Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-].[NH4+]>C(#N)C.O>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([C:13]2[CH:12]=[N:11][N:10]([C:8]3([CH2:32][C:33]#[N:34])[CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:9]3)[CH:14]=2)=[N:20][CH:19]=1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (6, 327 g, 655 mmol) in acetonitrile (3 L) and water (300 mL) was added LiBF4 (614 g, 6.55 mol, 10.0 equiv). The resulting reaction mixture was stirred at 75° C. for overnight. The reaction mixture was cooled to 0° C. before a solution of ammonium hydroxide (NH4OH, 570 mL) in water (2.2 L) was added slowly to keep the temperature below 10° C. (pH 9-10). The mixture was stirred at room temperature for overnight. When the reaction was deemed complete, water (10 L) was added and the resulting mixture was vigorously stirred for 3 h at room temperature. The solids were collected by filtration, washed with water (6.7 L) and heptane (6.7 L), and dried in vacuum oven at 45° C. over the weekend. The dried solid was then dissolved in 20% MeOH in dichloromethane (12 L), and was purified by column chromatography on 1.3 Kg of silica gel eluting with a 20% MeOH in dichloromethane solution (18L) to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 243.3 g theoretical, 83.8% yield) as an off-white solid. For 7: 1H NMR (300 MHz, d6-DMSO) δ 1.25 (t, 3H), 3.25 (q, 2H), 3.75 (s, 2H), 4.25 (d, 2H), 4.65 (d, 2H), 7.10 (d, 1H), 7.65 (dd, 1H), 8.50 (s, 1H), 8.70 (s, 1H), 8.95 (s, 1H), 12.2 (bs, 1H); MS: m/z calcd. 372.12; found: 372.0.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N1C2C=C(Cl)C=CC=2N=N1)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@H:20]([C:25]([OH:27])=[O:26])[C@H:21]([CH2:23][CH3:24])[CH3:22].C(N(CC)CC)C>O.C(O)(C)(C)C>[C:1]([O:5][C:6]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[C@H:21]([CH2:23][CH3:24])[CH3:22])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)On1nnc2ccc(Cl)cc21
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Yield: 104.7 %

Procedure:
A suspension of 1-tert-butoxycarbonyloxy-6-chloro-1H-benzotriazole (2.7 g.), L-isoleucine (1.3 g) and triethylamine (3.5 ml.) in a mixture of water (8 ml.) and tert-butyl alcohol (12 ml.) was stirred for 2 hours at 60° to 62° C. tert-Butyl alcohol was distilled off from the reaction mixture under reduced pressure and water (15 ml.) was added to the residue. The mixture was adjusted to pH 3 with a citric acid aqueous solution under ice-cooling and extracted with ethyl acetate. The extract was then washed with water and a saturated sodium chloride aqueous solution. The thus formed precipitates were filtered off and then the filtrate was dried over magnesium sulfate. The solution was concentrated and a mixture of ether and petroleum ether (1:1) was added to the residue. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give N-tert-butoxycarbonyl-L-isoleucine (2.4 g.), oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:10]=2[N:11]=1.Cl[C:20]1[CH:25]=[C:24](Cl)[CH:23]=[CH:22][C:21]=1[S:27]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35](C2C=CC3N=CN=C(OC4CCOCC4)C=3N=2)[CH:36]=1)(=[O:29])=[O:28].C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:13]1([S:12][C:9]2[C:10]3[N:11]=[C:2]([C:35]4[CH:36]=[C:31]([NH:30][S:27]([C:21]5[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=5)(=[O:28])=[O:29])[CH:32]=[N:33][CH:34]=4)[CH:3]=[CH:4][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Cl)cc1Cl
Reactant: Clc1ccc2ncnc(SC3CCCCC3)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(SC4CCCCC4)c3n2)c1)c1ccccc1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A mixture of 6-chloro-4-(cyclohexylthio)pyrido[3,2-d]pyrimidine (Intermediate 15) (0.12 g, 0.429 mmol), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (Intermediate 2) (0.12 g, 0.429 mmol), 1 N aq. sodium bicarbonate (0.858 ml, 0.858 mmol) and PdCl2(dppf)-CH2Cl2 (0.035 g, 0.043 mmol) in dioxane (2.14 ml) was subjected to microwave irradiation for 1 hour at 110° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with DCM. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(5-(4-(cyclohexylthio)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfon-amide (0.09 g, 89%) as a brown solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.26-1.28 (1H, m), 1.34-1.43 (1H, m), 1.52-1.85 (4H, m), 1.85-1.87 (2H, m), 2.19-2.23 (2H, m), 4.12-4.19 (1H, m), 7.48-7.58 (3H, m), 7.92 (2H, d, J=8.8 Hz), 8.21 (1H, d, J=8.8 Hz), 8.32 (1H, d, J=9.2 Hz), 8.41-8.43 (2H, m), 8.99 (1H, s), 9.13 (1H, s). m/z=478.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].O[NH:13][C:14](=[NH:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][N:23]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:13]=1
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: COc1ccccc1C(=N)NO
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CCCCc1nc(-c2ccccc2OC)no1
Yield: 62.1 %

