Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][NH:13][C:12]3=O)=[CH:3][CH:2]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2>>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([NH:20][C:12]3[C:11]4[C:16](=[CH:17][CH:18]=[C:9]([CH:8]=[CH:7][C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH:10]=4)[N:15]=[CH:14][N:13]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=c1[nH]cnc2ccc(C=Cc3ccncc3)cc12
Product: C(=Cc1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1)c1ccncc1
Temperature: 60 °C
Yield: 74.3 %

Procedure:
The title compound (250 mg, 1.0 mmol) from Example 20 was activated in an analogous method to Example 21 and combined with 5 -aminoindole (171 mg, 1.3 mmol). The reaction mixture was heated at 60° C. overnight and then cooled to room temperature. The resin was filtered off and the solution was concentrated in vacuo. The crude residue was chromatographed on silica gel in 10% acetone/ethyl acetate to provide 270 mg (74%) of the product.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[C:11]=2[CH3:18])[O:4][CH2:3]1.C(OC(=O)C)(=[O:22])C.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:17][OH:22])[C:11]=2[CH3:18])[O:4][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC2OCC(C)(C)CO2)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CO
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 39.7 %

Procedure:
The 4-((5,5-dimethyl-1,3-dioxan-2-yl)methoxy)-2,3-dimethylpyridine 1-oxide (3.1 g, 11.6 mmol) obtained by the step (1c) was mixed with acetic anhydride (9.87 ml, 104 mmol). After the mixture was stirred at 85° C. for 45 minutes, acetic anhydride was removed. The residue was dissolved in methanol (40 ml) and a 5N aqueous sodium hydroxide solution (5.1 ml, 25.5 mmol) was added to the mixture while cooling on ice. The mixture was stirred at room temperature for one hour. Methanol was distilled off and ice water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resultant mixture was purified by silica gel column chromatography (silica gel: 120 g, elution solvent: ethyl acetate/heptane=1/4 to 4/1) to obtain the title compound (1.23 g, yield: 39.7%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C@@H:5]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[NH2:6].C(N(C(C)C)CC)(C)C.[Br:30][C@H:31]([CH3:35])[C:32](Cl)=[O:33]>ClCCl>[Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C@H:5]([NH:6][C:32](=[O:33])[C@H:31]([Br:30])[CH3:35])[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: N[C@@H](Cc1ccccc1Br)C(=O)OCc1ccccc1
Reactant: C[C@@H](Br)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Br)C(=O)N[C@@H](Cc1ccccc1Br)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 25.7 g of benzyl (S)-2-bromophenylalaninate and 150 ml of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 20 ml of diisopropylethylamine followed by 13.2 g of (2R)-2-bromopropionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with dilute acetic acid solution, and evaporate off the solvents to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:6][C:7]([C:9]1([NH:14][C:15](=[O:21])[C@@H:16]([SH:20])[CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH3:2].[CH:31]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[NH:6][C:7]([C:9]1([NH:14][C:15](=[O:21])[C@@H:16]([S:20][C:36]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:37])[CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH3:2]
