Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C(Cl)Cl>[O:9]1[C:13]2([CH2:18][CH2:17][CH:16]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1
Reactant: Nc1ccccc1O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1ccccc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A mixture of 2-aminophenol (2 g, 18.327 mmol), 1,4-dioxa-spiro[4.5]decan-8-one (3.721 g, 23.825 mmol), and sodium triacetoxyborohydride (5.826 g, 27.491 mmol) in DCE (20 ml) and acetic acid (0.2 ml) was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM and washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and the solvent was evaporated in vacuo. The solid residue was triturated with diisopropyl ether to yield D19 (3.78 g) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([NH2:15])=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.Cl.O1CCOCC1.[Na]>O>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]2[CH2:14][CH:12]3[CH2:13][N:3]([CH2:1][CH3:2])[CH2:4]2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC2CC(C1)c1cc(N)ccc12
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CC2CC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 120 °C
Yield: 77.6 %

Procedure:
10-ethyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (75 mg, 0.37 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (120 mg, 0.41 mmol) and 4N HCl in dioxane (275 μl, 0.41 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil (87 mg). The crude reaction was purified on a 80 g Isco basic alumina column using 0-2% methanol in methylene chloride as the eluent to yield 2-[5-Chloro-2-(10-ethyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (133 mg, 78%) as a beige powder. MP: 220° dec.; 1H-NMR (CDCl3) δ 10.97 (s, 1H), 8.66 (d, J=8.3, 1H), 8.09 (s, 1H), 7.50-7.38 (m, 3H), 7.21 (d, J=5 Hz, 1H), 7.08 (m, 2H), 6.91 (s, 1H), 6.20 (br s, 1H), 3.12-2.95 (m, 5H), 2.87 (br, s), 2.45-2.20 (m, 6H), 1.69 (d, J=10.1 Hz, 2H), 0.90 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:26])[CH2:13][C:14]([OH:25])([CH3:24])[CH:15]([OH:23])[C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19].[CH3:27]I>CCOC(C)=O.[Ag]=O>[CH3:27][O:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:26])[CH2:13][C:14]([OH:25])([CH3:24])[CH:15]([OH:23])[C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C=C(C)C(O)C(C)(O)CC(C)CCCCC1OC(=O)C1CO
Reactant: CI
Agent: O=[Ag]
Solvent: CCOC(C)=O
Product: COCC1C(=O)OC1CCCCC(C)CC(C)(O)C(O)C(C)=CC(=O)OC
Temperature: 53 °C

Procedure:
10 mg of methyl 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl-2-undecenoate in 2 ml of EtOAc was added 35 mg of silver oxide and 0.3 ml of methyl iodide. The mixture was heated at 53° C. overnight. The solution was filtered and concentrated by dryness. The product was purified by prep. TLC (EtOAc:Hexane=1:1) to afford methyl 11-(3-methoxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl-2-undecenoate. ##STR26##
Reaction SMILES: ClC1C=C(C#CC=O)C=CC=1.C([O:14][CH:15](OCC)[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)C>>[CH3:24][C:20]1[CH:19]=[C:18]([C:17]#[C:16][CH:15]=[O:14])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(C#Cc1cccc(C)c1)OCC
Agent: O=CC#Cc1cccc(Cl)c1
Product: Cc1cccc(C#CC=O)c1

Procedure:
The title compound was synthesized following the procedure reported for Compound 31d, but starting from Compound 91a instead of Compound 31c. The crude title compound was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC=CC=1.[OH-].[CH2:18]([N+:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:19]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([N+:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc([O-])cc1
Yield: 94.7 %

Procedure:
A mixture of 4-nitrophenol (13.9 g, 0.10 mol) and benzene (250 mL) was treated with tetraethylammonium hydroxide (14.7 g, 0.10 mol), added as a 20% aqueous solution. The mixture was heated under reflux until all water was removed by azeotropic distillation. The solution was allowed to cool with continued stirring. Upon standing, 25.4 g of a yellow solid was obtained; it was recrystallized from THF. 1H NMR (CDCl3) confirmed the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([OH:21])=[C:6]([CH:8](Cl)[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=2[OH:19])[CH:7]=1.[CH2:25]([OH:29])[CH:26]([CH3:28])[CH3:27].[H-].[Na+]>O>[CH2:25]([O:29][CH:8]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[OH:19])[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]=1[OH:21])[CH:26]([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(Cl)c2cc(Cl)cc([N+](=O)[O-])c2O)c1O
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)COC(c1cc(Cl)cc([N+](=O)[O-])c1O)c1cc(Cl)cc([N+](=O)[O-])c1O