Procedure:
Add 5-chlorocarbonylpentanoic acid methyl ester (15.30 g, 86 mmol) to a solution of N-hydroxy-2-methoxybenzamidine (12.0 g, 71 mmol) in pyridine (40 mL) and under nitrogen at a rate to keep the mixture at a gentle reflux. Then, heat the mixture at reflux for 4 hours. Dilute the mixture with water (300 mL) and extract with methylene chloride (3×200 mL). Wash the combined organic extracts with brine (100 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:19), to afford 5-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]pentanoic acid methyl ester (12.8 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17]C(=O)OC(C)(C)C)=[N:15][CH:16]=3)=[CH:9][N:8]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:9][N:8]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.1 %

Procedure:
A solution of tert-butyl N-[5-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-pyridyl]carbamate (0.13 g, 0.315 mmol) in dichloromethane (5.5 ml) was cooled to 0° C. then treated with trifluoroacetic acid (0.6 ml). The solution was stirred at 0° C. for 5 minutes then warmed to ambient temperature and stirred for a further 18 hours. The solvents were evaporated under reduced pressure then the residue was partitioned between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (10 ml). The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give 5-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-pyridinamine (92 mg): RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=10.73 min; MS: MH+314.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[S:9][N:8]=1.Cl.CCCCCC>O1CCCC1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[S:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccn3)ns2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(-c2nsc(N3CCNCC3)n2)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 4-(3-pyridin-2-yl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxylate (6.35 g, 17.0 mmol) was dissolved in tetrahydrofuran (100 ml), and a solution of 4 N hydrogen chloride in ethyl acetate (50 ml) was added thereto, followed by stirring at room temperature for 5 hours. Hexane (250 ml) was poured to the reaction mixture, and a solid was separated by filtration. The obtained solid was dissolved in an aqueous saturated sodium hydrogen carbonate solution, followed by stirring at room temperature for 2 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with a mixed solution of ethyl acetate/tetrahydrofuran (1:1). The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and 2.79 g (67.0%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH:3]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: Nc1nccs1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2nccs2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A suspension of 4-methyl-2-chloropyridine (5.10 g, 40.0 mmol), 2-aminothiazole (4.81 g, 48 mmol, 1.2 eq), sodium carbonate (5.94 g, 56.0 mmol, 1.4 eq) and XANTPHOS (0.278 g, 0.48 mmol, 0.012 eq) in THF (100 mL, bubbled with argon for 5 minutes) was bubbled again with argon for 5 additional minutes. Tris(dibenzylideneacetone)dipalladium (0) (0.146 g, 0.16 mmol, 0.004 eq) was then added to the suspension which was heated at 130° C. for 2 days. Additional quantities of XANTPHOS (0.278 g) and tris(dibenzylideneacetone)dipalladium (0) (0.146 g) were added again and the reaction was heated at 130° C. for 4 more days. The mixture was cooled to RT and filtered. The resulting solid was suspended in water and stirred for 1 hour. After filtration, the resulting solid was dried under vacuum overnight. The THF filtrate was evaporated and the residue was combined to the previously isolated solid. This was precipitated from MeOH to give the title compound (5.14 g, 67%) as a solid. The mother liquor was evaporated and the residue purified by silica gel chromatography (50% ethyl acetate/dichloromethane to 100% ethyl acetate) and afforded the title material (0.825 g, 11%) as a solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 2.36 (3H, s), 6.71 (1H, s), 6.75 (1H, br d, J=5.1 Hz), 6.84 (1H, d, J=3.5 Hz), 7.43 (1H, d, J=3.5 Hz), 8.24 (1H, d, J=5.3 Hz). LC/MS (M+H)+: 192. HPLC ret. time (Condition A): 1.285 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+].CC([O-])(C)C.