Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CO>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: Nc1cc2cccnc2c(Br)n1
Solvent: CO
Product: Nc1cc2cccnc2c(N2CCOCC2)n1
Yield: 60.8 %

Procedure:
To a mixture of 800 mg of 6-amino-8-bromo-1,7-naphthyridine and 3.12 g of morpholine, 40 ml of methanol was added. The resultant mixture was refluxed for 13 hours. After the reaction, methanol was distilled off under reduced pressure and chloroform was added to the residue. After washing the chloroform solution with water, it was dried with anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure and a small amount of acetone was added to the residue to dissolve same. Hexane was then added to the residue, followed by removal of insoluble matter by filtration. The filtrate was concentrated and the residue was recrystallized from a mixed solvent of chloroform and hexane, thereby obtaining 500 mg of 6-amino-8-morpholino-1,7-naphthyridine (Compound No. 3) as yellowish crystals (yield: 60.9%).
Reaction SMILES: [NH2:1][C:2]1[C:7](C(OC)=O)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+].[CH2:15]([OH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[NH2:1][C:2]1([C:12]([O:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH:7]=[N:6][CH:5]=[CH:4][NH:3]1
Reactant: CCCCCCCCO
Reactant: COC(=O)c1nccnc1N
Reactant: C[O-]
Agent: [Na+]
Product: CCCCCCCCOC(=O)C1(N)C=NC=CN1
Reaction time: 48 h

Procedure:
Together there was stirred methyl (2-aminopyrazin-3-yl)formate (5 g; 0.327 mol) and n-octanol (30 ml), together with sodium methoxide (0.3 g), at 85° C. for 1 hour, then 160° C. for 2 days. The n-octanol was distilled off under vacuum, and the residue was passed through a silica gel column, eluting with dichloromethane, to give the title compound (5.78 g).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:13]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([F:20])[CH:5]=1)=[O:3].[OH-].[Na+].ClCCl>CO>[NH2:1][C:2]([C:4]1[C:13]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:20])[CH:5]=1)=[O:3]
Reactant: CCC(CC)Nc1cc(C(=O)OC)c(F)cc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C(=O)O)c(F)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of methyl 4-(aminocarbonyl)-2-fluoro-5-(pentan-3-ylamino)benzoate (73.7 mg, 0.26 mmol) in methanol (1 mL) at 0° C. was added 1 N sodium hydroxide (520 uL, 0.52 mmol). The mixture was stirred 30 min at 0° C., and was then warmed to room temperature. Dichloromethane (500 uL) was added to improve solubility, and the homogeneous solution was stirred 3.5 h at room temperature. After acidification with 1 N hydrochloric acid (500 uL), the volatile solvents were removed by rotary evaporation. An insoluble solid material was then isolated from the aqueous residue by filtration. The solid was dried to give 4-(aminocarbonyl)-2-fluoro-5-(pentan-3-ylamino)benzoic acid (61.7 mg, 0.23 mmol, 88% yield). 1H NMR (400 MHz, CD3OD): 7.41 (d, 1H), 7.16 (d, 1H), 3.43-3.28 (m, 1H buried), 1.68-1.46 (m, 4H), 0.95 (t, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:32]=[CH:31][C:15]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][C:13]=2[CH3:33])=O)=[CH:4][C:3]=1[CH3:34].Cl.[NH2:36][C:37]([NH2:39])=[O:38]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:12]3[CH:32]=[CH:31][C:15]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)=[CH:14][C:13]=3[CH3:33])[NH:39][C:37](=[O:38])[N:36]=2)=[CH:4][C:3]=1[CH3:34]
Reactant: Cc1cc(/C=C/C(=O)c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cc2C)ccc1O
Reactant: NC(N)=O
Agent: Cl
Product: Cc1cc(-c2cc(-c3ccc(OCC4CCNCC4)cc3C)[nH]c(=O)n2)ccc1O
Temperature: 110 °C
Yield: 6.9 %

