Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C(=O)C(C)C)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1sc(C(=O)C(C)C)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Yield: 108 %

Procedure:
To a mixture of methyl 4-({cyclohexyl[2-ethyl-5-(2-methylpropanoyl)thiophen-3-yl]methyl}amino)benzoate (268 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred with heated under reflux for 2 hr. To the reaction mixture was added 1N hydrochloric acid (10 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (280 mg, quantitative) as a pale-brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]2[S:15][CH2:16][C:17](O)([C:19]([F:22])([F:21])[F:20])[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[Br:1][C:2]1[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(Br)cn1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A suspension of 1-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydrothiazol-2-yl)pyridin-2-yl)-3-ethylurea (Intermediate 7, 175.8 g, 430 mmol) and triethylamine (295 mL, 2.13 mol) in tetrahydrofuran (3 L) was prepared and stirred at room temperature. Methane sulfonyl chloride (106 mL, 1.36 mol) was added dropwise over the course of an hour. This mixture was stirred at room temperature for 6 hours. The solid was collected by filtration, rinsed with tetrahydrofuran (2×500 mL), and the filtrate was retained while the solid was discarded. The combined tetrahydrofuran layers were concentrated to a viscous, yellow semi-solid which was then washed with water (2×500 mL). This solid was further stirred with water (500 mL) for 18 hours, then filtered and dried in the vacuum oven at 50° C. for 12 hours to give 121.8 g (73%) of 1-(5-bromo-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-2-yl)-3-ethylurea as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21].Cl.[F:23][C:24]([F:34])([F:33])[C:25]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:26].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:30]1[CH2:31][CH2:32][CH:28]([NH:27][C:25](=[O:26])[C:24]([F:34])([F:33])[F:23])[CH2:29]1)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21]
Reactant: CCOC(=O)c1c2n(c3cc(F)c(F)cc3c1=O)C(C)S2
Reactant: O=C(NC1CCNC1)C(F)(F)F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCC(NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.2 %

Procedure:
A mixture of 1.00 g of ethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, 2.1 g of 3-trifluoroacetylaminopyrrolidine hydrochloride, 1.46 g of 1,8-diazabicyclo[5,4,0]-7-undecene and 20 ml of N,N-dimethylformamide was stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo, and, to a suspension of the residue in 20 ml of methanol, 30 ml of water was added. The precipitate was collected by filtration to give 1.22 g of the desired compound, which was recrystallized from a mixture of chloroform and ethanol to give colorless crystals, m.p. 255°-257° C. (decomp.).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[CH:15]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:15]#[C:14][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Brc1nccs1
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C(#Cc1nccs1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
2-Bromo-1,3-thiazole (0.15 mL, 1.6 mmol), CuI (98 mg, o.51 mmol), PdCl2(PPh3)2 (120 mg, 0.17 mmol) and triethylamine (2.8 mL, 20 mmol) were combined in DMF (6.8 mL) and cooled in an ice bath. 3-Ethynylpyridine (520 mg, 5.04 mmol) was then added to the mixture as a solution in DMF (3.0 ML). The ice bath was removed and the reaction was allowed to stir at ambient temperature for 16 h. The reaction mixture was filtered through a pad of Celite.™, and the pad was washed thoroughly with ethyl acetate. The filtrate was washed with brine (3.times.20 mL). A partial emulsion was observed. The mixture was concentrated in vacuo and the residue was taken up in CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 80:20 followed by 30:20 hexane:ethyl acetate to afford 3-(1,3-thiazol-2-ylethynyl)pyridine (160 mg) as a mixture with another product exhibiting a mass of 204 in the GC/MS, assigned as pyridylalkyne dimer. A portion of the mixture (100 mg) was further purified by preparative reverse phase HPLC eluting with a gradient of 80:20 to 0:100 water: acetonitrile over twenty minutes. The fractions containing the desired product were collected (detection by uv at 210 nm) to afford 3-(1,3-thiazol-2-ylethynyl)pyridine as a white waxy solid (15 mg). 1H NMR (CDCl3, 300 MHz) Δ9.3-8.5 (br s, 2H), 7.92-7.90 (m, 2H), 7.50-7.30 (m, 2H). MS (ESI) 187.0 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>N1C=CC=CC=1>[S:11]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: OCCc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 55.4 %