Procedure:
A mixture of bis(5-chloro-2-hydroxy-3-nitrophenyl)methyl chloride (5 g) and isobutanol (50 ml) was stirred at a temperature of 0° C. and sodium hydride (1 g) was added portionwise. On completion of the addition the mixture was stirred for a further hour and poured into water. The aqueous solution was extracted into ether/petroleum ether and the solvents removed by distillation under reduced pressure. The residue was recrystallised from petroleum ether (b.p. 40°-60° C.) to give 4.3 g of bis(5-chloro-2-hydroxy-3-nitrophenyl)methyl isobutyl ether m.p. 95° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)/[CH:14]=[CH:15]/[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)#[N:6]>CN(C)C=O>[NH:1]1[C:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)/[CH:14]=[CH:15]/[C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:6][N:3]=[N:2]1
Reactant: N#CCCCNc1cccc(/C=C/c2nc3ccccc3s2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=C/c1nc2ccccc2s1)\c1cccc(NCCCc2nnn[nH]2)c1
Temperature: 120 °C
Yield: 34.5 %

Procedure:
To 5 ml of dimethylformamide were added 390 mg of sodium azide and 638 mg of 2-[trans-3-(3-cyanopropylamino)styryl]benzothiazole, and the mixture was heated to 120° C. for 7 hours. After cooled to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent was evaporation under reduced pressure. The concentrate was purified through silica gel column chromatography by use of ethyl acetate to obtain 250 mg (yield 35%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=2)[C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1.Br[CH:26]([CH3:28])[CH3:27]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH:19]3[CH2:24][CH2:23][N:22]([CH:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]3)[N:14]=2)[C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1
Reactant: O=c1oc(-c2cc(Cl)cc3c2OCCC3)nn1C1CCNCC1
Reactant: CC(C)Br
Agent: Cl
Product: CC(C)N1CCC(n2nc(-c3cc(Cl)cc4c3OCCC4)oc2=O)CC1
Yield: 118.9 %

Procedure:
From 0.5 g (1.34 mmol) of 5-(6-chloro-3,4-dihydro-2H-benzopyran-8-yl)-3- (piperidin-4-yl) -1,3,4-oxadiazol-2(3H)-one hydrochloride and 0.378 g (1.34 mmol) of 1-bromo-1-methylethane, and by carrying out the preparation as described in Example 15, 0.33 g of compound is obtained. Melting point: 241° C.
Reaction SMILES: [O:1]=[C:2]1[C:11](B(O)O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Br[C:16]1[S:20][C:19]([N:21]([CH3:32])[CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[N:18][N:17]=1>>[CH3:32][N:21]([CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]1)[C:19]1[S:20][C:16]([C:11]2[C:2](=[O:1])[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:17][N:18]=1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: O=c1[nH]c2ccccc2cc1B(O)O
Product: CN(c1nnc(-c2cc3ccccc3[nH]c2=O)s1)C1CC(C)(C)NC(C)(C)C1

Procedure:
Following a similar procedure as described for Step 3 in Example 101, (2-oxo-1,2-dihydroquinolin-3-yl)boronic acid and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (858 mg, 2.57 mmol) were reacted to provide the crude product, which was purified by preparative HPLC under basic condition to give 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one (14 mg, MS: 398.2 [M+H+], LCMS Rt=0.51 min (LCMS method D); 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.74 (s, 1H), 7.67-7.80 (m, 1H), 7.47-7.57 (m, 1H), 7.31 (d, J=8.08 Hz, 1H), 7.19-7.27 (m, 1H), 4.34 (br. s., 1H), 2.99 (s, 3H), 1.71 (dd, J=12.63, 3.03 Hz, 2H), 1.50 (t, J=12.38 Hz, 2H), 1.28 (s, 6H), 1.10-1.23 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]>CCO>[NH2:2][CH2:1][C:3]1[C:4]([F:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccnc1F
Solvent: CCO
Product: NCc1cccnc1F
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A round bottom flask was charged with 0.3 g (2.46 mM) of 3-cyano-2-fluoropyridine (19), which was then diluted in 20 mL EtOH. The solution was flushed with argon, and then while under a blanket of argon, 60 mg of 10% Pd/C (20% by weight), was added. The system was then sealed by septum and put under vacuum. A hydrogen balloon was then added, and the reaction was stirred for three hours (followed by TLC). The reaction was then put under vacuum again, then exposed to air, and filtered (keeping catalyst wet). The resulting solution was dried and evaporated to give 0.28 g (90%) of the title compound, 3-aminomethyl-2-fluoropyridine (20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])=[O:8].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]([F:21])([F:22])[F:23])=[O:8]
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1OC(=O)N1CCOCC1
Yield: 92.1 %

