Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[N:2]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cccnn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 9.3 %

Procedure:
To a solution of pyridazine-3-amine (2.00 g, 21.0 mmol) and pyridine (5.10 ml, 63.1 mmol) in tetrahydrofuran (100 ml) was added 2,2,2-trichloroethyl chloroformate (4.34 ml, 31.5 mmol) with ice-cooling, the mixture was stirred for 50 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product (530 mg, 9.3%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:13]([O-])([O-])=O.[K+].[K+].CI.CCOCC>CN(C=O)C>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH:11]=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)c1cc(Cl)ccc1C=O
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a heterogeneous mixture of 5-chloro-2-formyl-benzoic acid (1.0 g, 5.42 mmol) and K2CO3 (1.12 g, 8.13 mmol) in DMF (7 ml) was added MeI (0.41 ml, 6.5 mmol) at RT. The reaction mixture was stirred for 4 h then diluted into Et2O and washed with water (2×). The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (700 mg, 3.52 mmol, 65%) as a light yellow solid, which was used without further purification. HPLC: AtRet=1.84 min; LC-MS: m/z 199.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 3.91 (s, 3H), 7.84-7.94 (m, 3H), 10.33 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([CH2:25]Br)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:27]([C:21]1[CH:22]=[C:23]([CH2:25][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:24]=[CH:19][CH:20]=1)#[N:28]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C#N)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-m-tolunitrile (1.0 g, 4.9 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL of DMF was stirred at 25° C. for 24 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was dried in vacuo to afford 1.18 g (82%) of the 9-[(3-cyanophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.65-7.2 (m, 6H), 7.15 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.25 (m, 2H). IR (KBr, cm−1) 2226, 1729, and 1646. MS (ES) m/e 357, 359.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[OH-].[Na+].C(O)COCCO.Cl>O>[OH:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Oc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Yield: 91 %

Procedure:
A mixture of 8.42 g of 5-methoxy-2-(4-benzyloxyphenyl)pyrimidine, 6.9 g of sodium hydroxide, and 84 ml of diethylene glycol was heated at 190° to 200° C. for 2 hours. After cooling, the reaction mixture was poured into 300 ml of water, neutralized with a 1% hydrochloric acid aqueous solution, and extracted with ethyl acetate. Distillation of the extract to remove ethyl acetate gave 7.3 g (26.2 mmol; percent yield: 91.8%) of 5-hydroxy-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:4]=1[CH2:5][C@@H:6]1[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C@@H:7]12.I[CH3:20].O>O1CCCC1>[CH3:20][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C@H:6]2[CH2:5][C:4]3[C:15]([C@@H:7]12)=[CH:16][CH:17]=[CH:18][CH:3]=3
Reactant: CI
Reactant: c1ccc2c(c1)C[C@@H]1c3ccccc3N[C@H]21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1c2ccccc2[C@H]2Cc3ccccc3[C@H]21
Reaction time: 1 h

Procedure:
A flame dried flask was charged with sodium hydride (60 mg, 2.5 mmol), and tetrahydrofuran (THF) (5 cm3) protected under an atmosphere of nitrogen. To the stirring suspension was added cis-4b,5,9b,10-tetrahydroindeno[1,2-b]indole (500 mg, 2.4 mmol) in THF (5 cm3) dropwise. The reaction was stirred for 1 hour, a pink colour developing. Iodomethane (0.2 cm3) was added, and the solution was stirred overnight. Water (5 cm3) was added, and the THF removed in vacuo. The colourless solid thus obtained was filtered, and dried in a vacuum desiccator. The product was dissolved in 5% ethyl acetate petrol (60°-80° C.) and filtered through a pad of flash silica. After evaporation of the solvent in vacuo, the title compound was obtained as a colourless solid. Yield: 450 mg (85%). M.p. 76°-77° C. 1H NMR (CDCl3) δ: 3.0 (3H, s,), 3.1 (1H, dd,), 3.4 (1H, dd,), 4.1 (1H, ddd,), 4.9 (1H, d,), 6.4 (1H, d,), 6.7 (1H, dd,), 7.1-7.5 (6H, m,).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](O)([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(O)(CC(=O)O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=CC(=O)O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1

