Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[Cl:28])=[C:11]([F:19])[C:12]3[O:16][N:15]=[C:14]([CH3:17])[C:13]=3[CH:18]=2)=[O:8])CC1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH:46]([O:48]CCON)=[CH2:47].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH:46]([O:48][CH2:1][CH2:4][O:5][NH:6][C:7]([C:9]1[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[Cl:28])=[C:11]([F:19])[C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH:18]=1)=[O:8])=[CH2:47]
Reactant: C=COCCON
Reactant: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCC3CC3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 144 h
Yield: 63.4 %

Procedure:
To a solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (10a) (75.2 mg, 0.188 mmol) in DMF (1.5 mL) was added HOBt (38.2 mg, 0.249 mmol), Et3N (0.080 mL, 0.571 mmol), O-(2-vinyloxyethyl)hydroxylamine (28.5 mg, 0.276 mmol), and EDCI (47.2 mg, 0.246 mmol) at room temperature. After 6 days, the reaction mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated in vacuo, and purified by flash column chromatography using the Biotage system (3% MeOH in CH2Cl2) to give 57.8 mg (63%) of the desired product (11a).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:14][O:13][C:10]1[C:11]2[O:12][CH2:16][CH2:17][O:1][C:2]=2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=1
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1OCCO2
Reaction time: 6 h
Yield: 81.3 %

Procedure:
A mixture of methyl 2,3-dihydroxy-4-methoxybenzoate (0.176 mol), 1,2-dibromo-ethane (0.282 mol), K2CO3 (0.444 mol) and CuO (1.4 g) in DMF (1000 ml) was stirred for 6 hours, cooled, filtered and the filtrate was evaporated. Water (300 ml) was added. The mixture was extracted twice with DCM (300 ml). The organic layer was separated, washed with a saturated NaHCO3 solution, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 32.1 g of methyl 2,3-dihydro-8-methoxy-1,4-benzodioxin-5-carboxylate (intermediate 1, mp. 84° C.).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]#[N:29])[N:19]=1>CN1C(=O)CCC1>[C:28]([C:20]1[N:19]=[C:18]([NH:1][CH2:2][C@@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:27]2[C:22]([CH:21]=1)=[CH:23][CH:24]=[CH:25][CH:26]=2)#[N:29]
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(C#N)cc2ccccc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (350 mg, 1.750 mmol) in NMP (4 mL) at 0° C. was treated with NaH (70.0 mg, 1.750 mmol) and stirred for 1 hour. Next, 1-chloroisoquinoline-3-carbonitrile (300 mg, 1.591 mmol) was added and the reaction mixture was stirred at RT for 15 minutes and then heated at 140° C. for 15 minutes in a microwave reactor. The crude reaction mixture, which contained the title compound, was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH:10]([OH:22])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.C>[Pd].O1CCOCC1>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH:10]([OH:22])[CH2:9][O:8][C:7]2[CH:23]=[CH:24][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(OCC(O)COc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(OCC(O)COc2ccc(N)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 33.4 g (0.1 mole)-viscous liquid of 1,3-bis (4-nitrophenoxy)-2-propyl alcohol obtained in Example 6, 3 g of activated charcoal powder containing 5% Pd, and 250 ml of 1,4-dioxane were placed in a reaction vessel (hydrogenating apparatus). And the reaction mixtures were heated at 60° C. under a hydrogen atmosphere. In approximately 8 hours, 14.4 L of hydrogen was absorbed and the reaction was completed when the absorption of hydrogen stopped. Then the reacted solution was separated by filtration and the filtrate was concentrated for removing the catalyst. 27.4 g of 1,3-bis (4-aminophenoxy)-2-propyl alcohol was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([N:47]=[C:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:43](O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].P([N:78]=[N+:79]=[N-:80])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C@H:44]([N:47]=[C:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@H:43]([N:78]=[N+:79]=[N-:80])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N=C(c2ccccc2)c2ccccc2)C(O)C1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](N=C(c2ccccc2)c2ccccc2)[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
