Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:31](=[O:35])[C:32]([NH2:34])=[O:33])=[C:9]([CH:28]1[CH2:30][CH2:29]1)[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].CO>[NH2:34][C:32](=[O:33])[C:31]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:36])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]=1[CH:28]1[CH2:29][CH2:30]1)=[O:35]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C1CC1)n2Cc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)C(=O)c1c(C2CC2)n(Cc2ccccc2-c2ccccc2)c2cccc(OCC(=O)O)c12
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
A mixture of 175 mg (0.36 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]acetic acid methyl ester in 4 mL of 1N NaOH and 10 mL of MeOH was stirred for 0.5 hours, concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic with 1N HCl to pH 2-3 and extracted with EtOAc. The EtOAc solution was dried (MgSO4), evaporated and the residue stirred with EtOAc/ether. The insoluble material was filtered to give 105 mg (62% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]acetic acid, mp, 172°-174° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[NH:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1C(O)=O.N1CCCC1>[Cu]I.CS(C)=O>[N:24]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:31][CH2:30][CH2:29][CH2:25]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: C1CCNC1
Product: c1cc2cc(N3CCCC3)ccc2[nH]1
Temperature: 95 °C
Reaction time: 18 h
Yield: 383.5 %

Procedure:
t-Butyl 5-bromo-1H-indole-1-carboxylate (200 mg, 0.68 mmol) was placed in a 10 mL sealed tube. Cs2CO3 (440 g, 1.35 mol) was then added, followed by CuI (13 mg, 0.07 mmol), L-proline (16 mg, 0.14 mmol), DMSO (3 mL), and pyrrolidine (480 g, 6.75 mol). After sparging with nitrogen, the resulting solution was stirred at 95° C. for 18 hours. The mixture was extracted with ethyl acetate (3×40 mL), and the organic layers were combined and washed with brine. The residue was purified by column chromatography using 1:5 and 1:2 ethyl acetate/petroleum ether solvent systems. The collected fractions were combined and concentrated to give 100 mg (80%) of 5-(pyrrolidin-1-yl)-1H-indole as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)=[O:4].[H-].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH3:24].Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:7](=[O:18])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: CCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)CC(C(=O)OC)C(=O)c2ccc(Cl)cc21

Procedure:
The starting material is prepared as follows: The suspension of 6.0 g of 8-chloro-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester in 125 ml of dimethyl formamide is added portion-wise to that of 2.1 g of a 57% mineral oil suspension of sodium hydride in 300 ml of dimethylformamide while stirring under argon. After stirring for 3 hours at room temperature 4.6 g of n-butyl iodide are added dropwise and stirring is continued over night at said temperature. The pH of the mixture is adjusted to 2 with 3N hydrochloric acid and the whole evaporated. The residue is partitioned between water and chloroform, the organic solution separated and the aqueous solution extracted with chloroform. The combined extract is washed with water, dried, evaporated and the residue taken up in diethyl ether. The mixture is treated with charcoal, filtered hot and the filtrate concentrated, to yield the 8-chloro-1-n-butyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester, melting at 89°-90°.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([C@@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:18]I>O.CC(O)=O>[I:18][C:9]1[CH:10]=[CH:11][C:6]([C@@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])=[CH:7][CH:8]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
A solution of H2SO4 (0.1 mL) in water (1 mL) and AcOH (4 mL) in a 25 mL flask was added trans-2-phenylcyclopropanecarboxylic acid (200 mg, 1.23 mmol), iodine (173 mg, 0.68 mmol) and KIO3 (61 mg, 0.28 mmol). The reaction mixture was heated to reflux, and added AcOH (6 mL) in portions of 2 mL to rinse iodine down the condenser. After 4 hours, when no further color changes appeared, the reaction was cooled to room temperature, quenched with 1M Na2S2O4 and added water. The mixture was extracted with EtOAc (3×), and the combined extracts were washed with brine, dried over MgSO4 and concentrated under vacuum. The crude product containing minor impurities of starting material and the ortho-iodinated product, was recrystallized from PE to provide 157 mg (44%) trans-2-(4-iodophenyl)cyclopropanecarboxylic acid as a pure and white crystalline product: Rt=11.33 min (HPLC method I); 1H NMR (CDCl3) δ 7.62-7.58 (m, 2H), 6.87-6.84 (m, 2H), 2.56-2.51 (m, 1H), 1.89-1.84 (m, 1H), 1.69-1.64 (m, 1H), 1.39-1.34 (m, 1H); 13C NMR (CDCl3) δ 179.3, 139.2, 137.6, 128.3, 91.7, 26.5, 23.9, 17.4; ESI-MS m/z 311.0 (M+Na+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C-:24]#[N:25].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([C:24]#[N:25])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 65 °C
Reaction time: 9 h
Yield: 92.3 %