Procedure:
1 g. of 3-(3',4'-dichloro-4-biphenylyl)-3-hydroxybutyric acid and 0.1 g. of p-toluenesulfonic acid in 35 ml. of toluene are heated under reflux for 3 hours and water by-product is removed. The reaction mixture is worked up to give 3-(3',4'-dichloro-4-biphenylyl)-2-butenoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[F:14])[N:5]=[N:4][C:3]=1[C:15]([O:17]CC)=[O:16].CC[O-].[Na+].C(CC(OCC)=O)#N.N(C1C=CC=C(Cl)C=1F)=[N+]=[N-]>CCO.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[F:14])[N:5]=[N:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1nnn(-c2cccc(Cl)c2F)c1N
Agent: CC[O-]
Agent: [N-]=[N+]=Nc1cccc(Cl)c1F
Agent: [Na+]
Solvent: CCOC(=O)CC#N
Solvent: CCO
Solvent: O
Product: Nc1c(C(=O)O)nnn1-c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
Ethyl 5-amino-1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate: (PCT International Application No. 2006/047516 (2006)) To a solution of NaOEt (4.99 g, 15.39 mmol) in EtOH (10 mL) at 0° C. was added ethyl 2-cyanoacetate (1.501 ml, 14.11 mmol). The reaction was stirred at 0° C. for 10 min and added 1-azido-3-chloro-2-fluorobenzene (2.2 g, 12.82 mmol). The reaction was allowed to slowly warm up to rt and stirred for 14 h. The mixture was treated with water (3 mL) and extracted with EtOAc (3×30 mL). The combined extracts were concentrated and purified by silica gel chromatography to yield the desired product (2.1 g, 58%). MS(ESI) m/z: 285.1 (M+H)+.
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]([OH:9])(=O)[CH2:6][CH3:7].C(Cl)(=O)CC.[Cl-].[CH2:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18].CCCCC1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:5](=[O:9])[CH2:6][CH3:7])=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Cc1ccccc1
Reactant: CCC(=O)O
Agent: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClP(Cl)Cl
Solvent: CCCCc1ccccc1
Solvent: ClCCl
Product: CCC(=O)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
In a 500 ml. 3-necked, round bottomed flask there was placed 25.50 ml. (40.14 g., 0.29 mmole) of phosphorus trichloride and 43.65 ml. (43.34 g., 0.58 mmole) of propionic acid. This mixture was stirred for 2.25 hours under nitrogen atmosphere at room temperature to prepare the propionyl chloride. By NMR propionyl chloride formation was complete in about 1.5 hours. Then 80 ml. of anhydrous methylene chloride was added and the resulting solution was cooled to about -5° C. (an ice-methanol bath). While stirring the cooled mixture, 87.50 g. (0.66 mmole) of alumium chloride (technical grade) was added. After 10 minutes of stirring, 67.11 g. (0.50 mmole) of isobutylbenzene was added dropwise from an addition funnel over 55 minutes while maintaining the temperature of the mixture at about 0° to 5° C. The isobutylbenzene was about 99.6% pure and contained about 0.3% n-butylbenzene. The mixture was stirred for an additional 1.25 hours to insure as complete a reaction as possible and then poured into a solution of 250 ml. of ice water and 150 ml. of concentrated hydrochloric acid with vigorous stirring. The Friedal-Crafts reaction was complete in about 45 minutes under these conditions (by GLC analysis). The resulting mixture was extracted three times with 300 ml. portions of methylene chloride. The combined methylene chloride extracts were washed with 250 ml. of water and three times with 250 ml. of molar concentration aqueous sodium carbonate solution. The aqueous sodium carbonate extracts were back-extracted with 100 ml. of methylene chloride and the combined methylene chloride layers were dried over sodium sulfate. The dried methylene chloride solution was concentrated under vacuum to give crude p-isobutylpropiophenone as a pale yellow oil weighing 97.85 g. By GLC analyses, 3% methylene chloride was present. The chemical yield was about 95 g. or about 100% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Mg]Cl.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([CH3:14])[CH:3]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(Br)cc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1C
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a solution of 4-bromo-N-methoxy-2,N-dimethyl-benzamide (886 mg, 3.43 mmol) in anhydrous tetrahydrofuran (20 mL) at −60° C. under an atmosphere of nitrogen was added 3.0 M methylmagnesium chloride in tetrahydrofuran (1.26 mL, 3.78 mmol) via syringe. The reaction was stirred for 20 minutes at −60° C., then at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added, the mixture was poured into a separatory funnel and extracted with diethyl ether (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(4-bromo-2-methyl-phenyl)-ethanone (700 mg, 96%). HR-MS: calcd for C30H29BrN4O4 [M+H+] 589.1445. Found 589.1445.
Reaction SMILES: BrC1C=CC(S(O[C@H:12]2[CH2:45][N:15]3[C:16](=[O:44])[C@@H:17]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][C@@H:25]4[CH2:30][C@@:26]4([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:27][C:28](=[O:29])[C@@H:14]3[CH2:13]2)(=O)=O)=CC=1.[F:46][C:47]1[CH:48]=[CH:49][C:50]2[C:59]([CH:60]=1)=[N:58][C:57]([OH:61])=[C:56]1[C:51]=2[CH:52]=[CH:53][CH:54]=[CH:55]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:40]([O:39][C:37]([NH:36][C@@H:17]1[C:16](=[O:44])[N:15]2[CH2:45][C@H:12]([O:61][C:57]3[N:58]=[C:59]4[C:50](=[C:51]5[C:56]=3[CH:55]=[CH:54][CH:53]=[CH:52]5)[CH:49]=[CH:48][C:47]([F:46])=[CH:60]4)[CH2:13][C@H:14]2[C:28](=[O:29])[NH:27][C@:26]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:25]2[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Reactant: Oc1nc2cc(F)ccc2c2ccccc12
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of (2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(4-bromophenylsulfonyloxy)-6-(tert-butoxycarbonylamino)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (1b, 2.3 g, 3.2 mmol), 3-fluorophenanthridin-6-ol (Example 1a, 0.688 g, 3.23 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in dimethylformamide (32 ml) was heated @80° C. for 5 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 2 N HCl. The organic phase was washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated. The resulting solid was purified by flash chromatography on silica gel, eluting with acetone/hexane, to provide the title compound (1.3 g, 60% yield).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCOc3ccccc3C2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc2c(c1)CNCCO2
Reaction time: 5 h
Yield: 95.9 %

