]=[C:41]([CH:45]2[CH2:47][CH2:46]2)[N:40]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:45]1([C:41]2[N:40]=[C:39]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:9][N:8]=5)[CH:11]=4)[N:15]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:20])=[O:21])[CH:14]=3)[CH:44]=[N:43][CH:42]=2)[CH2:47][CH2:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: Clc1cncc(C2CC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 120 °C
Yield: 53.5 %

Procedure:
To a 20 mL microwave vial was added N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (167 mg, 0.379 mmol), 2-chloro-6-cyclopropylpyrazine (CombiPhos Catalyst Inc., 64.5 mg, 0.42 mmoles), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (10.9 mg, 0.023 mmol), Pd2(dba)3 (10.4 mg, 0.011 mmol), and K3PO4 (242 mg, 1.138 mmol) followed by purging with argon. The solids were treated with dioxane (4.0 mL) and H2O (0.4 mL) and heated in the microwave at 120° C. for 20 min. The mixture was treated with H2O and extracted with EtOAc, dried over MgSO4, filtered and concentrated. Purification with flash chromatography (eluting with 5-100% EtOAc in Hex) afforded 5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (104.4 mg, 54%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 515.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (1H, s), 8.74 (1H, s), 8.42 (1H, s), 8.16 (1H, s), 8.07-8.11 (1H, m), 7.98-8.03 (1H, m), 7.84 (2H, d, J=8.4 Hz), 7.28 (2H, s), 3.97-4.08 (1H, m), 2.36 (3H, s), 2.14 (1H, td, J=8.5, 4.2 Hz), 1.35 (6H, d, J=6.5 Hz), 1.24-1.30 (2H, m), 1.10-1.17 (2H, m).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[N:4]1)[CH3:2].[F:10][C:11]([F:22])([F:21])[C:12]1[N:17]=[CH:16][C:15]([CH2:18][C:19]#N)=[CH:14][CH:13]=1>CO.[Pd]>[CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][CH2:19][CH2:18][C:15]2[CH:16]=[N:17][C:12]([C:11]([F:22])([F:10])[F:21])=[CH:13][CH:14]=2)[C:5]([CH3:9])=[N:4]1)[CH3:2]
Reactant: CCn1cc(N)c(C)n1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: CCn1cc(NCCc2ccc(C(F)(F)F)nc2)c(C)n1
Reaction time: 1.5 h
Yield: 13 %

Procedure:
A solution of 1-ethyl-3-methyl-1H-pyrazol-4-ylamine (1.345 g, 10.75 mmol, commercially available) and (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (distilled 166-175° C./2 mb, 1.0 g, 5.4 mmol) in MeOH (10 mL) was treated with HCO2NH4 (1.694 g, 26.86 mmol) and 10% Pd/C (200 mg) and stirred at 80° for 1.5 h. Filtration, concentration and purification by HPLC afforded the title compound (0.213 g, 13%) as a light brown oil. MS m/e: 299.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:31][CH:32]=C)[C@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:34]=O.[BH4-].[Na+].[Cl-].[NH4+]>CO>[C:1]([O:5][C:6]([C@@:8]1([CH2:31][CH2:32][OH:34])[C@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CC[C@@]1(C(=O)OC(C)(C)C)CN([C@H](C)c2ccccc2)C(=O)[C@H]1COCc1ccccc1
Reactant: O=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: C[C@H](c1ccccc1)N1C[C@@](CCO)(C(=O)OC(C)(C)C)[C@H](COCc2ccccc2)C1=O

Procedure:
A solution of (3S,4R)-3-allyl-4-benzyloxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (8.00 g, 17.8 mmol) in methanol (177 mL) was bubbled with oxygen for 10 minutes. After bubbling with ozone for 30 minutes with stirring under cooling with dry ice-methanol, ozone was removed by bubbling with nitrogen. Sodium borohydride (1.68 g, 44.4 mmol) was added under cooling with ice-acetone, and the mixture was stirred under cooling for 1.5 hours. A saturated ammonium chloride solution (150 mL) was added to the reaction solution, and methanol was evaporated by concentration under reduced pressure. The mixture was extracted with ethyl acetate (200 mL×1, 150 mL×1). The organic layer was washed with brine (300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→50:50) to give 3.79 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[C:6]([CH3:15])=[C:5]([CH3:16])[C:4]=1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[CH2:2]>[C].[Pd].C(O)C>[CH2:1]([C:3]1[C:8]2[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[C:6]([CH3:15])=[C:5]([CH3:16])[C:4]=1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)[CH3:2]
Reactant: C=Cc1c2c(c(C)c(C)c1N1CCN(c3ccc(OC)cc3)CC1)OC(C)(C)C2=O
Agent: [Pd]
Solvent: CCO
Product: CCc1c2c(c(C)c(C)c1N1CCN(c3ccc(OC)cc3)CC1)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.5 %

Procedure:
5% palladium carbon (50% water content, 100 mg) was added to a solution of ethanol (5 mL) containing 4-ethenyl-5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (100 mg, 0.246 mmol) synthesized in Reference Example 23, and the mixture was stirred under hydrogen atmosphere at room temperature for 20 hours. Palladium carbon was removed by filtration, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0 to 95:5) to give 36.7 mg of the title compound (yield: 36%).
Reaction SMILES: S(Cl)(C)(=O)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:41][O:42][CH3:43])[C:15]([NH:17][CH:18]2[C:39](=[O:40])[N:20]3[CH:21]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=4)=[O:27])[CH:22](O)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1)=[O:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:41][O:42][CH3:43])[C:15]([NH:17][CH:18]2[C:39](=[O:40])[N:20]3[C:21]([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=4)=[O:27])=[CH:22][CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1)=[O:7]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(O)CS[C@H]12)c1csc(NC=O)n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 12.4 %