Procedure:
To a sealed pressure vessel was added (E)-tert-butyl 4-((4-(3-(4-hydroxy-3-methylphenyl)acryloyl)-3-methylphenoxy)methyl)piperidine-1-carboxylate (100 mg, 0.215 mmol), 4N HCl in dioxanes (2.0 mL), and urea (64 mg, 1.07 mmol). The pressure vessel was sealed and heated to 110° C. overnight. The reaction was then cooled to rt, concentrated via rotary evaporation and purified via preparatory HPLC (5-85% AmAc) to give 4-(4-hydroxy-3-methylphenyl)-6-(2-methyl-4-(piperidin-4-ylmethoxy)phenyl)pyrimidin-2(1H)-one (6.0 mg, 7% yield).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([S:8][C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:4][CH2:5][CH2:6][CH3:7]>>[I-:2].[CH2:3]([S:8][C:9]1[C:13]([C:14]2[CH:15]=[N+:16]([CH3:1])[CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CI
Reactant: CCCCCSc1nsnc1-c1cccnc1
Product: CCCCCSc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl iodide (0.5 ml, 7.5 mmol) was added to a solution of 3-(3-pentylthio-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[OH:9][C:10]1[C:18]2[S:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[N:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>C(#N)C.C(OCC)C>[OH:9][C:10]1[C:18]2[S:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[N:15][C:14]=2[CH:13]=[CH:12][C:11]=1[N+:7]([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: CCNC(=O)Nc1nc2cccc(O)c2s1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCNC(=O)Nc1nc2ccc([N+](=O)[O-])c(O)c2s1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 10.4 %

Procedure:
To a solution of 2-methylpyridone (0.020 mL, 0.20 mmol, 1.2 eq) in anhydrous acetonitrile (0.5 mL), nitronium tetrafluoroborate (0.045 g, 0.32 mmol, 1.9 eq) was added. The suspension was stirred at about 20° C. for about 5 minutes to get an orange solution. The solution was then transferred to a suspension of 1-(7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 8 (0.040 g, 0.17 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at about 20° C. for about 15 minutes, then taken up in diethyl ether (8 mL), and neutralized by washing with saturated sodium bicarbonate solution (1.5 mL). The organic extract was concentrated and dissolved in methanol (2 mL). LC/MS purification was followed by flash chromatography purification on silica (methylene chloride/methanol=40/1) to afford 0.005 g (10%) of the desired compound 17. 1H NMR (DMSO) δ 11.20 (br s, 1H, NH), 8.02 (d, 1H, J=9.0 Hz, ArH), 7.23 (d, 1H, J=7.5 Hz, ArH), 6.78 (br s, 1H, NH), 3.20 (m, 2H, CH2), 1.10 (t, 3H, J=7.2 Hz, CH3). LC/MS 283 (MH+); RP-HPLC RT 2.74 minutes.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[CH2:16]1[O:33][C:19]2([CH2:24][CH2:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=3)=[CH:21][CH2:20]2)[O:18][CH2:17]1.Cl>C(Cl)Cl>[CH2:17]1[O:18][C:19]2([CH2:24][CH2:23][C:22]3([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=4)[CH:21]([CH2:1]3)[CH2:20]2)[O:33][CH2:16]1
Reactant: N#Cc1cccc(C2=CCC3(CC2)OCCO3)c1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C23CCC4(CC2C3)OCCO4)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
Diethylzinc(1 M in hexane, 19 ml, 19 mmole) was mixed with 50 ml methylene chloride and the mixture was cooled to 0° C. Trifluoroacetic acid (2.1 g, 19 mmole) in 20 mL methylene chloride was added. The mixture was stirred at 0° C. for 20 minutes. Diiodomethane (5 g, 19 mmole) in 10 ml methylene chloride was then added, followed by 4-(3-cyanophenyl)-3-cyclohexene-1-one ethylene ketal (1.5 g, 6.2 mmole) in 20 mL methylene chloride. The mixture was stirred at room temperature overnight. 50 ml 1N hydrogen chloride solution was added to quench the reaction. The organic layer was separated, washed with water (2×50 mL) and dried over sodium sulfate. The product was purified by column using ethyl acetate/hexane (10/90) as the eluent to afford 6-(3-cyanophenyl)bicyclo[4.1.0]heptane-3-one ethylene ketal (0.8 g, 50%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[S:24](Cl)(=[O:26])=[O:25].Cl>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[S:24]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])(=[O:25])=[O:26]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: OCC1CCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
Piperidin-2-yl-methanol (17.39 mmol, 1 eq) was dissolved in methylene chloride (20 ml) and triethylamine (43.47 mmol, 2.5 eq) at 0° C. and a solution of 2-chloro-6-methyl-benzenesulfonyl chloride (17.39 mmol, 1 eq) in methylene chloride (65 ml) was added dropwise. The reaction solution was stirred at room temperature for 90 min. 0.5 M HCl (75 ml) was then added and the mixture was stirred for a further 15 min. The organic phase was washed with water (10 ml), dried over sodium sulfate and concentrated to dryness under reduced pressure. Yield: 90%
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]([NH2:11])[CH2:5]1)(=[O:3])[CH3:2].Cl[C:13](OC1C=CC([N+]([O-])=O)=CC=1)=[O:14].C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[CH:40][C:41]([NH2:45])=[N:42]2)=[CH:37][CH:36]=1>>[NH2:45][C:41]1[CH:40]=[C:39]([N:46]2[CH2:51][CH2:50][N:49]([C:13]([NH:11][C@H:6]3[CH2:7][CH2:8][CH2:9][CH2:10][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]3)=[O:14])[CH2:48][CH2:47]2)[C:38]2[C:43](=[CH:44][C:35]([Cl:34])=[CH:36][CH:37]=2)[N:42]=1
Reactant: CC(=O)N1CCCC[C@@H](N)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1