Procedure:
To a solution of 1-benzhydryl-3-(methanesulfonyloxy)azetidine (7.52 g) in N,N-dimethylformamide (60 ml) were added water (7.2 ml) and sodium cyanide (3.48 g), followed by stirring at 65° C. for 9 hr. To the reaction mixture were added water, sodium carbonate and ethyl acetate, and this was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with brine, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, and the resultant crystals were suspended by addition of diethyl ether (10 ml). The crystals were collected by filtration and washed with diethyl ether. This was dried under aeration to provide the titled compound as pale yellow crystals (5.43 g, 92.3%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:21]#[N:22])[CH2:17][CH2:16]1.S([O-])(O)(=O)=O.[Na+]>C(OCC)C.C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([C:15]2([OH:14])[CH2:20][CH2:19][C:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:21]#[N:22])[CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCC(O)(c2cccc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
8.00 g of 1,3-dibromobenzene were dissolved in 200 ml of dry diethyl ether and 22.61 ml of an n-butyllithium solution (1.5 M in n-hexane) were added dropwise between 0° C. and 5° C. The reaction mixture was stirred for 5 min at 0° C. Subsequently a solution of 6.76 g of 4-oxo-1-phenylcyclohexanecarbonitrile in 70 ml of dry THF was injected at −70° C. The reaction mixture was allowed to warm to room temperature and was stirred for 30 min at room temperature. The reaction mixture was then poured onto 200 ml of a saturated aqueous sodium hydrogensulfate solution, and the phases were separated and the aqueous phase extracted with 200 ml of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was stirred with 70 ml of HEP. 7.50 g of the title compound were obtained as a resinous, partially crystallizing solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[C:8]([CH:13]=1)[C:9](OC)=[O:10])([O-:3])=[O:2].[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[C:8]([CH2:9][OH:10])[CH:13]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)OB(c2ccc([N+](=O)[O-])cc2CO)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Methyl 5-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (C) (2.5 g, 8.14 mmol) was dissolved in DCM (25 mL), flushed with argon and cooled in an ice bath to 0° C. A solution of 1 M diisobutylaluminum hydride in DCM (20.5 mL, 20.35 mmol) was added dropwise so that the temperature remained below 3° C. over 2 h. The black reaction mixture was stirred at 0° C. for an additional 2 h. After this time, MeOH (3 mL) was added causing a yellow precipitate to form. 1 M aqueous HCl (50 mL) was then added and reaction was stirred for 30 min at 0° C. The layers were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine and dried over anhydrous MgSO4 to produce (5-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (CI) as a black oil (1.25 g, 4.48 mmol, 55% yield, purity 85%). The product was used without further purification for step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([NH:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=2)[CH2:8][CH2:9]1)=[O:26]
Reactant: Nc1cncc(C(=O)O)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(N)c3)CC2)ccc1Cl
Yield: 37 %

