Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:16][C:14]2=[C:15]3[C:10](=[CH:11][CH:12]=[CH:13]2)[C:9]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:8]=2[N:7]3[CH2:6][CH2:5]1)(=O)C.Cl>CO.[OH-].[Na+]>[CH2:6]1[N:7]2[C:15]3[C:10]([C:9]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:8]=42)=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:16][NH:4][CH2:5]1
Reactant: CC(=O)N1CCn2c3c(c4cccc(c42)C1)CCCCCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1cc2c3c(c1)c1c(n3CCNC2)CCCCCC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
3-Acetyl-1,2,3,4,8,9,10,11,12,13-decahydrocycloocta[b][1,4]diazepino[6,7,1-hi]indole (1.3 g) was dissolved in methanol and diluted with 2.5N NaOH and excess solid NaOH was added. The solution was heated at 95° C. overnight. The volatiles were evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic phase was separated and evaporated and the residue was purified by chromatography on silica gel eluting with 3-4% methanol in methylene chloride to give a colorless oil. The oil was treated with 4 N HCl with stirring and warming. The precipitate that formed was isolated by filtration, triturated with ethanol, and allowed to stand overnight. A yellow solid was isolated by filtration and dried to give the hydrochloride salt of the title compound (683 mg), mp: 316-318° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][N:19]([C:32]([O:34][CH3:35])=[O:33])[C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O.CO>O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][N:19]([C:32]([O:34][CH3:35])=[O:33])[C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cccc(N(Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)C(=O)OC)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A mixture of methyl [3-[[(4,5-diphenyl-2-oxazolyl)methyl](methoxycarbonyl) amino]phenoxy]acetate (4.16 g, 9 mmol), LiOH.H2O (0.56 g, 13 mmol), MeOH (45 mL) and H2O (15 mL) was stirred at room temperature for about 3 hours. The solvent was removed in vacuo, the residue diluted with H2O and 2N HCl until pH=2 and a yellow solid filtered off. Recrystallization from a mixture of CH2Cl2 and hexanes gave [3-[[(4,5-diphenyl-2-oxazolyl)methyl](methoxycarbonyl)amino]phenoxy]acetic acid (2.25 g, 55%), mp 153-155° C. IR (KBr) 2700-2500 (CO2H), 1750 (NCO2CH3), 1710 (CO2H) cm-1 ; 1H NMR (CDCl3) δ3.68 (3H, s, NCO2CH3), 4.51 (2H, s, OCH2CO2H), 4.60 (1H, bs, CO2H), 4.95 (2H, s, CH2 -oxazole), 6.77 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H), 6.94 (2H, m, aromatic H), 7.15 to 7.40 (7H, m, aromatic H), 7.45 to 7.65 (4H, m, aromatic H); MS m/z 459 (MH+).
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>>[C:25]1(=[O:34])[N:24]([CH2:23][CH2:22][CH2:21][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][C:8]4[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=4[C@@H:6]3[CH2:1]2)[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNC[C@@H]21
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN2c3ccccc3Cc3ccccc3[C@@H]2C1

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(3-bromopropyl)phthalimide, the title compound was obtained in a quantitative yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[CH3:34])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[F:33][CH:31]([F:32])[O:30][C:26]1[CH:25]=[C:24]([S:21]([NH:20][C:18]2[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)(=[O:22])=[O:23])[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[5-(3-Difluoromethoxy-benzenesulfonylamino)-2-methyl-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.097 g, 0.195 mmol) was dissolved in 5 mL of dichloromethane. A solution of 0.293 mL of 2N hydrochloric acid in diethyl ether was added and the mixture stirred for 16 h at room temperature. The solvents were evaporated, the residue purified via reversed phase HPLC and fractions containing the product were combined. The pH was adjusted to 9 with aqueous sodium bicarbonate and the aqueous layer extracted with dichloromethane. The organic phase was then dried over magnesium sulphate, filtered and evaporated to dryness. The residue was treated with a solution 2N hydrochloric acid in diethyl ether and the mixture evaporated to dryness to yield the title compound (0.017 mg).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27].Cl.Cl.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:28])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CCOC(=O)[C@@H](N)CCCNC(=N)N
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Z-Leu-OH 172.5 g and H-Arg-OEt.2HCl 178.9 g were added to 800 mL of a DMF/THF(1/1) mixed solution. The solution was neutralized by adding 143 mL of N-methylmorpholine at 0° C. Next 147.5 mL of DCC was added to the solution and then it was stirred at 0° C. for 5 minutes and at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure then 1000 mL of water was added to the residue obtained. After the product was washed twice with 500 mL of ethyl acetate, the aqueous layer was extracted three times with 1000 mL of n-butanol. The obtained n-butanol layer was concentrated under reduced pressure to obtain Z-Leu-Arg-OEt.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:13]=[C:12]3[NH:29][N:30]=[C:31]([C:32]#[N:33])[C:11]=23)=[CH:6][CH:5]=1.O.CC[O:37]C(C)=O>CC(O)(C)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:13]=[C:12]3[NH:29][N:30]=[C:31]([C:32]([NH2:33])=[O:37])[C:11]=23)=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: NC(=O)c1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12
Yield: 28 %