Procedure:
As described for example 78, (3R)-1-acetylhexahydro-1H-azepin-3-amine, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 445 (M++1). 1H NMR (CDCl3) δ 7.70 (d, 1H), 7.60 (s, 1H), 7.15 (d, 1H), 6.02 (s, 1H), 4.70 (s, 2H), 4.22 (d, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 3.60 (m, 4H), 3.10 (m, 6H), 2.25 (m, 1H), 2.15 (s, 3H), 1.60–1.90 (m, 3H), 1.30–1.40 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K+].[Br-]>C(Cl)(Cl)Cl.CO>[C:13]1([C:12]2[O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(O)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(-c3ccccc3)nc2c1
Yield: 85 %

Procedure:
Prepared from 2-amino-4-nitrophenol and benzoic acid, in a manner similar to that of Example 9b. Yield: 85%; Rf (9/1 chloroform/methanol): 0.92; Elem. anal. C13H8N2O3; theory C, 65.00; H, 3.35; N, 11.66. found C, 64.54; H, 3.35; N, 11.85. IR (KBr): 1615, 1530, 1345 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2C[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon to (+)-trans-3-tert butoxycarbonylamino-1,2,3,4-tetrahydro-2-naphthalenol (70 mg) in methylene chloride (1 ml) was added Dess-Martin periodinane (172 mg). The mixture was stirred for 1 hour at room temperature under argon and filtered through a silica gel column [10 g, elution with ethyl acetate: cyclohexane mixtures. 1:9 (150 ml) and 2:8 (50 ml)]. Evaporation of solvent gave a solid which was recrystallized from pentane to yield the title compound as white needles, m.p. 76° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:6]
Reactant: NCC(c1ccc(Cl)cc1)N1CCCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chlorophenyl)-2-(pyrrolidin-1-yl)ethanamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]3[O:18][CH2:19][C:20](=[O:22])[NH:21][C:16]=3[N:15]=[C:14]([CH3:23])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:24]1[CH2:28][CH:25]1[CH2:26][OH:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[OH:24][CH:25]([CH2:26][OH:27])[CH2:28][N:21]1[C:20](=[O:22])[CH2:19][O:18][C:17]2[C:12]([N:9]3[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)=[N:13][C:14]([CH3:23])=[N:15][C:16]1=2
Reactant: OCC1CO1
Reactant: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3CC(O)CO)CC1
Reaction time: 5 h
Yield: 83 %