Procedure:
The title compound (0.18 g, 37%) was prepared analogously to example 28 from 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine and 5-aminonicotinic acid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.C([Si](C)(C)[O:15][CH2:16][C:17]#[CH:18])(C)(C)C.C(N(CC)CC)C>CN1C(=O)CCC1.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([C:18]#[C:17][CH2:16][OH:15])[CH:7]=[CH:6][CH:5]=1
Reactant: OCc1cccc(I)c1
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: OCC#Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Copper (I) iodide (0.037 g) and tetrakis(triphenylphosphine)palladium (0) (0.075 g) were added to a solution of (3-iodophenyl)methanol (2.27 g), tert-butyldimethyl(prop-2-ynyloxy)silane (1.1 g) and triethylamine (2.7 mL) in NMP (20 mL) and the mixture stirred at ambient temperature under nitrogen for 18 hours. The mixture was diluted with water and extracted into ethyl acetate (×3). The combined extracts were washed successively with 10% brine, 30% brine and saturated brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, elution gradient 10, 15 and 20% ethyl acetate in isohexane. Appropriate fractions were evaporated to dryness to give a mixture of product and starting material. The mixture was purified by preparative HPLC (XBridge™, Gradient: 65-99% acetonitrile in 0.2% aqueous TFA) to afford the subtitled compound as a pale yellow oil. Yield 0.44 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[C:29]([CH2:31][CH2:32][NH2:33])[N:28]=[CH:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][C:29]4[N:28]=[CH:27][NH:26][CH:30]=4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCc1c[nH]cn1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCCc1c[nH]cn1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(1H-imidazol-4-yl)ethylamine employing methods similar to those described in Example 11 and was obtained as an off-white solid: 1H NMR (CF3CO2D) δ 8.66 (1H, s), 8.60 (1H, s), 8.43 (1H, s), 7.39 (1H, s), 7.22 (2H, m), 7.08 (2H, t, J=8.4 Hz), 4.36 (2H, s), 4.00 (2H, br, t, J=6 Hz), 3.29 (2H, br t, J=6 Hz); ES+ MS: 408 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][CH:21]([C:23]2[S:27][C:26]([N:28]=[C:29]=[O:30])=[N:25][N:24]=2)[CH3:22])=[CH:18][CH:17]=1>C1C=CC=CC=1.CCCCCC>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH:21]([C:23]2[S:27][C:26]([NH:28][C:29](=[O:30])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:25][N:24]=2)[CH3:22])=[CH:31][CH:32]=1
Reactant: Cc1ccc(OC(C)c2nnc(N=C=O)s2)cc1
Reactant: CNCC(OC)OC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(C)cc2)s1)OC
Reaction time: 8 h

Procedure:
Methylaminoacetaldehyde dimethylacetal (1.8 grams, 0.015 mole) was added to a benzene solution containing 4.0 grams (0.015 mole) of the 5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 20 minutes, topped on a roto-vac at 70° C. to form a viscous red-orange oil, which was redissolved in benzene-hexane mixture and left to stand overnight. Crystals formed which were removed by suction filtration, and dried in a vacuum oven at 70° C. to 3.2 grams of tan crystals of [5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl-1-methyl-1-(2,2-dimethoxyethyl)urea, (melting point 94°-100° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32](=[NH:35])[NH:33][OH:34])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:36].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].[H-].[Na+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32]3[NH:35][C:37](=[O:38])[O:34][N:33]=3)=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:36]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=N)NO)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2noc(=O)[nH]2)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-phenyl]-5-hydroxycarbamimidoyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.1 g) in N,N-dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (62 mg) at room temperature. To the mixture was added sodium hydride (55%, 38 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (62 mg).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2>CN(C)C=O.C(OCC)C>[CH3:1][O:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Oc1cnc2ccccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.05 g of anhydrous potassium carbonate and 0.48 ml of methyliodide are added to a solution of 1.0 g of 3-hydroxyquinoline in 8.5 ml of dimethylformamide and the reaction mixture is stirred at room temperature for 18 h. It is diluted with diethyl ether, the resulting suspension is filtered and the filtrate is concentrated. The crude product is purified by FC over 60 g of silica gel (mobile phase F) to give 3-methoxyquinoline: Rf (A)=0.53.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[NH2:19][C:20]1[N:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[N:21]=1>C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([Cl:26])[N:25]=[C:20]([N:19]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:21]=1
Reactant: BrCCOCCBr
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(Cl)nc(N2CCOCC2)n1
Yield: 28.1 %