Procedure:
Mesyl chloride (0.406 g.) was dropwise added to a stirred mixture of 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxycepham-4-carboxylate (syn isomer, 1 g.), N,N-dimethylformamide (10 ml.) and potassium carbonate (0.732 g.) at 0° to 5° C. over 2 minutes, and the solution was stirred at room temperature for 2.5 hours. After ethyl acetate and water were added to the resultant solution, the solution was extracted with ethyl acetate. The remaining aqueous layer was extracted again with ethyl acetate. The ethyl acetate extract solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (30 g.) and eluted with a mixture of chloroform and ethyl acetate. The eluate was concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 0.12 g.), mp 224° C. (dec.).
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[H-].[Na+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.453 g, 1.75 mmol) in anhydrous THF (7 ml), sodium hydride (60%, dispersion in mineral oil, 70 mg, 1.75 mmol) was added and stirred for 15 minutes at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.175 g, 439 mmol) in anhydrous THF (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 4 hours. Only a trace amount of the target product (3) was obtained.
Reaction SMILES: FC(F)(F)O[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=NC(C3C=CC(C#N)=CC=3)=[N:11]2)=[CH:6][CH:5]=1.N1C=CN=N1.IC1C=CC(OC(F)(F)F)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O[C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:58]=1[N:57]=[CH:56]C=C2>[Cu]I.CN(C=O)C.O>[C:58]1([N:57]2[CH:56]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:9][CH:8]=3)[NH:11]2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: N#Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Oc1cccc2cccnc12
Agent: [Cu]I
Agent: FC(F)(F)Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C1=CN(c2ccccc2)NN1c1ccccc1
Yield: 13 %

Procedure:
4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzonitrile. The triazole (70 mg, 0.41 mmol), 1-iodo-4-trifluoromethoxybenzene (142 mg, 0.493 mmol), Cs2CO3 (535 mg, 1.644 mmol), CuI (3 mg, 0.012 mmol), 8-hydroxyquinoline (2 mg, 0.012 mmol), and DMF/H2O (2 mL 10:1 solution) were combined in a 10 mL CEM Microwave reaction vessel fitted with magnetic stir bar and subjected to microwave irradiation at 150° C. for 30 min. The contents were then filtered and concentrated to dryness affording the 1,3-diphenyl triazole intermediate (18 mg, 13%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[C:15]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[S:14][C:13]=2[CH:39]=1)C1C=CC=CC=1.Br[CH2:41][CH2:42][CH2:43][C:44]#[N:45].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:23]=3)=[C:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][CH2:43][C:44]#[N:45])=[CH:34][CH:33]=3)[S:14][C:13]=2[CH:39]=1
Reactant: Oc1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 80 °C
Yield: 98 %

Procedure:
A mixture of 6-benzyloxy-2-(4-hydroxyphenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Part D), 4-bromobutyronitrile (1.2 mol/mol of phenol), and Cs2CO3 (2 mol/mol of phenol) in DMF (about 10 mL/mmol of phenol) was heated to 80° C. for 3 h, poured into 4 volumes of water and extracted with EtOAc. After drying (K2CO3) and evaporation, the title compound was obtained as a foam in 98% yield following MPLC (SiO2; 0.5% in CHCl3 sat'd with NH4OH).
Reaction SMILES: ClC(OCC)=O.[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.O.[BH4-].[Na+]>O1CCCC1>[C:7]([C:11]1[CH:19]=[CH:18][C:14]([CH2:15][OH:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(CO)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
10 ml of a tetrahydrofuran solution containing 3.12 g (28.8 mol) of ethyl chloroformate were added dropwise over a period of 10 minutes to 60 ml of a tetrahydrofuran solution containing 6.0 g (26.9 mmol) of 4-t-butyl-3-nitrobenzoic acid and 3.12 g (30.9 mmol) of triethylamine, whilst ice-cooling. The reaction solution was stirred for 45 minutes at this temperature, after which it was filtered using a Celite filter aid. The precipitate was washed with tetrahydrofuran, and the filtrate and the washings were combined. The combined solution was then added dropwise to a mixed solution which was composed of 40 ml of tetrahydrofuran and 40 ml of water containing 3.76 g (9.95 mmol) of sodium borohydride, over a period of 25 minutes, on an ice bath. The reaction mixture was then stirred for 2 hours at the temperature of the ice bath, after which it was condensed by evaporation under reduced pressure. As much as possible of the tetrahydrofuran was then removed by distillation under reduced pressure, and the residue was distributed between diethyl ether and water. The product was extracted from the aqueous layer with diethyl ether. The organic layers were combined and washed twice with water and then once with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 100 g of silica gel. Elution with mixtures of ethyl acetate and hexane ranging from 20:80 to 30:70 by volume afforded 5.24 g (yield 93%) of the title compound as an oily substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>ClCCl>[CH3:10][S:11]([O:1][CH2:2][CH2:3][C:4]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1(O)CCCC1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of 1-(2-hydroxyethyl)cyclopentanol (19 0 mg, 1.46 mmol) in dry dichloromethane (2 mL) was added methanesulfonyl chloride (200.3 mg, 1.75 mmol) dropwise at 0° C., followed by TEA (295 mg, 2.92 mmol). Then the mixture was stirred at room temperature 1 h. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product (50 mg, 31.1% yield), which was used without purification.