Procedure:
A suspension containing 0.96 g of 4-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Example 1), 0.44 g of 2,3-epoxy-1-propanol, 0.0966 g of tetra(n-butyl)-ammonium bromide and 20 ml of abs. benzene is boiled under stirring for 5 hours and left to stand at room temperature overnight. The crystals are filtered, washed with diisopropyl ethyl and dried to give 0.98 g (83%) of the product, m.p.: 146°-148° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 10.00 g; 48.31 mmol) in THF (300 mL) was treated with a solution of cyclohexylamine (Fluka, 5.53 mL; 48.3 mmol) and triethylamine (7.37 mL; 53.1 mmol) in THF (100 mL). The reaction mixture was stirred for 16 hours at RT. Water (50 mL) was poured into the reaction mixture which was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:3]=1[CH2:4][C:5]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6]1.C(C1([CH2:29][OH:30])CCCCC1)C1C=CC=CC=1.Cl.[NH2:32][C@@H:33]([CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([NH:54][CH3:55])=[O:53])[CH:34]([OH:46])[C:35]([NH:37][C@@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:39])=[O:36].Cl.N[C@H](C(O)C(=O)N[C@@H](C1C=CC=CC=1)C)CCCCNC(N1CCOCC1)=O>>[OH:46][CH:34]([C@@H:33]([NH:32][C:29](=[O:30])[O:10][CH2:9][C:5]1([CH2:4][C:3]2[C:2]([F:1])=[CH:14][CH:13]=[CH:12][C:11]=2[F:15])[CH2:6][CH2:7][CH2:8]1)[CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([NH:54][CH3:55])=[O:53])[C:35](=[O:36])[NH:37][C@@H:38]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH3:39]
Reactant: OCC1(Cc2ccccc2)CCCCC1
Reactant: CNC(=O)NCCCC[C@H](N)C(O)C(=O)N[C@H](C)c1ccccc1
Reactant: OCC1(Cc2c(F)cccc2F)CCC1
Agent: C[C@@H](NC(=O)C(O)[C@@H](N)CCCCNC(=O)N1CCOCC1)c1ccccc1
Agent: Cl
Product: CNC(=O)NCCCC[C@H](NC(=O)OCC1(Cc2c(F)cccc2F)CCC1)C(O)C(=O)N[C@H](C)c1ccccc1

Procedure:
[1-(2,6-Difluorobenzyl)cyclobutyl]methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate was prepared as in example 9i except that [1-(2,6-difluorobenzyl)cyclobutyl]methanol was substituted for (1-benzylcyclohexyl)methanol, and (3S)-3-amino-2-hydroxy-7-{[(methylamino)carbonyl]amino}-N-[(1R)-1-phenylethyl]heptanamide hydrochloride was substituted for N-((5S)-5-amino-6-hydroxy-7-oxo-7-{[(1R)-1-phenylethyl]amino}heptyl)-4-morpholinecarboxamide hydrochloride. 1H NMR (300 MHz, DMSO-d6) δ 8.06 (m, 1H), 7.01-7.45 (m, 8H), 6.43 (d, J=8 Hz, 1H), 5.83 (m, 1H), 5.60 (m, 2H), 4.94 (m, 1H), 3.70-4.00 (m, 4H), 3.35 under water peak (m, 3H), 2.65-3.00 (m, 4H), 1.60-1.85 (m, 6H), 1.10-1.50 (m, 9H). ES-LCMS m/z 573 (M−H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:17])[CH3:16])[N:11]=[CH:10]1>CC(O)=O.C1COCC1>[Br:1][C:13]1[S:9][CH:10]=[N:11][C:12]=1[NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Nc1cscn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)Nc1ncsc1Br
Temperature: 25 °C
Yield: 54.3 %