Procedure:
A solution of KOH (0.07 g, 1.3 mmol) in tBuOH (2.5 mL) was added under argon atmosphere to 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (0.05 g, 0.1 mmol, obtained in example 65) and heated to reflux overnight. Water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 15 mg of the title compound in solid form (yield: 28%)
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCc1ccncc1
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1ccncc1

Procedure:
Using the general method of Example 11, 6.8 g of 2,4-dichloro-3-nitroquinoline was reacted with 4-(aminomethyl)pyridine to provide 7.8 g of crude 2-chloro-3-nitro-N-(4-pyridylmethyl)-4-quinolinamine. This material was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([C:8](OCC)=[O:9])=O)[CH3:2].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>C(O)C.O>[CH2:1]([O:3][C:4]([C:5]1[N:18]=[C:19]([NH2:21])[NH:20][C:8](=[O:9])[CH:6]=1)=[O:13])[CH3:2]
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(=O)[nH]c(N)n1

Procedure:
A solution of oxalacetic acid diethyl ester (8.5 g, 45.2 mmol) in ethanol (100 mL) was treated with guanidine carbonate (8.1 g, 45.2 mmol) and this was stirred under reflux for 2 hours. The mixture was diluted with water, concentrated to removed ethanol, and the solid was collected by filtration. The solid was then suspended in ethanol (40 mL) and concentrated hydrochloric acid (1 mL) and refluxed for 15 minutes. The mixture was then cooled, basified with potassium carbonate, diluted with water and concentrated to removed ethanol. The white solid was collected by filtration and vacuum dried to give J1.1 (1.67 g, 20%). 1H-NMR (DMSO-d6) δ: 10.34 (1H, br s), 8.92 (1H, br s), 7.46 (1H, br, s), 5.42 (1H, s), 4.18 (2H, q, J=7 Hz), 1.24 (3H, t, J=7 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([OH:19])[N:9]=1.Br[CH2:21][CH2:22][CH3:23]>O>[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([O:19][CH2:21][CH2:22][CH3:23])[N:9]=1
Reactant: Oc1cc2c(Cl)cccc2c(Cl)n1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCOc1cc2c(Cl)cccc2c(Cl)n1
Temperature: 50 °C
Yield: 91.9 %

Procedure:
Potassium carbonate (646 mg, 4.67 mmol) was added to a solution of 1,5-dichloroisoquinolin-3-ol (500 mg, 2.336 mmol) and 1-bromopropane (0.234 mL, 2.57 mmol) and heated to 50° C. for 3 hrs. After 3 hours the reaction was diluted with water and extracted with EtOAc (2×). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product 1,5-dichloro-3-propoxyisoquinoline (550 mg, 92% yield), which was used as is in the next step. MS: MS m/z 256.1(M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH2:19][CH2:20][OH:21])O.[N:22]([Si](C)(C)C)=[N+:23]=[N-:24].B(F)(F)F.CCOCC>C1COCC1>[N:22]([C:5]1([CH2:19][CH2:20][OH:21])[C:6]2[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([F:13])[C:7]=2[O:14][C:15]2[C:4]1=[CH:3][C:2]([Br:1])=[CH:17][CH:16]=2)=[N+:23]=[N-:24]
Reactant: OCCC1(O)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: [N-]=[N+]=NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of 7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-ol (48 g, 128 mmol) in THF (58 mL) were added azidotrimethylsilane (34.0 ml, 256 mmol) and boron trifluoride diethyl etherate (31.6 ml, 256 mmol). The reaction mixture was heated to 60° C. for 15 h. Additional azidotrimethylsilane (34.0 ml, 256 mmol) and boron trifluoride diethyl etherate (31.6 ml, 256 mmol) were added and heating was continued for 3 h. The reaction mixture was quenched with aqueous, saturated NaHCO3 solution and extracted with EtOAc. The organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (0-30% EtOAc/hexanes) to afford 2-(5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (41 g, 103 mmol, 80% yield) as a pale yellow solid-foam.
Reaction SMILES: CN(C)[C:3](=[O:24])[CH2:4][C:5]1[N:12]2[C:8]([S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)=[N:7][C:6]=1[C:17]1[CH:21]=[C:20]([CH3:22])[S:19][C:18]=1[CH3:23].[OH-:26].[Na+]>COCCO>[CH3:23][C:18]1[S:19][C:20]([CH3:22])=[CH:21][C:17]=1[C:6]1[N:7]=[C:8]2[N:12]([C:5]=1[CH2:4][C:3]([OH:24])=[O:26])[C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[S:9]2
Reactant: Cc1cc(-c2nc3sc4ccccc4n3c2CC(=O)N(C)C)c(C)s1
Reactant: [OH-]
Agent: [Na+]
Solvent: COCCO
Product: Cc1cc(-c2nc3sc4ccccc4n3c2CC(=O)O)c(C)s1
Temperature: 100 °C