Reactant: O=C(O)C1CCCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](S)C(C)C)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](SC(=O)C2CCCC2)C(C)C)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[[1-[(2-(S)-mercapto-3-methyl-1-oxobutyl)amino]-1-cyclopentyl]-carbonyl]-L-tyrosine ethyl ester (0.32 g, 0.73 mmole), cyclopentanecarboxylic acid (0.083g, 0.73 mmole), dicyclohexylcarbodiimide (0.15 g, 0.73 mmole), 1-hydroxy-7-azabenzotriazole (0.10 g, 0.73 mmole), and triethylamine (0.10 ml, 0.73 mmole) in methylene chloride (30 ml) is stirred overnight at room temperature. The resulting mixture is filtered, washed with sodium bicarbonate solution, then with brine, dried over magnesium sulfate and evaporated to dryness. The residue is purified by flash chromatography on silica gel eluting with hexane ethyl acetate. The pure fractions are concentrated and the residue is crystallized from diethyl ether to yield N-[[1-[(2-(S)-cyclopentylcarbonylmercapto-3-methyl-1-oxobutyl)amino]-1-cyclopentyl]-carbonyl]-L-tyrosine ethyl ester, m.p. 130°-131° C., the compound of formula III wherein R4 is 4-hydroxyphenyl, R2 is ethyl, R3 is cyclopentylcarbonyl, and R4 is isopropyl.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[Li].[F:14][C:15]1[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CCOCC.C1COCC1>[F:14][C:15]1[CH:22]=[C:21]([CH:23]([OH:24])[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: Brc1cccnc1
Reactant: N#Cc1ccc(C=O)cc1F
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(C(O)c2cccnc2)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Bromopyridine (1.40 g, 8.86 mmol) was dissolved in anhydrous Et2O (15 mL). The solution was cooled to −78° C., treated with a 1.6 M solution of n-BuLi (5.53 mL, 8.86 mmol), and stirred for 15 min. The lithium solution was cannulated into a −78° C. solution of 2-fluoro-4-formyl-benzonitrile (Example 1, Step D) in THF (15 mL) and stirred for 15 min. The reaction was quenched with H2O, partitioned between CH2Cl2 and saturated NaHCO3 solution and separated. The aqueous layer was washed with CH2Cl2 (2×), the organic layers combined, dried (Na2SO4), filtered and concentrated to give the title compound after chromatography on SiO2 eluting with 0-3% MeOH/CH2Cl2 w/NH4OH.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1.C(Cl)Cl.O.FC(F)(F)C1C=CC(S(Cl)(=O)=O)=CC=1>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[CH2:7]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@H]1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
(2S)-2-methylpiperazine (15 g, 150 mmol) was dissolved in tetrahydrofuran (300 mL) and the solution was cooled down to 0° C. Sodium hydroxide (150 mL, 449 mmol) was added, then 4-(trifluoromethyl)benzenesulfonyl chloride (40 g, 164 mmol) (dissolved in 200 ml THF) was added dropwise and the resulting mixture was stirred for 1 h. Further 4-(trifluoromethyl)benzenesulfonyl chloride (0.06 eq, 2.2 g) was added and mixture stirred for 10 min. The mixture was diluted with DCM (500 ml) and water (500 ml) and stirred for min. The phases were separated, the aqueous layer was extracted with DCM (1000 ml) and the organic phases concentrated under reduced pressure. The residue was taken-up with 1 M HCl (500 ml) and washed with DCM in order to extracted impurities. The aqueous phase was basified to pH=9 with NaOH 3M, extracted with DCM (3×500 ml) and the combined organic phases dried over Na2SO4 before the solvent was removed under reduced pressure to give the title compound (30 g).
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[N:25]1[C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[NH:27][C:26]=1[CH2:34][NH2:35].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:35][CH2:34][C:26]4[NH:27][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][C:33]=5[N:25]=4)[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: NCc1nc2ccncc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(NCc3nc4ccncc4[nH]3)c21
Temperature: 120 °C
Yield: 19.4 %