Procedure:
1-Bromopyrrolidine-2,5-dione (0.48 g, 2.67 mmol) was added to the solution of N-(thiazol-4-yl)acetamide (0.38 g, 2.67 mmol) in AcOH/THF (10 mL/10 mL). The mixture was heated to 25° C. for 2 h. The solvent was removed and the solution was adjusted to pH˜9 with 2 N NaOH solution. It was extracted with EA (3×50 mL), the combined organic phase was washed with brine, dried with Na2SO4 and concentrated to give the title compound (1.32 g, 1.45 mmol, 54.2%) as light yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][C@@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:5]([CH2:23][C:24]#[CH:25])([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C=O.[C:44](O)(=O)C>O1CCOCC1>[CH3:1][CH:2]([CH3:36])[CH2:3][C@@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[C:5]([CH2:23][C:24]#[C:25][CH2:44][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(=O)O
Reactant: C#CCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Reactant: C1CCNC1
Agent: C=O
Solvent: C1COCCO1
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CC#CCN1CCCC1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.501 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(prop-2-yn-1-yl)-1,1,2(R)-pentanetricarboxylate, 0.17 ml of pyrrolidine, 0.083 g of paraformaldehyde, 0.39 ml of glacial acetic acid and 0.004 g of cuprous chloride in 7 ml of dioxan was stirred at room temperature under a nitrogen atmosphere for 15 minutes and then heated to reflux for 2 hours. The mixture was then stirred at room temperature for a further 2 hours and evaporated, and the residue was partitioned between water and dichloromethane. The pH of the aqueous phase was adjusted to 10 by the addition of ammonium hydroxide and the dichloromethane layer was separated. The aqueous phase was extracted with three portions of dichloromethane and the combined extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to give a brown oil which was purified by flash chromatography on silica gel using ethyl acetate/hexane (4:1) for the elution. There was obtained 0.489 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(4-pyrrolidinylbut-2-yn-1-yl)-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil; MS 576 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][C:16]=1[NH:24][C:25](=[O:41])[CH2:26][CH:27]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH3:14])([CH3:13])[CH3:12].[C:42](N1C=CN=C1)(=[O:44])[CH3:43]>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH:22][C:42](=[O:44])[CH3:43])=[CH:17][C:16]=1[NH:24][C:25](=[O:41])[CH2:26][CH:27]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccccc1OC
Reactant: CC(=O)n1ccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(C)=O)ccc1C(C)(C)C)c1ccccc1OC
Reaction time: 0.25 h

Procedure:
2.39 ml (1.19 mmol) of a 0.5 M potassium bis(trimethylsilyl)amide solution in toluene were added dropwise at room temperature over a period of 3 minutes to a solution of 338 mg (0.78 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(2-methoxyphenyl)octanamide (prepared as described in Example 151) in 5.0 ml of dry tetrahydrofuran, and the resulting mixture was stirred for 15 minutes, after which 175 mg (1.59 mmol) of 1-acetylimidazole were added. The reaction mixture was stirred for 40 minutes, after which it was diluted with ethyl acetate, and the diluted solution was washed with a saturated aqueous solution of potassium hydrogensulfate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 363 mg (a quantitative yield) of the title compound as a colorless foam-like substance.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:15][C:16]3[CH:17]=[N:18][C:19]([O:28][CH3:29])=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:8]([CH:14]=2)[C:9]([O:11]CC)=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O.CO.N>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:15][C:16]3[CH:17]=[N:18][C:19]([O:28][CH3:29])=[C:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[C:8]([CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)ccc1Nc1cnc(OC)c(-c2ccccc2)c1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: COc1ncc(Nc2ccc(C3CC3)cc2C(=O)O)cc1-c1ccccc1
Temperature: 60 °C
Yield: 77 %

Procedure:
The solid residue obtained in step A was dissolved in 2.5 ml of ethanol and 0.180 ml of aqueous solution 2N NaOH were added. The mixture was heated at 60° C. for 2 hours, the solvent was evaporated and the solid obtained was suspended in water. The pH was taken to 6.5 and extracted with CHCl3. The crude mixture was purified over a SCX cartridge eluting with MeOH/NH3 10:1 affording 0.025 g (yield 77%) of the expected product.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12]>O1CCCC1>[CH2:8]([O:7][C:3](=[O:10])[CH2:12][C:11](=[O:13])[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH3:9]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccs1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A 0.254 g portion of 60% sodium hydride and 1.95 g of diethyl carbonate were charged using 1.0 ml of tetrahydrofuran at 24° C. and then the temperature was increased to carry out reflux. At said temperature (79° C.) a solution prepared by dissolving 0.5 g of 2-acetylthiophene in 1 ml of tetrahydrofuran was added dropwise thereto spending 15 minutes. Thereafter, the mixture was stirred at said temperature for 1 hour, and when the reaction was completed, the reaction solution was analyzed by a liquid chromatography under the same conditions of the aforementioned Production Example 1 to find that the reaction yield was 89%.