Procedure:
4-Hydroxyphenethyl alcohol (3.2 g) was dissolved in 50 ml of pyridine, to which 4.0 g of tosyl chloride was added in small portions under ice cooling. The temperature of the reaction mixture was allowed to rise to room temperature, at which it was stirred for 2 hours. Then, insoluble matter was filtered off, and pyridine was distilled off under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (eluent: CHCl3), whereby 3.4 g of the compound (1) were obtained (yield: 59%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:12])[CH:8]=2)[N:3]=1.[CH2:13]([CH2:15][NH2:16])O.S(Cl)(Cl)=O>>[I:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]1[CH2:13][CH2:15][N:16]=[C:2]1[CH:11]=[CH:10]2
Reactant: Clc1ccc2cc(I)ccc2n1
Reactant: NCCO
Solvent: O=S(Cl)Cl
Product: Ic1ccc2c(c1)C=CC1=NCCN12
Temperature: 50 °C

Procedure:
2-Chloro-6-iodo-quinoline (200 mg, 0.69 mmol) and ethanolamine (1 mL) were heated at 130° C. for 1 hour. The reaction was cooled and purified by silica gel chromatography (4:1 EtOAc:Hex), and the isolated product was dissolved in CHCl3. Thionyl chloride (0.12 mL, 1.65 mmol) was added, and the reaction was heated at 50° C. for 1 hour. The reaction was quenched with methanol and basified with saturated aqueous Na2CO3. The mixture was extracted with CH2Cl2, and the combined organic layers were combined, dried, filtered, and concentrated to give the desired product, 2a.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C@H:12]([C:14]([NH:16][CH:17]1[C:23](=[O:24])[N:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[N:19]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:18]1=[O:37])=[O:15])[CH3:13]>>[CH:1]1([CH2:6][C:7]([NH:11][C@H:12]([C:14]([NH:16][CH:17]2[C:18](=[O:37])[N:19]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[N:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:23]2=[O:24])=[O:15])[CH3:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: CC(C)CN1C(=O)C(NC(=O)[C@H](C)N)C(=O)N(CC(C)C)c2ccccc21
Agent: Cl
Product: CC(C)CN1C(=O)C(NC(=O)[C@H](C)NC(=O)CC2CCCC2)C(=O)N(CC(C)C)c2ccccc21

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-S), the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.31 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[CH2:14][C:15](Cl)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:1]1[C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[O:12][CH2:14][C:15]1=[O:16]
Reactant: Nc1cnc2ccccc2c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2c(cnc3ccccc23)N1
Reaction time: 0.5 h

Procedure:
In a 50 ml flask equipped with a reflux apparatus, 3-amino-quinolin-4-ol (421 mg, 2.628 mmol) was dissolved in N,N-dimethyl formamide (13 ml) under nitrogen atmosphere, and then chloroacetyl chloride (0.21 ml, 2.76 mmol) was added thereto dropwise at 0□, and then stirred at 0□ for 30 minutes. Potassium carbonate (24 g, 177 mmol) was added thereto and the mixture was heated to 100□ under reflux. After 16 hours, N,N-dimethyl formamide solvent was evaporated under reduced pressure and methanol was added to the residue, and then the mixture was filtered on celite. The filtrate was evaporated under reduced pressure to obtain the target compound, i.e., 1H-4-oxa-1,9-diaza-phenanthren-2-one, as brown solid (526 mg, quantitative yield).
Reaction SMILES: [Na].[C:2](OCC)(=[O:6])[C@H:3]([CH3:5])[OH:4].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH2:18][C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1.Cl>C(O)C.O>[CH3:5][CH:3]1[C:2](=[O:6])[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:21])([F:22])[F:10])[CH:13]=2)=[C:19]([NH2:20])[O:4]1
Reactant: CCOC(=O)[C@H](C)O
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1OC(N)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Yield: 18.3 %