Procedure:
2-bromoethylether (3.65 g), potassium carbonate (8.29 g), and N,N-dimethylformamide (75 mL) were added to 2-amino-4,6-dichloropyrimidine (2.46 g), and the mixture was refluxed for 3 hours while heated. Subsequently, the reaction mixture was diluted with ethyl acetate, was washed with water, and was dried over anhydrous sodium sulfate. The solvent was removed and the resulting residue was purified on a silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 4,6-dichloro-2-(morpholine-4-yl)pyrimidine (985 mg, 28%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH2:17]Cl)[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>ClC(Cl)CCl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:25])[Cl:26])=[O:21])=[C:15]([CH3:19])[CH2:17][S:16][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: ClCC(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 25.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2-methyl-2-chloromethylpenam-3-carboxylate (0.50 g.) in 1,1,2-trichloroethane (7 cc) and pyridine (0.16 g.) was heated under reflux for 3.5 hours. After cooling, the reaction mixture was washed with water, dried and then concentrated under reduced pressure. The residue was subjected to chromatography on silica gel and eluated with chloroform. The eluate was concentrated and the residue was crystallized with ether to yield crystals (0.12 g.) of 2,2,2-trichloroethyl 7-(2-phenylacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 161°-162° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl[C:29]1[N:34]=[C:33]([S:35][C:36]#[N:37])[C:32]([N+:38]([O-:40])=[O:39])=[CH:31][N:30]=1.O>O1CCCC1>[CH:1]1([N:4]([C:29]2[N:34]=[C:33]([S:35][C:36]#[N:37])[C:32]([N+:38]([O-:40])=[O:39])=[CH:31][N:30]=2)[C:5]2[CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3]1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC2CC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(N(c2ncc([N+](=O)[O-])c(SC#N)n2)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [3-(cyclopropylamino)phenyl]carbamate (5.51 g, 15.4 mmol) in tetrahydrofuran (100 mL) were added N-ethyl-N-isopropylpropane-2-amine (8.06 mL, 46.2 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (6.66 g, 30.7 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with saturated brine (30 mL), and filtered through a silica gel pad. The obtained filtrate was concentrated under reduced pressure to give tert-butyl {3-[cyclopropyl(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate as a brown amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16](C)[C:15](=O)[N:14]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:13]=2[N:12]=[C:11]1[CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:18]([C:17]([NH:16][CH3:15])=[O:19])=[C:13]([NH:14][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:12]=[C:11]1[CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nc2c(c(=O)n(C)c(=O)n2-c2ccc(Cl)cc2Cl)n1COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCc1nc(Nc2ccc(Cl)cc2Cl)c(C(=O)NC)n1COCc1ccccc1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
7-benzyloxymethyl-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione (5.20 g, 11.32 mmol) was dissolved in dioxane (25 mL) and the mixture was treated with EtOH (25 mL) and aqueous NaOH (50 mL, 3 N). The reaction mixture was heated at 60° C. for 2 h. The mixture was then cooled to rt and was transferred to a separatory funnel containing saturated aqueous NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (40% ethyl acetate in hexanes→40% ethyl acetate in hexanes with 0.2% MeOH) to afford 1-benzyloxymethyl-4-[(2,4-dichlorophenyl)amino]-2-ethyl-N-methyl-1H-imidazole-5-carboxamide (2.90 g, 59% yield) as a light yellow amorphous solid: 1H NMR (300 MHz, CDCl3) δ 9.35 (s, 1H), 8.41 (d, J=8.8 Hz, 1H), 7.44-7.29 (m, 7H), 7.16 (dd, J=9.1, 2.5 Hz, 1H), 5.45 (s, 2H), 4.63 (s, 2H), 2.89 (d, J=4.8 Hz, 3H); 2.65 (q, J=7.7 Hz, 2H), 1.35 (t, J=7.7 Hz, 3H); LRMS (APCI) m/e 433.1 [(M+H)+, calcd for C21H23N4O2Cl2 433.1].
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH:12]([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:9]([O:8][P:1]([CH:12]([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)C(F)Br
Product: CCOC(=O)C(F)P(=O)(OCC)OCC
Temperature: 150 °C
Yield: 77.4 %

Procedure:
A mixture of 4.00 g (24.0 mmol) of triethyl phosphite and 4.45 g (24.0 mmol) of ethyl bromofluoroacetate (purchased from PCR Inc. Gainesville, Fla.) was heated to 150° C. for 4 h under argon. The contents of the flask were cooled to RT and then distilled under vacuum (0.5 mm Hg) to provide 4.5 g (77%) of title compound as a colorless oil.