In a flame-dried flask triphenylphosphine (3.86 g; 14.7 mmol; 2 eq.) was dissolved in anhydrous THF (15 ml) and cooled to 0 C. DIAD (2.97 g; 14.7 mmol; 2 eq.) was slowly added dropwise. Upon addition a white precipitate formed. A THF solution containing tert-butyl-4-[(diphenylmethylene)amino]-3-hydroxypiperidine-1-carboxylate (Intermediate 268, 2.8 g; 7.36 mmol) was added (amount of THF added was such that the final concentration of alcohol was ca. 0.5-1M). The resultant reaction slurry was stirred at 0 C for 30 minutes. (PhO)2PON3 (4.05 g; 14.7 mmol; 2 eq.) was then added and the reaction was allowed to warm to RT and stirred for 12 hrs. Monitored by LC/MS. The reaction was concentrated and purified by flash column chromatography (0-30% EtOAc/hexanes with 0.1% triethylamine). Isolation gave 2.13 g of the title compound in 71% yield. LC/MS (ES+)[(M+H)+]: 406 for C23H27N5O2.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:5]([NH:7][CH:8]1[C:31](=[O:32])[N:10]2[C:11]([C:28]([O-:30])=[O:29])=[C:12]([CH2:15][O:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[CH2:39](O)[CH3:40]>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:5]([NH:7][CH:8]1[C:31](=[O:32])[N:10]2[C:11]([C:28]([O:30][CH:17]([C:40]3[CH:39]=[CH:5][CH:4]=[CH:33][CH:37]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:29])=[C:12]([CH2:15][O:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(=O)c3ccc([N+](=O)[O-])cc3)CS[C@H]12)c1csc(N)n1
Reactant: CCO
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)c3ccc(N)cc3)CS[C@H]12)c1csc(N)n1
Reaction time: 3 h

Procedure:
Platinic oxide (0.4 g.) was added to a solution of benzyhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-nitrobenzoyloxymethyl)-3-cephem-4-carboxylate (syn isomer) (4.3 g.) in a mixture of ethanol (50 ml.) and tetrahydrofuran (50 ml.), and the suspension was subjected to catalytic reduction at ambient temperature under ordinary pressure for 3 hours. After removing the catalyst from the resultant mixture by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diethyl ether to give benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-aminobenzoyl-oxymethyl)-3-cephem-4-carboxylate (syn isomer) (3.0 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:16][NH2:17])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The obtained 2-[(3-nitro-4-phenylphenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione was dissolved in ethanol (30 mL), an aqueous solution of hydrazine monohydrate (2 mL) was added thereto, and the mixture was stirred at 70° C. for 1 hour. The reaction solution was filtered, to the filtrate was added 0.6 M hydrochloric acid and ethyl acetate, and the mixture was stirred vigorously. The aqueous layer was separated and, after being neutralized with a 5M aqueous solution of sodium hydroxide, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (3-nitro-4-phenylphenyl)methanamine as a crude material (305.5 mg)
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].[C:28]([NH:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:28]([NH:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([NH:1][CH2:2][C:3]([N:5]([C:7]2[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]3)[CH3:6])=[O:4])=[O:41])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), (E)-3-(6-acetamidopyridin-3-yl)acrylic acid (56.1 mg) and N,N-dimethylformamide (2 ml) were added 1-hydroxy-benzotriazole (43.4 mg) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (56.9 mg) in a nitrogen stream at 0° C., and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was washed with an aqueous solution of saturated sodium hydrogencarbonate, water and brine successively, and dried over magnesium sulfate, and thereafter the solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol:dichloromethane=1:10, v/v), and solidified with diethyl ether and ethyl acetate to give 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloyl-glycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methyl-quinoline (FR173657) (78.8 mg) as a grayish white solid.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[Br:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:9]([O:26][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:19][Br:18])=[CH:21][CH:22]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(COC(=O)c1ccc(CBr)cc1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