Procedure:
10.2 g of 4-benzyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine were dissolved in 100 mL of ethanol and hydrogenated for 5 hours at room temperature using 1.2 g of palladium (10% on carbon) as catalyst. Filtration followed by removal of the solvent in vacuo gave 6.1 g of 2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine as an oil. EI-MS: 149 (M+).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][CH2:28][C:29](O)=[O:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:28](=[O:27])[CH2:29][OH:30])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)CO
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (70 mg, 73%), MS (ISP) m/z=385.4 [(M+H)+], mp 161° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-hydroxy-acetic acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:16][C@@H:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@@H:4]2[CH2:3]1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]1[CH2:16][C@@H:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:8][C@@H:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(=O)C[C@H]2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(O)C[C@H]2C1
Reaction time: 3 h
Yield: 93 %

Procedure:
Compound 1019 (4 g; 0.018 mole) was dissolved in 50 mL of ethanol. Sodium borohydride was added at RT portionwise. After stirring for 3 hours, the reaction was concentrated in vacuo. The resulting oil was dissolved in DCM (200 mL), washed with water, brine, (Na2SO4), and concentrated in vacuo to yield (3aR,6aS)-tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a yellow oil (Compound 1020, 3.79 g; 93% yield); 1H NMR (CDCl3): δ 4.2 (m, 1H), 3.55 (dd, 2H), 3.4 (dd, 2H), 2.7 (m, 2H), 2.2 (m, 2H), 1.6 (m, 2H), 1.5 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[N:11]=[C:12]([CH3:23])[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[C:7]2[NH:6][C:5]=1[CH3:24].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:15]1([CH3:22])[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[C:13]1[C:12]([CH3:23])=[N:11][N:8]2[C:9](=[O:10])[C:4]([CH2:3][CH:2]=[O:1])=[C:5]([CH3:24])[NH:6][C:7]=12
Reactant: Cc1cc(C)c(-c2c(C)nn3c(=O)c(CCO)c(C)[nH]c23)c(C)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c(-c2c(C)nn3c(=O)c(CC=O)c(C)[nH]c23)c(C)c1
Reaction time: 3 h
Yield: 67.6 %