[K+]>O.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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35](=[O:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: CCOC(=O)CCC(=O)N1CCC(N)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCC(=O)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 25-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (300 mg, 0.65 mmol, 1.00 equip, 99%), ethyl 4-(4-aminopiperidin-1-yl)-4-oxobutanoate (295.1 mg, 0.97 mmol, 1.50 equip), Pd2(dba)3 (60 mg, 0.06 mmol, 0.10 equip, 99%), dppf (126.7 mg, 0.23 mmol, 0.35 equip, 99%), Cs2CO3 (532.7 mg, 1.62 mmol, 2.50 equip, 99%), t-BuOK (146.4 mg, 1.29 mmol, 2.00 equip, 99%), and 1,4-dioxane (9 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with water (80 mL). The resulting solution was extracted with ethyl acetate (3×80 mL) and the organic layers combined. The resulting mixture was washed with water (1×80 mL) and brine (1×80 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBD 5 μm, 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B:CH3CN (20% CH3CN up to 80% in 8 min, up to 100% for 0.1 min, hold 100% in 1.9 min, down to 20% in 0.1 min, hold 20% in 1.9 min); Detector, UV 220 & 254 nm to yield ethyl 4-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]-4-oxobutanoate as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3.[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH3:7][C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][CH:19]([OH:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3
Reactant: C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
Refer to FIG. 189. LAH (21.3 mg, 0.561 mmol) was added to a solution of 17β-methylandrost-4-en-3-one (7, 143.2 mg, 0.4999 mmol) (J. B. Jones and K. D. Gordon, Can. Chem. 1972, 50, 2712-2718) in 2.8 ml of anh. ether. After stirring the suspension for 30 min. Glauber's salt (0.76 g) was added and the mixture stirred a further 1/2 h. Ether (10 ml) was added and the suspension was filtered through diatomaceous earth. The residue was washed with three 10 ml portions of ether and the combined filtrates were concentrated under reduced pressure. The crude product was separated by preparative TLC (silica gel GF, 1000μ, 5% ethyl acetate/methylene chloride as eluent) into a more polar component (Rf 0.30, 77.9 mg, 0.270 mmol, 54%) and a less polar component (Rf 10 0.43, 10.3 mg, 0.0357 mmol, 7%).
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)([CH3:7])[C:3]([O:5]C)=O.F[C:19]1[C:28]([N+:29]([O-])=O)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([C:32](F)(F)F)[CH:20]=1>>[CH3:7][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:3](=[O:5])[NH:29][C:28]2[CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:21]([CH3:32])=[CH:20][C:19]=2[O:1]1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C(F)(F)F
Reactant: COC(=O)C(C)(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1cc2c(cc1C)OC(C)(c1cccc(C(F)(F)F)c1)C(=O)N2

Procedure:
Using methyl 2-hydroxy-2-[3-(trifluoromethyl)phenyl]propanoate and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[H-].[Na+].[CH3:22][O:23][C:24]([C:26]1[O:27][C:28]([CH2:31]Cl)=[CH:29][CH:30]=1)=[O:25].C(#N)C.O>C1COCC1.[Cl-].[NH4+].O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:31][C:28]2[O:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:30][CH:29]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)c1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)o1
Temperature: 68 °C