Procedure:
200 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 346.22 mg C-(3H-imidazo[4,5-c]pyridin-2-yl)-methylamine and 359.24 μl diisopropylethylamine are placed in 4 ml dioxane, heated to 120° C. in the microwave for 0.3 hours and heated for another 0.3 hours at 120° C. Then the reaction mixture is mixed with water. The precipitated substance is suction filtered and washed with water. The product is purified by semipreparative HPLC (method A). 50 mg of the product are obtained as a powder. Analytical HPLC-MS (method B): RT=1.55 min.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:17]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+].C([OH:22])C>O>[O:22]1[CH2:2][CH:3]1[C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: CCO
Reactant: BrCCc1cccc2c1CCc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)CCc1cc(C3CO3)ccc1-2
Reaction time: 0.08 h

Procedure:
To a boiling solution of 1.51 g (5 mmol) of (28) in ethanol (40 mL), a solution of 285 mg (7,5 mmol) of NaBH4 in 5 mL of water was added dropwise. Boiling was continued for 5 min, the solution was cooled, diluted with water, and extracted with ether. The ether extract was washed with water, dried, and the solvent was removed at reduced pressure to provide (29) as a colorless oil. This soldified on trituration with a few drops of ether to yield (29), m.p. 65°-66° C.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[F:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:22])[N:19]([CH3:21])[CH3:20])=[C:11]([N+:25]([O-:27])=[O:26])[CH:10]=1.CI>C(OCC)(=O)C.O>[F:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:3])[C:18]([N:19]([CH3:21])[CH3:20])=[O:22])=[C:11]([N+:25]([O-:27])=[O:26])[CH:10]=1
Reactant: CN(C)C(=O)NCCCOc1ccc(F)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N(C)CCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
Sodium hydride (55% in oil) (396 mg, 9.1 mmol) was added, while being cooled with ice, to a DMF solution (9 ml) of 2.0 g of 3-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,1-dimethyl urea (7.0 mmol) and the mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.735 ml, 11.8 mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture and extraction with ethyl acetate was performed. After being washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=9:1→6:1). The purified product was concentrated under reduced pressure to thereby obtain 0.83 g of oily pale yellow 1-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,3,3-trimethylurea (yield: 40%).
Reaction SMILES: C1(C2C=CC=C(C3C=CC=CC=3)[C:8]=2[OH:19])C=CC=CC=1.C[Al](C)C.O1COCOC1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40](=[C:43](Br)[C:44]#[N:45])[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C([Mg]Br)(C)C.C=O>C(Cl)Cl.C1COCC1.O>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40](=[C:43]([C:44]#[N:45])[CH2:8][OH:19])[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)C#N)CC1
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: C1OCOCO1
Agent: C=O
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)CO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of 2,6-diphenylphenol (10.5 g, 42 mmol) in 60 mL CH2Cl2 at room temperature was added AlMe3 (2.0 M in hexane, 10.5 mL, 21 mmol). Gas evolution was observed and the mixture was stirred at room temperature for 30 min. The solution was cooled to 0° C. and 1,3,5-trioxane (630 mg, 7 mmol) in 6 mL CH2Cl2 was added dropwise and the solution was stirred for 1 h. In a separate flask 4-(bromo-cyano-methylidene)-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 7 mmol) was dissolved in 20 mL THF at −40° C. and to this solution was added isopropylmagnesium bromide (1M in THF, 8.4 mL, 8.4 mmol) dropwise. The mixture was stirred at −40° C. to −30° C. for 1.5 h. The above freshly prepared Grignard reagent was added dropwise to the formaldehyde solution and the mixture was stirred at 0° C. for 1 h. Water was carefully added and the mixture was extracted with ethyl acetate. Purification by chromatography (EtOAc/hexanes=1:1) yielded the title compound (800 mg, 45%) as a white solid. MS 253 (M+H).
Reaction SMILES: B.[CH2:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](O)=[O:11])[CH2:6][CH2:5]1)[CH3:3]>C1COCC1>[CH2:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[CH3:3]
Reactant: CC[C@H]1CC[C@H](C(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Borane in THF (1 M, 64.1 mL, 64.1 mmol) was added dropwise to trans-4-ethylcyclohexanecarboxylic acid (10.0 g, 64.1 mmol) in dry THF (100 mL) at −60° C. under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 12 h. The reaction was quenched with saturated ammonium chloride solution at 0° C., diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (2×200 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain (trans-4-ethylcyclohexyl)methanol. 1H NMR (300 MHz, CDCl3): δ 3.44 (d, J=6.0 Hz, 2H); 1.85-1.70 (dd, J=1.19, 10.5 Hz, 4H); 1.50-1.35 (m, 1H); 1.30-1.10 (m, 4H); 0.95-0.85 (m, 6H).
Reaction SMILES: Cl[CH:2](Cl)[O:3]C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[C:8]=1[Cl:17].O>C(Cl)Cl.[Ti](Br)(Br)(Br)Br>[Cl:6][C:7]1[C:8]([Cl:17])=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[CH:11][C:12]=1[CH:2]=[O:3]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(Cl)c(Cl)c1OC
Agent: Br[Ti](Br)(Br)Br
Solvent: ClCCl
Solvent: O
Product: COc1cc(C=O)c(Cl)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.2 %

Procedure:
105.2 g of dichloromethoxymethane are added to a solution of 122.6 g of 1,2-dichloro-3,4-dimethoxybenzene in methylene chloride, and titanium tetrabromide is added dropwise to the mixture at -50° to -60° C. The mixture is stirred at room temperature for 20 hours. The reaction mixture is poured into water and the organic layer is separated. The aqueous layer is extracted with chloroform, and the extract and the above-obtained organic layer are combined. The mixture is washed with water, dried and evaporated to remove solvent. The residue is washed with n-hexane to give 106 g of 2,3-dichloro-4,5-dimethoxybenzaldehyde.
Reaction SMILES: C([O:5][C:6]([CH:8](C(OC(C)(C)C)=O)[C:9]1[C:18]2[C:13](=[C:14]([NH:19][C:20](=[O:29])[C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][C:9]1[C:18]2[C:13](=[C:14]([NH:19][C:20](=[O:29])[C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])([OH:7])=[O:5]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 4-[bis(tert-butoxycarbonyl)methyl]-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (5.8 g) in dichloromethane (15 ml) was dropwise added trifluoroacetic acid (45 ml) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was pulverized with diethyl ether to give 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (4.08 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1)[NH:6][C:5]2=[O:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[OH:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([C:7]2[NH:6][C:5](=[O:21])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[CH:3]=3)[N:8]=2)=[CH:13][C:14]=1[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2nc3ccc(N)cc3c(=O)[nH]2)cc(C)c1O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nc(-c3cc(C)c(O)c(C)c3)[nH]c(=O)c2c1
Reaction time: 4 h
Yield: 17 %