Procedure:
Des Martin reagent was added gradually to a solution of 6-(2-hydroxyethyl)-3-mesityl-2,5-dimethyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-7-one (2.65 g, 8.14 mmol) in dichloromethane (200 mL) at room temperature, followed by stirring for three hours. A saturated solution of sodium thiosulfate was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane, 10% ethyl acetate/methanol), to give the title compound (1.78 g) as a yellow amorphous.
Reaction SMILES: [NH2:1][CH:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]([C:9]3[C:12](=[O:13])[C:11](=[O:14])[C:10]=3[CH3:15])[CH2:7][S:8][C@H:3]12.[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:50]/[O:51][CH3:52])/[C:41](N2C(=S)N(C)N=N2)=[O:42])[N:39]=1.CN(C)C=O>O1CCCC1.C(OCC)(=O)C>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:50]/[O:51][CH3:52])/[C:41]([NH:1][CH:2]2[C:32](=[O:33])[N:4]3[C:5]([C:16]([O:18][CH:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])=[C:6]([C:9]4[C:12](=[O:13])[C:11](=[O:14])[C:10]=4[CH3:15])[CH2:7][S:8][C@H:3]23)=[O:42])[N:39]=1
Reactant: Cc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Reactant: CO/N=C(\C(=O)n1nnn(C)c1=S)c1csc(N)n1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
A mixture of diphenylmethyl 7-amino-3-(3,4-dioxo-2-methyl-1-cyclobutenyl)-3-cephem-4-carboxylate (100 mg, 0.217 mmol) and 1-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl]-4-methyltetrazole-5-thione (65 mg, 0.217 mmol) in tetrahydrofuran (1 mL) was stirred at 5° C. for 0.25 hr and then for 1 hr at 22° C. when N,N-dimethylformamide (0.05 mL) was added. The solution was diluted with ethyl acetate. The solution was sequentially washed with dilute aqueous NaHCO3 (2×), H2O, and saturated NaCl and then was dried over Na2SO4. Removal of the solvent left a yellow solid which was chromatographed on SiO2 (6 g) with methylene chloride/2-propanol (96:4) to afford the title compound (120 mg, 86% yield) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].FC(S(OO[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O)(F)F.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[CH2:19][O:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cccc(Cl)c1O
Reactant: O=S(=O)(OOCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-hydroxy-3-chlorotoluene (5 g, 35 mmol) in DMF (75 mL) at 0° C. was added 2,2,2-trifluoroethoxy trifluoromethylsulfonate (16 g, 70 mmol) and Cs2CO3 (22 g, 68 mmol). The mixture was stirred at 0° C. for 3 h and then at ambient temperature for 14 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (150 mL) and water (3×75 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc:hexanes as eluant to give 2-(2,2,2-trifluoroethoxy)-3-chlorotoluene as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13].[C-:14]#[N:15].[Na+]>CO.O>[C:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13])#[N:15]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CC#N)c(F)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-fluorobenzoate (18 g, 73 mmol) in MeOH (150 ml) was added the solution of NaCN (7.2 g, 146 mmol) in H2O (40 ml). The mixture was stirred at 65° C. for 5 hours. Most of MeOH was evaporated and additional water was added and extracted by EtOAc (200 ml×3), dried with anhydrous Na2SO4, filtered and evaporated to give the crude product. Purification by column chromatography (PE/EtOAc=50/1 to 10/1) gave the product (8 g, 63.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][CH2:31][C:25]=3[N:24]([CH3:39])[C:23]=2[N:40]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:1].[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([C:19]2[CH:20]=[CH:21][C:22]3[C:26]4[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][C:25]=4[N:24]([CH3:39])[C:23]=3[N:40]=2)[C:8](=[O:12])[CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(Cl)cc2Cl)cc[nH]1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5Cl)cc4=O)nc31)CNCCC2
Temperature: 135 °C
Reaction time: 18 h
Yield: 130.1 %

Procedure:
A suspension of 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (85 mg, 0.31 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (131 mg, 0.345 mmol), CuI (71 mg, 0.38 mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs2CO3 (112 mg, 0.345 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 18 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH), 100:0 to 0:100) afforded a tan solid. 2 N HCl in Et2O (100 mL) was added to a solution of the tan solid in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 24 h. The suspension was filtered, and the solid was washed with Et2O and put in a vacuum oven at 45° C. for 1 h to afford 102 mg (64%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 8.88-8.81 (m, 2H), 8.16 (d, J=8.5 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.53 (dd, J=8.0, 2.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.18 (dd, J=8.0, 2.5 Hz, 1H), 6.03 (d, J=2.5 Hz, 1H), 5.21 (s, 2H), 4.52-4.48 (m, 2H), 3.77 (s, 3H), 3.50-3.43 (m, 2H), 3.19-3.12 (m, 2H), 2.13-2.05 (m, 2H); ESI MS m/z 469 [M+H]−