Procedure:
Using 5-chloro-2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:13]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[N:12]=[C:11]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO.O1CCCC1.[OH-].[Na+].O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:13]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[N:12]=[C:11]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:44])[F:42])=[CH:37][CH:36]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3/C=C/c3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3/C=C/c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Methyl 3-(4-{[4-({5-[(E)-2-phenylvinyl]-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)benzyl]oxy}phenyl)propanoate (250 mg, 0.419 mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and 2 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and neutralized with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure to give the title compound (220 mg, yield 90%) as colorless crystals. MS: m/z 583 (MH+), 1H NMR (DMSO-d6) δ: 2.45 (2H, t, J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz), 5.00 (2H, s), 5.65 (2H, s), 6.86 (2H, d, J=8.5 Hz), 7.09 (2H, d, J=8.5 Hz), 7.22-7.46 (10H, m), 7.64 (2H, d, J=7.4 Hz), 7.77 (2H, d, J=8.2 Hz), 8.05 (2H, d, J=8.0 Hz), 12.05 (1H, s).
Reaction SMILES: Br[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:10]1([N:16]2[C:24](=[O:25])[C:23]3[C@@H:22]4[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]4)[C:18]=3[NH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O.CO>[CH2:2]([N:17]1[C:18]2[C@@:19]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:22]([CH2:21][CH2:20]3)[C:23]=2[C:24](=[O:25])[N:16]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:3]
Reactant: CCBr
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: CCn1c2c(c(=O)n1-c1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A mixture of bromoethane (1.05 mL, 14.1 mmol), potassium carbonate (3.58 g, 25.9 mmol), and (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 1.74 g, 6.5 mmol) in acetone (20 mL) and methanol (3 mL) was stirred at room temperature over the weekend then the solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was evaporated, and the residue was chromatographed (0-50% ethyl acetate/hexanes) and recrystallized from ethyl acetate to give (4S,7R)-1-ethyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (168 mg, 9%) as a white solid. APCI-MS (M+H) 297.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11](=O)[CH2:12][C:13]([C:15]1[C:16]([OH:36])=[C:17]([CH:25]2[CH2:29][CH2:28][N:27]([CH3:30])[CH:26]2[CH2:31][O:32]C(=O)C)[C:18]([O:23][CH3:24])=[CH:19][C:20]=1[O:21][CH3:22])=[O:14].C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[O:36][C:16]2[C:15]([C:13](=[O:14])[CH:12]=1)=[C:20]([O:21][CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[C:17]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32]
Reactant: COc1cc(OC)c(C2CCN(C)C2COC(C)=O)c(O)c1C(=O)CC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c2c(=O)cc(-c3ccc([N+](=O)[O-])cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the compound of example (45)(20 g, 37.5 mmol) in dioxane (150 mL) was added dropwise to a suspension of sodium hydride (60% dispersion, 5.68 g, 142 mmol) in dioxane (50 mL) and the reaction mixture stirred at room temperature for 12 hrs. The reaction mixture was quenched with dropwise addition of methanol and the solvents evaporated under reduced pressure. The residue was acidified with dilute HCl, basified with 10% NaHCO3 solution to pH 8 to 9 and extracted with EtOAc (3×250 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give acetic acid 3-{3-[3-(2-chloro-4-nitrophenyl)-3-oxopropionyl]-2-hydroxy-4,6-dimethoxyphenyl}-1-methyl-pyrrolidin-2-ylmethyl ester as an oil (18.2 g). This ester was dissolved in conc. HCl (50 mL) and stirred at room temperature for 3 hrs. At the end of 3 hrs, the reaction mixture was basified with solid NaHCO3 to pH 8 to 9. The aqueous layer was extracted with chloroform (3×250 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried over vacuum. The residue was purified by column chromatography with 3% methanol in chloroform and 0.1% ammonia as eluent to yield the compound (+)-trans-2-(2-chloro-4-nitrophenyl)-8-(2-hydroxymethyl-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([Cl:19])[CH:15]=[CH:14][C:13]=3[F:20])[C:5]([NH2:8])=[N:6][CH:7]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([F:20])=[C:12]2[C:17]=1[CH:18]=[C:9]([C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[CH:3]=1)[N:10]=[CH:11]2
Reactant: OB(O)c1ccsc1
Reactant: Nc1ncc(Br)cc1-c1cc2c(Cl)ccc(F)c2cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2ccsc2)cc1-c1cc2c(Cl)ccc(F)c2cn1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromo-3-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-2-ylamine (BB4) (25 mg, 0.070 mmol), 3-thienylboronic acid (20 mg, 0.10 mmol) and potassium carbonate (29 mg, 0.21 mmol) in 1,4-dioxane (1.0 mL) and H2O (0.4 mL) was degassed and refilled with argon (3×) prior to the addition of Pd(dppf)Cl2 (5 mg, 0.01 mmol). The reaction mixture was degassed and refilled with argon (2×) and left to stir at 100° C. in the microwave reactor for 30 min. Then, the mixture was passed through PL-Thiol MP SPE resin and concentrated in vacuo. The residual oil was partitioned between DCM and H2O. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification via MDP afforded the title compound as a yellow solid. MS (ES+): m/z=356.03/358.05 (100/50) [MH+]. HPLC: tR=3.22 min (ZQ2, polar—5 min).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([O:6][CH2:7][C:8]1[CH2:25][S:24][C@@H:11]2[C@H:12]([NH:15]C(CCCC(O)=O)=O)[C:13](=[O:14])[N:10]2[C:9]=1[C:26]([OH:28])=[O:27])=[O:5]>>[CH3:3][C:4]([O:6][CH2:7][C:8]1[CH2:25][S:24][C@@H:11]2[C@H:12]([NH2:15])[C:13](=[O:14])[N:10]2[C:9]=1[C:26]([OH:28])=[O:27])=[O:5]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCCC(=O)O)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 1 h