Procedure:
14 g (0.0379 mole) of N,N-dimethyl-2-(2,5-dimethylthien-3-yl)imidazo[2,1-b]benzothiazole-3-acetamide and 350 ml of 2-methoxyethanol are introduced into a 1000 ml round-bottomed flask, the solution is heated to 100° C., 25 ml of a solution at 30% sodium hydroxide (0.189 mole) are added, the mixture is heated at boiling temperature for 30 minutes, a further 25 ml of 30% sodium hydroxide are added and the heating is maintained for 4 h. 25 ml of a solution at 30% sodium hydroxide are again added and the mixture is heated for a further 3 h. The solvents are evaporated under reduced pressure, the residue is taken up in 500 ml of water, the insoluble matter is separated by filtration and the pH of the filtrate is adjusted to 4 with acetic acid. A yellow precipitate is obtained which is separated by filtration and it is washed with water and then with diethyl ether. After crystallization from methanol, 9 g of light yellow crystals are obtained. Melting point: 249°-250° C.
Reaction SMILES: O[Li].O.O.C([O:7][C:8]([C:10]1([CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]2([C:27]([O:29]CC)=[O:28])[CH2:26][CH2:25][CH2:24]2)[CH2:13][CH2:12][CH2:11]1)=[O:9])C>CCO>[C:27]([C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14][C:10]2([C:8]([OH:9])=[O:7])[CH2:11][CH2:12][CH2:13]2)[CH2:26][CH2:25][CH2:24]1)([OH:29])=[O:28]
Reactant: CCOC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OCC)CCC2)CCC1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(CCCCC1(C(=O)O)CCC1)CCCCC1(C(=O)O)CCC1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
LiOH.H2O (3.94 g, 93.9 mmol) and H2O (30 mL) were added to a solution of ethyl 1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate (9.20 g, 23.3 mmol) in EtOH (90 mL) and the resulting mixture was stirred at reflux temperature for 17 h, allowed to cool to rt and concentrated in vacuo to a smaller volume. H2O (150 mL) was added and the resulting mixture was extracted with Et2O (50 mL), acidified with aqueous HCl (6 M, 25 mL) and extracted with Et2O (1×100 mL, 2×50 mL). The latter organic layers were combined, washed with brine (50 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was recrystallized from a mixture of iPr2O and heptane to give 1-[9-(1-carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylic acid (4.41 g, 56%) as small, white granules. mp 69-70° C. 1H NMR (CDCl3): δ=11.2 (br s, 2H), 2.50-2.37 (m, 4H), 2.39 (t, J=7.2 Hz, 4H), 1.96-1.84 (m, 8H), 1.81-1.75 (m, 4H), 1.57 (quintet, J=7.4 Hz, 4H), 1.26-1.12 (m, 4H). 13C NMR (CDCl3): δ=210.6, 183.4 (2×), 47.6 (2×), 42.7 (2×), 37.8 (2×), 30.1 (4×). 24.7 (2×), 24.1 (2×), 15.7 (2×). Anal. calcd for C19H30O5: C, 67.43; H, 8.93. found: C, 67.19; H, 8.97.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][C:12]1[NH:13][C:14](=[O:24])[CH:15]=[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:17]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:10]([CH2:11][C:12]3[NH:13][C:14](=[O:24])[CH:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=3)[O:1][C:2]=2[CH:7]=1
Reactant: Cc1ccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc2nc(Cc3nc(N4CCOCC4)cc(=O)[nH]3)oc2c1