Procedure:
To a round-bottomed flask were added 2-amino-5-nitro-benzamide (0.681 g, 3.76 mmol), 4-hydroxy-3,5-dimethyl-benzaldehyde (0.565 g, 3.76 mmol), sodium bisulfite (0.747 g, 4.2 mmol), p-toluenesulfonic acid, monohydrate (0.072 g, 0.376 mmol) and N,N-dimethylacetamide (60 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off, washed with water and methanol to obtain a crude which was purified by column chromatography (silica gel (50 g) employing 1-20% methanol in dichloromethane as eluents, to obtain 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 19%). The compound 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 0.71 mmol) was hydrogenated in dimethyl formamide (20 mL) using palladium on activated carbon (0.076 g, 0.071 mmol) at room temperature for 14 h. The solvent was evaporated and the crude was purified by column chromatography (silica gel 25 g) employing 1-5% methanol in dichloromethane as eluents to obtain 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.132 g). The compound 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one was dissolved in pyridine under nitrogen. Acetic anhydride was added at room temperature and stirred for 4 h. Pyridine was removed and the residue was dried. Methanol was added to the flask and a solution of potassium carbonate in water was added and stirred for 4 h. The solvent was removed, acidified with 1 N hydrochloric acid and the precipitated solid was filtered off and dried to obtain N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (0.037 g, 17%). Selected data: MS (ES) m/z: 324.1; MP 336.5° C. (decomposed).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].CN(C=O)C.Br[CH2:26][CH2:27][Cl:28]>O>[Cl:28][CH2:27][CH2:26][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[C:11]1=[O:19]
Reactant: ClCCBr
Reactant: O=c1[nH]c2ccccc2n1CCOC1CCCCO1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CCCl)c2ccccc2n1CCOC1CCCCO1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
Into a stirred solution of 1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (6.5 g, 25 mmoles) in DMF (40 ml) 80% sodium hydride (0.9 g, 30 mmoles) was added. After 30 minutes of stirring and heating to 35° C., 1-bromo-2-chloroethane (6.2 g, 48 mmoles) was added, the reaction temperature was increased to 90° C. and kept for 6 hours then cooled at room temperature. The reaction mixture was poured into water, extracted with diethyl ether, and the organic layer was taken to dryness. The residue was purified by flash chromatography (cyclohexane-ethyl acetate 50-50) to give 2.8 g of the title compound as a thick oil which was used without any further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].C(O)(=O)C(C)C>C(OCC(C)C)(=O)C(C)C>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: CC(C)COC(=O)C(C)C
Solvent: CC(C)C(=O)O
Product: CC1(C)C(O)C(C)(C)C1O

Procedure:
A solution of 18.0 wt % 2,2,4,4-tetramethylcyclobutane-1,3-dione and 3.90 wt % isobutyric acid in isobutyl isobutyrate was added to the reactor system containing 405 mL of a 2 wt % Ru-0.5 wt % Re-0.025 wt % Sn on alumina catalyst at a rate of 20 mL/min. The pressure at the top of the reactor was maintained at 500 psig and the temperature at the top of the catalyst bed was 128° C. These conditions were maintained for 24 hours. The average conversion of the dione was 98.4%. 2,2,4,4-Tetramethylcyclobutane-1,3-diol (16.5 wt %) was obtained at a rate of 24.8 lb/ft3 catalyst/hr (3.50 mmol/g/hr). The average conversion of isobutyric acid was 44.4% (0.592 mmol/g-hr).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][CH2:7][C:8]#[N:9].S(Cl)([Cl:15])=O>C(OCC)C.CN(C)C=O>[Cl:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][CH2:7][C:8]#[N:9]
Reactant: N#CCOc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#CCOc1cccc(CCl)c1

Procedure:
α-(3-Hydroxymethylphenoxy)acetonitrile (0.055 mol) in diethylether (150 ml) is stirred with thionyl chloride (0.060 ml) and a few drops of dimethylformamide at 40° C. for 1 hr. The solution is washed with water and brine, then evaporated to give α-(3-chloromethylphenoxy)acetonitrile as a yellow oil which is used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(=O)(O)[O-].[Na+].O.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[C:27]([NH:1][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)CN)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)CNC(=O)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a stirred solution of 0.80 g. (2.7 mmole) of 6-(2-aminoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 0.453 g. (5.4 mmole) of sodium bicarbonate in 21 ml. of water and 15 ml. of acetone at 0°-5° C. is added 0.32 ml. (2.8 mmole) of benzoyl chloride. Starting is continued for a further 20 minutes at ca. 0° C., and then the acetone is removed in vacuo. The aqueous residue is extracted with ethyl acetate and the extracts are discarded. The pH of the aqueous phase is adjusted to 2.0, and the product is extracted into ethyl acetate. The solvent is dried (Na2SO4), and then concentrated in vacuo to give 150 mg. (37% yield) of the title compound, m.p. 85°-93° C. IR (KBr disc): 1785 cm-1 (β-lactam) and 1695 cm-1 (amide I). NMR (in D2O): 7.90 ppm (m, 2 H), 7.50 ppm (m, 3H), 5.82 ppm (s, 1H), 5.58 ppm (s, 1H), 5.19 ppm (s, 1), 4.25 ppm (m, 2H), 1.67 ppm (s, 3H), 1.67 ppm (s, 1H).