Procedure:
CC Acylase immobilized on HPA 25 (20 mL) and prepared in the above-mentioned (2) was packed in a column with a jacket, and 6.0 mg/mL glutaryl 7-aminocephalosporanic acid (GL7-ACA) solution (100 mL) was circulated for one hour at 20° C. at circulation flow rate of about 70 mL/min while adjusting the pH to 7.75 with NaOH, whereby 7-ACA was obtained. After the reaction, the reaction mixture in the column was pushed out with water and 7-ACA was recovered. The above-mentioned reaction was repeated 100 times (continuous batch reaction), which was taken as one cycle.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Sn](C)(C)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CN1C(=O)CCC1.CCOC(C)=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]>[N:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Reactant: C[Sn](C)(C)c1ccccn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccn3)C(=O)CC2)cc1
Temperature: 100 °C
Yield: 19.6 %

Procedure:
To a degassed r.t. solution of 2-bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (1.103 g, 3.5 mmol), Pd2 (dba)3 (0.064 g, 0.07 mmol), and AsPh3 (0.171 g, 0.56 mmol) in NMP (7.5 mL) was added a degassed NMP solution (10 mL) of 2-trimethylstannanyl pyridine (~7.0 mmol). The resulting mixture was heated to 100° C. for 16 hours. The mixture was then cooled to r.t., diluted with EtOAc, washed 3 times with 10% NH4OH and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (5% MeOM/EtOAc) to provide 0.215 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[O:4][N:3]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[O:4][N:3]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1cccc(-c2cc(O)no2)c1
Reactant: CC(C)(C)OC(=O)NCCO
Product: COc1cccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)c1
Yield: 80.6 %

Procedure:
3-Hydroxy-5-(3-methoxyphenyl)isoxazole (0.22 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.31 g, 82%) as a colorless powder.
Reaction SMILES: [CH2:1](N(CC1C=CC=CC=1)[C@@H](CC)C=O)C1C=CC=CC=1.[C:21]([O:24][C@@H:25]([C@@H:32]([N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][CH3:34])[C:26]([NH:28][CH:29]1[CH2:31][CH2:30]1)=[O:27])(=[O:23])[CH3:22]>>[C:21]([O:24][C@@H:25]([C@@H:32]([N:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:33][CH2:34][CH3:1])[C:26]([NH:28][CH:29]1[CH2:31][CH2:30]1)=[O:27])(=[O:23])[CH3:22]
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC[C@@H]([C@H](OC(C)=O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1
Product: CCC[C@@H]([C@H](OC(C)=O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Similarly, following the procedure of Example 5A, but replacing (S)-2-(dibenzylamino)pentanal with (S)-2-(dibenzylamino)butanal, (2S,3S)-1-(cyclopropylamino)-3-(dibenzylamino)-1-oxopentan-2-yl acetate is prepared.