Procedure:
A dry, 500-ml, three-neck, round-bottom flask equipped with a mechanical stirrer, addition funnel and a reflux condenser was charged with 100 ml of ethanol. To the stirred solvent were added 3.5 g of sodium. After all the metal had dissolved, a solution of 13.0 g of ethyl L-(+)-lactate and 18.5 g of m-trifluoromethylphenylacetonitrile in 30 ml of ethanol was added dropwise to the reaction mixture. The mixture became a deep red and after the addition was complete, the mixture was heated at reflux overnight (about 18 hours). The mixture was then cooled to room temperature and added to 300 ml of water and the resulting mixture was acidified (pH about 1) with 10% hydrochloric acid. The mixture was then extracted with ether (three times) and the organic extracts were washed (two times) with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to yield a thick oil. This oil was taken up in a mixture of ether/petroleum ether and the desired compound crystallized as a yellow powder. Two crops of crystals were collected to afford a total of 4.7 g of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[O:15]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16]1.C(=O)(O)[O-].[Na+]>O.C(COC)OC.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>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:17]2[CH:18]=[CH:19][O:15][CH:16]=2)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1ccc(-c2ccoc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 63 %

Procedure:
A mixture of 1d from Example 18 (8.5 g, 32.8 mmol), 3-furanylboronic acid (3.67 g, 32.8 mmol), sodium bicarbonate (13.8 g, 0.16 mol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g) in a mixture of water (40 ml) and dimethoxyethane (80 ml) is heated to 80° C. under a stream of nitrogen over night. After cooling the mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated under reduced pressure.(*). The residue is dissolved in 40 ml dimethoxyethane. Aqueous sodium hydroxide (78 ml, 1 M) is added and the mixture is stirred at ambient temperature over night. The mixture is poured into water and rendered acidic with diluted hydrochloric acid. The precipitate is filtered off, washed with water and dried to yield 1e (5.09 g, 76%). Mp 152-154° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].Br[C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][C:45]=1[Cl:51]>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.O>[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:44]3[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][C:45]=3[Cl:51])=[CH:31][CH:32]=2)[N:26]=1)=[O:16])[CH:12]([CH3:13])[CH3:14]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3Cl)cc2)c[nH]1)C(C)C
Temperature: 90 °C

Procedure:
Saturated aqueous sodium carbonate (0.2 mL) was added to a mixture of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (100 mg, 0.20 mmol), 4-bromo-3-chloroaniline (46 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), and water (0.3 mL). The reaction mixture was purged with nitrogen and then 1,4-dioxane (0.7 mL) was added. The reaction mixture was degassed, stirred, and heated at 90° C. overnight. Water and ethyl acetate were added; the reaction mixture was concentrated; dissolved in 1:1 acetic acid:water (1 mL) and purified by preparative HPLC. Fractions were combined, adjusted to pH 8-9 with aqueous sodium bicarbonate, and extracted with DCM. Extracts were washed with water, dried with sodium sulfate, and concentrated. The concentrate was dissolved in methanol and concentrated under vacuum to provide the title compound (m/z): [M+H]+ calcd for C26H30ClN5O3 496.20 found 496.7.
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C.[CH3:21][S:22]([O-:24])=[O:23].[Na+]>CO>[CH3:21][S:22]([C@@H:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:24])=[O:23]
Reactant: CS(=O)[O-]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
To a solution of 0.494 g of (3S,4S)-4-acetoxy-3-phenoxyacetamido-2-oxoazetidine in 14 ml of 50% methanol is added 0.51 g of sodium methylsulfinate and the mixture is stirred at room temperature for 18 hours. The methanol is distilled off under reduced pressure to give 222 mg of (3R,4S)-4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine.
Reaction SMILES: [OH:1][CH2:2][C:3]([N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7]1)([CH3:5])[CH3:4].N1C=CN=C1.Cl[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3]([N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7]1)([CH3:5])[CH3:4])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(=O)n(C(C)(C)CO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(C(C)(C)CO[Si](C)(C)C(C)(C)C)c1