Procedure:
The product is prepared according to the procedure described in Example 2, using 390 mg of N-(2-hydroxy-4-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide and 108 mg of 4-methylbenzenesulphonic acid hydrate, and replacing the toluene with xylene. After recrystallization from 20 ml of ethanol and 5 ml of methanol, 105 mg of 2-[(6-methyl-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:37][C:38](=[O:40])[CH3:39])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17](CC[Si](C)(C)C)[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:37][C:38](=[O:40])[CH3:39])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-acetylamino-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (137 mg, 0.23 mmol) in DMF (5 mL) is added CsF (175 mg, 1.15 mmol) and the mixture is stirred at 70° C. for 2 h. Ethyl acetate is added and the mixture is washed with 1N HCl and brine. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:11]([O-])(O)=O.[Na+]>CO.ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH3:11][O:8][C:6]1[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C([O-])O
Agent: [Ti+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC1=CC(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 5,5-dimethyl-cyclohexane-1,3-dione (80.0 g, 0.57 mol) in anhydrous methanol (600 mL) was treated with a 1 M solution of titanium chloride (TiCl4) in dichloromethane (17.2 mL). After stirring 1 hour at room temperature, the mixture was slowly poured into cold 5% NaHCO3 solution and extracted with diethyl ether (450 mL×6). The organic layers were collected, washed with brine, dried on Na2SO4 and evaporated to dryness affording the title compound (81.5 g, 92% yield) as a pale yellow oil.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17]OS(C)(=O)=O)[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Na+].[I-:35]>CN(C=O)C>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][I:35])[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOS(C)(=O)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCI
Temperature: 60 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
To a solution of (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-6-methyl-8-(2(methylsulfonyloxy)ethyl)-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (350 mg, 0.71 mmol) in DMF (3 mL) at room temperature (about 22° C.) was added NaI (1.06 g, 7.06 mmol), and the resulting reaction mixture was heated to 60° C. and stirred for 6 h. The reaction mixture was partitioned between sat'd aqueous NaHCO3 solution (20 mL) and EtOAc (25 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (2×25 mL) and the combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (300 mg, 81%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 5.43-5.15 (m, 2H), 5.07 (t, J=9.8 Hz, 1H), 4.95-4.75 (m, 2H), 3.72-3.51 (m, 1H), 3.24 (ddd, J=10.6, 6.6, 4.3 Hz, 1H), 3.00-2.87 (m, 1H), 2.82 (td, J=10.9, 3.0 Hz, 1H), 2.62 (hept, J=7.0 Hz, 1H), 2.35-2.21 (m, 1H), 1.86-1.69 (m, 1H), 1.45 (s, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.22 (dd, J=7.0, 3.9 Hz, 6H); ESIMS m/z 550 ([M+Na]+).
Reaction SMILES: F[C:2]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:16])[CH:3]=1.[F:17][S:18]([F:29])([F:28])([F:27])([F:26])[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[CH3:15][S:12]([C:11]1[C:2]([O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:18]([F:29])([F:17])([F:26])([F:27])[F:28])[CH:20]=2)=[CH:3][C:4]([CH3:16])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:14])=[O:13]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Reactant: Oc1cccc(S(F)(F)(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 25 °C
Yield: 27.6 %

Procedure:
600 mg of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate, 700 mg of 3-pentafluorosulfanylphenol and 1.6 g of Cs2CO3 were stirred in 4 ml of anhydrous DMF at 100° C. for 3 h. The mixture was then cooled to RT, diluted with 100 ml of EA and washed 3 times with 20 ml of water each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with DIP. 300 mg of a colorless oil were obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:15]([OH:17])=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[NH:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:15]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.9 %

Procedure:
7.67 g (40.0 mmol) of EDCl was added to 50 ml of THF solution of 3.50 g (20.0 mmol) of Boc-Gly-OH (manufactured by Tokyo Chemical Industry Co., Ltd), and 1.82 ml (20.0 mmol) of aniline, followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed with brine (two times for each), and the organic layer was dried over sodium sulfate. After the drying agent was separated by filtration, the filtrate was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1 to 1/1 (volume ratio)), thereby obtaining 4.85 g of the product with a yield of 96.9%.