Triethylamine (16 ml, 115 mmol) and bromoacetophenone (22.9 g, 115 mmol) were dissolved in 450 ml of ethyl acetate. The solution was stirred at 50° C. and 4-(bromomethyl)benzoic acid (17.5 g, 155 mmol) was added in seven equal portions over a three hour period. Stirring was continued for an additional 8 hours at 50° C. Precipitated triethylaminehydrobromide was removed by filtration, and the ethyl acetate solution was washed with (3×150 ml each) of 10% citric acid, brine, saturated sodium bicarbonate and brine. The organic phase was dried with sodium sulfate and concentrated in vacuo. The residue was recrystallized from dichloromethane-petroleum ether to give fine white crystals (10.2 g, 27% yield). 1H NMR (DMSO-d6) δ7.99 (m, 4H), 7.69-7.54 (m, 5H), 5.74 (s, 2H), 4.77 (s. 2H); 13C NMR (DMSO-d6) δ193.7, 165.9, 144.6, 134.9, 131.2, 131.0, 130.7, 130.6, 130.2, 129.9, 128.8, 128.6, 68.2, 34.0.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:14]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:14]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:16]=1
Reactant: CCOC(=O)CCc1cc(CCNC(=O)OC(C)(C)C)cc(Cc2ccc(F)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1cc(CCN)cc(Cc2ccc(F)cc2)c1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of ethyl 3-[2-(t-butoxycarbonylamino)ethyl]-5-[(4-fluorophenyl)methyl]benzene-propanoate (2.36 g) and trifluoracetic acid (5 ml) in dichloromethane (25 ml) was allowed to stand at room temperature overnight and then evaporated. The residue was partitioned between ether and dilute sodium hydroxide solution. The organic layer was separated, washed with water and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica eluting with mixtures of dichloromethane, methanol and concentrated ammonium hydroxide. The product containing fractions were combined and the solvent evaporated to give the title compound as a gum (1.13 g), Rf 0.1 (SS 4). N.M.R. δ(CDCl3): 1.24 (3H,t), 1.48(2H,s), 2.61(2H,t), 2.73(2H,t), 2.90-2.98(4H,m), 3.93(2H,s), 4.14(2H,q), 6.88(2H,s), 6.91(1H,s), 6.96-7.03(2H,m), 7.12-7.18(2H,m).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.C[OH:24]>O>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1)=[O:24]
Reactant: CO
Reactant: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1SC
Solvent: O
Product: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1S(C)=O
Yield: 70 %

Procedure:
The sulfide of Example 35, (300 mg, 0.95 mmoles), was reacted with 300 mg (1.41 mmoles) NaIO4 in 6 mL MeOH and 3 mL water at 25° C. for 24 h. The reaction mixture was partitioned between 100 mL EtOAc and 25 mL water and the EtOAc extract was washed with water, brine, dried and stripped in vacuo. The residue was purified by silica gel chromatography using 1:1 EtOAc/hexanes as eluent to give 220 mg product, (70% yield); mp 144-146° C. Elemental analysis for C18H25N3O5: Theory C, 65.22; H, 7.60; N, 12.68; S, 9.67. Found: C, 65.12; H, 7.63; N, 12.48; S, 9.71.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:35]2[CH:49]=[CH:48][C:38]([O:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:37][CH:36]=2)[CH:10]([S:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11](=[O:24])N2[C@@H](C3C=CC=CC=3)COC2=O)=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:24])[C@H:10]([S:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C@H:9]2[C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[CH:48][CH:49]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CSC(C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@H](Nc2ccc(F)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: COc1ccc(CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl (4-{(1R)-1-[(4-fluorophenyl)amino]-2-[(4-methoxybenzyl)thio]-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (9.3 g, 13.5 mmol) was dissolved in dry toluene (500 mL) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 9.9 mL, 40.6 mmol) was added and the mixture was stirred at 90° C. for one hour. The mixture was then given 45° C. and tetrabutylammonium fluoride (TBAF, 1 g) was added. The mixture was stirred at 45° C. for 24 hours. After cooling, the mixture was concentrated under reduced pressure and purified by flash-chromatography (Hex:EtOAc 6:1 then 5:1 then 4:1). This afforded the title compound.
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][N:29]([CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCCCc1ccccc1
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CCCc3ccccc3)C2=O)nc1C
Yield: 61 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with 1-bromo-3-phenylpropane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 61% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.27-7.13 (m, 5H), 4.27 (q, J=7.2 Hz, 2H), 4.02-3.96 (m, 2H), 3.52-3.46 (m, 2H), 3.37 (t, J=7.2 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.59 (s, 3H), 1.95-1.88 (m, 2H), 1.23 (t, J=7.2 Hz, 3H); MS (ES+) m/z 374.2 (M+1).