Procedure:
A solution of methyl 1-(1-hydroxy-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2000 mg, 8.88 mmol), 1H-imidazole (1.51 mg, 22.2 mmol), and chloro-tert-butyldimethylsilane (1405 mg, 9.32 mmol) in DMF (10 mL) was stirred overnight at 23° C. The mixture was partitioned between CH2Cl2 and 5% NaHCO3. The organic was dried over MgSO4 and reduced to an oil under reduced pressure from toluene. MS (ESI pos. ion) m/z (MH+): 340. Calc'd exact mass for C17H29NO4Si: 339.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH2:9]([NH:11][C:12]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1O
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
N-hydroxysuccinimide (11.5 g, 0.1 mol) was dissolved in 100 g of sufficiently dried tetrahydrofuran. To the solution was added dropwise 7.1 g (0.1 mol) of ethyl isocyanate, and then a catalytic amount of triethylamine was added. After stirring at room temperature overnight, the reaction solution was decolored with active carbon and concentrated. The deposited crystal was filtered and washed with a small amount of ether to obtain 16.1 g of N-(ethylcarbamoyloxy)succinimide represented by the following formula, yield 86.6%.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[C:16]([NH:15][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: N#Cc1cccc(N)c1
Product: N#Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
Carboxylic acid (56) (150 mg, 0.80 mmol) was coupled to 3-amino-benzonitrile (94 mg, 0.80 mmol) using Method C. The residue was purified by column chromatography eluting with 17% EtOAc in heptane to give the title compound.
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: CCOCC
Solvent: C1CCOC1
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:2]1[C:3]([CH:12]2[CH2:14][O:13]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[OH:15][CH2:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>CCO>[OH:15][CH2:16][C@H:17]1[N:22]([CH2:14][CH:12]([OH:13])[C:3]2[C:2]([CH3:1])=[CH:11][C:6]3[C:7](=[O:10])[O:8][CH2:9][C:5]=3[CH:4]=2)[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1
Reactant: Cc1cc2c(cc1C1CO1)COC2=O
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: Cc1cc2c(cc1C(O)CN1CCN(C(=O)OC(C)(C)C)C[C@H]1CO)COC2=O
Temperature: 25 °C

Procedure:
A mixture of 6-methyl-5-(oxiran-2-yl)-2-benzofuran-1(3H)-one (750 mg, 3.95 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (1.02 g, 4.74 mmol) in EtOH (5 mL) was reacted under microwave condition (140° C.) for 90 min. After cooling to r.t., the mixture was concentrated to dryness. The residue was purified by prep-TLC to give tert-butyl (3S)-3-(hydroxymethyl)-4-[2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].OO.[C:11]([OH:14])(=[O:13])[CH3:12]>C(OC(=O)C)(=O)C>[C:11]([O:14][CH2:8][C:2]1[C:3]([CH3:7])=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:13])[CH3:12]
Reactant: Cc1cccnc1C
Reactant: CC(=O)O
Agent: OO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1ncccc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2,3-lutidine (4.8363 g, 45.13 mmol) in glacial acetic acid (30 mL) at room temperature was added 30% H2O2 (4.6 mL) and the resultant solution was heated to 70° C. After 6 hours, the reaction mixture was cooled to room temperature, additional H2O2 (4.6 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was dissolved in CHCl3 (100 mL) and treated with solid Na2CO3 (14.12 g). After 1 hour, the supernatant was decanted and the residue was washed with warm CHCl3 (3×50 mL). The combined supernatants were filtered and concentrated to provide 4.6951 g as a yellow solid. The solid was dissolved in acetic anhydride (38 mL) and heated at 90° C. overnight. The mixture was cooled to room temperature and concentrated and the crude product was filtered through a silica plug (33 g silica, ethyl acetate) to give 6.13 g of 2-acetoxymethyl-3-methyl-pyridine as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:7]
Reactant: C1COCCN1
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Product: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)N2CCOCC2)c1I

Procedure:
4-[3-Amino-2,4,6-triiodo-5-(N-methylacetamido)benzoyl]morpholine [C; Ro is CH3CON(CH3), Q is H, Z is morpholino] was prepared from the acid chloride of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid and morpholine according to the procedure described in Example 45, part (a). The product obtained was used directly in the procedure described in part (b) below.