Procedure:
To a room temperature suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (330.1 mg, 1.00 mmol)) and NaH (48.0 mg, 2.0 mmol) in THF (1.6 mL) was added methyl-5-chloromethyl-2-furate (400 mg, 2.30 mmol). The resulting suspension was stirred and heated to 68° C. for 8 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ammonium chloride (saturated aqueous solution, 10 mL) and water (100 mL). This resulting emulsion was then extracted with ethyl acetate (3×300 mL). The resulting organic extract was separated, Na2SO4 dried, and concentrated. The resulting dark residue was subjected to SiO2 chromatography with ethyl acetate/hexanes (3:7) to furnish a solid. 1H NMR (400 MHz, CDCl3) δ 7.53 (app q, J=8.2 Hz, 1H), 7.07 (d, J=3.5 Hz, 1H), 6.93 (app dt, J=8.4, 1.5 Hz, 1H), 6.84 (app ddd, J=10.2, 8.7, 2.4 Hz, 1H), 6.53 (d, J=3.4 Hz, 1H), 6.00 (s, 1H), 5.27 (s, 2H), 5.18 (s, 2H), 3.85 (s, 3H), 2.54 (s, 3H); LC/MS C-18 column, tr=2.64 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 468 (M+H). ES-HRMS m/z 468.0276 (M+H calcd for C20H17BrF2NO5 requires 468.0253).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=O)[CH:11]=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.O.C(O)(=O)C>[N+:16]([CH2:19][CH2:14][C:10]1[CH:11]=[N:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)([O-:18])=[O:17]
Reactant: O=Cc1cncc(Oc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1cncc(Oc2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 28.2 %

Procedure:
To an acetic acid (15 mL) solution of 5-phenoxy-pyridine-3-carbaldehyde (607 mg, 3.05 mmol) described in Manufacturing Example 145-1-3 were added nitromethane (826 μL, 15.3 mmol) and ammonium acetate (470 mg, 6.10 mmol), which was stirred for 3 hours at 100° C. under nitrogen atmosphere. Water was added at room temperature to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. To a solution of this residue in dimethyl sulfoxide (10 mL) and acetic acid (1 mL) was added sodium borohydride (182 mg, 4.58 mmol), which was stirred for 20 minutes at room temperature. Sodium hydrogencarbonate and water were added to the reaction mixture at room temperature while cooling appropriately, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1) to obtain the title compound (210 mg, 28%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:8][CH:7]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:25]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)=[CH:10][CH:11]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (107 mg) in methanol (2 mL) were added benzaldehyde (30 μL) and sodium hydrogen carbonate (37.8 mg). The mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (17.0 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized (hexane/ethyl acetate) to give the title compound (66.0 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.O(P(O[C:27]1[CH2:28][C@@H:29]2[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]2[C:31]=1[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:44]([O:47][C:48]([N:50]1[CH2:54][C@@H:53]([SH:55])[CH2:52][C@H:51]1[CH2:56][CH:57]1[CH2:61][CH2:60][NH:59][C:58]1=[O:62])=[O:49])[CH:45]=[CH2:46].C(OCC)(=O)C>C(#N)C>[CH2:44]([O:47][C:48]([N:50]1[CH2:54][C@@H:53]([S:55][C:27]2[CH2:28][C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:52][C@H:51]1[CH2:56][CH:57]1[CH2:61][CH2:60][NH:59][C:58]1=[O:62])=[O:49])[CH:45]=[CH2:46]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1CCNC1=O
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3CCNC3=O)N(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 1 h
Yield: 76.7 %

Procedure:
N,N-diisopropylethylamine (0.13 ml, 0.76 mmol) was dropwise added to a solution of allyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (369 mg, 0.76 mmol) and (2R,4S)-N-allyloxycarbonyl-4-mercapto-2-(2-pyrrolidon-3-ylmethyl)pyrrolidine (216 mg, 0.76 mmol) in acetonitrile (5.6 ml) under cooling with ice. The reaction mixture solution was stirred at the same temperature for one hour and further stirred at 5° C. for 16 hours. Ethyl acetate (60 ml) was added to the reaction solution. The mixture was washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (Wakogel™ C-300, 40 ml, acetone-ethyl acetate 2:3). The fraction containing the desired product was concentrated to obtain allyl (5R,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (303 mg, yield: 76.7%) in the form of foam.