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[CH3:7][O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:2]([OH:4])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: COCn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COCn1ccnc1C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
At a temperature of -10° C., 27.5 g. (0.25 mol) of ethyl chloroformate was added drop-wise to a solution of 28 g. (0.25 mol) of 1-(methoxymethyl)imidazole and 25 g. (0.25 mol) of triethylamine in 125 ml. of anhydrous chloroform. The mixture was stirred at 0° C. and then kept standing for two days at room temperature. The precipitated triethylamine hydrochloride was filtered off and washed with diethyl ether. The filtrate was concentrated by evaporating the solvents and the residue was dissolved in diethyl ether. The solution was dried over sodium sulphate, the ether was distilled off and the residue was distilled. The ethyl ester of 1-(methoxymethyl)imidazole-2-carboxylic acid was obtained. Boiling point 120°-124°/2 mm. Hg.
Reaction SMILES: [CH:1]([N:4]([C:9]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:5](OC)=[O:6])([CH3:3])[CH3:2].[OH:18]O.Cl>C(O)C.[OH-].[Na+]>[CH:1]([N:4]1[C:9]2[C:10](=[CH:13][CH:14]=[C:15]([CH3:17])[CH:16]=2)[C:11](=[O:18])[NH:12][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: OO
Reactant: COC(=O)N(c1cc(C)ccc1C#N)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(=O)[nH]c(=O)n(C(C)C)c2c1

Procedure:
To a suspension of 300 g 2-(N-isopropyl-N-carbomethoxyamino)-4-methyl-benzonitrile in 750 ml of ethanol and 234 ml 10N sodium hydroxide are added dropwise over 80 minutes 576 g of a 40% solution of hydrogen peroxide. The resulting clear solution is acidified with 195 ml of concentrated hydrochloric acid, whereupon the title compound precipitates, m.p. 250°-251°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH:16]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[NH2:18][CH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH2:16][NH:18][CH2:19][C@@H:20]3[CH2:24][N:23]([C:25]4[CH:26]=[CH:27][C:28]5[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=5[N:34]=4)[C:22](=[O:36])[CH2:21]3)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1
Reactant: COc1cnc2ccc(=O)n(CCC=O)c2n1
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cnc2ccc(=O)n(CCCNC[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
To a solution of 3-(3-methoxy-6-oxopyrido[2,3-b]pyrazin-5 (6H)-yl)propanal (Reference Example 24, 120 mg, 0.515 mmol) in N,N-dimethylformamide (1.6 ml) were added 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 54, 175 mg, 0.66 mmol) and acetic acid (0.04 ml, 0.66 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled on ice, sodium triacetoxyborohydride (141 mg, 0.66 mmol) was added thereto and stirred overnight at room temperature. Two equivalents of sodium triacetoxyborohydride (282 mg, 1.32 mmol) were further added thereto and the reaction solution was stirred for 2 days. A sodium hydrogen carbonate aqueous solution was added to the reaction solution, which was then extracted with ethyl acetate and the obtained organic layer was washed with water and saturated sodium chloride solution. Subsequently, the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) to yield 27 mg (11%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.S(Cl)(Cl)=O.Cl.[NH2:19][C:20]1[C:28]([OH:29])=[C:27]2[C:23]([CH2:24][CH2:25][CH:26]2[CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:22][CH:21]=1.O>N1C=CC=CC=1.C(OCC)(=O)C>[C:33]([NH:32][CH2:31][CH2:30][CH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([NH:19][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:28]=2[OH:29])[CH2:24][CH2:25]1)(=[O:35])[CH3:34]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: O=C(O)CCCCc1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)CCCCc3ccccn3)c(O)c21
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
To 5-pyridin-2-ylpentanoic acid (72.8 mg, 0.406 mmol) was added thionyl chloride (0.4 mL), and the mixture was heated under reflux for 30 min. Thionyl chloride was evaporated under reduced pressure and the residue was diluted with pyridine (2 mL). The mixture was added to a solution of N-[2-(6-amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) in pyridine (2 mL) under ice-cooling, and the mixture was stirred for 15 min. Water was added, and the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (37.7 mg, yield 26%).