Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[C:25](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (700 mg, 2.1 mmol) in DMF (10 mL) at room temperature was added cesium carbonate (686 mg, 2.1 mmol) and methyliodide (299 mg, 0.13 mL, 2.1 mmol) and the resulting mixture stirred for 30 min. The resulting mixture was then evaporated and extracted with ethyl acetate and water. The organic extract was then washed with water, brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=4:1 to 2:3) afforded the title compound (354 mg, 49%) which was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][C:11]2[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=2)=[C:4]([OH:25])[CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH2:10][C:11]3[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[N:16]=3)[O:25][C:4]=2[CH:3]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccc(F)cc3o2)[nH]1
Yield: 13.2 %

Procedure:
The product is prepared according to the procedure described in Stage 2 of Example 2, using 120 mg of N-(4-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide, and 11 mg of 4-methylbenzenesulphonic acid hydrate, and replacing the toluene with xylene. After purification by silica gel column chromatography, eluent: CH2Cl2/MeOH: 98/02, 15 mg of 2-[(6-fluoro-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: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8](B(O)O)[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Br[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][NH2:29].C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:29][CH2:28][C:27]1[CH:26]=[CH:25][C:32]([F:33])=[C:31]([C:8]2[C:7](=[O:22])[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]3[N:12]=[C:13]([NH:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=2)[CH:30]=1
Reactant: CNc1nc(C)c2cc(B(O)O)c(=O)n(C3CCCC3)c2n1
Reactant: NCc1ccc(F)c(Br)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Product: CNc1nc(C)c2cc(-c3cc(CN)ccc3F)c(=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Yield: 43.4 %

Procedure:
To a solution of 8-cyclopentyl-4-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-ylboronic acid (30 mg, 0.099 mmol), 3-bromo-4-fluorobenzylamine hydrochloride (28.7 mg, 0.119 mmol), potassium carbonate (3 M, 0.10 mL) in DME (0.5 mL) and EtOH (0.5 mL) was added tetrakis(triphenylphosphine) palladium(0) (6 mg, 0.005 mmol). The mixture was degassed with N2, sealed and heated for 1 h at 100° C. in microwave. The mixture was removed under reduced pressure. The crude product was purified by chromatography to give the title compound (16.4 mg, 43.3%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[C:26]([CH3:42])=[N:25]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:29]4[CH:28]=[C:27]5[C:32](=[CH:31][CH:30]=4)[N:24]([CH3:23])[N:25]=[C:26]5[CH3:42])=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: Cc1nn(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)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: COCCOC
Product: Cc1nn(C)c2ccc(-c3cc4ncn(C5CC5)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc12
Temperature: 105 °C

Procedure:
To a 25 ml 3-neck flask with condenser and magnetic stir bar was added (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-on (120 mg, 0.33 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (112 mg, 0.41 mmol) and Pd(PPh3)4 (32 mg, 0.027 mmol) then evacuated and filled with N2 3×. Added 2 mL DME and 2N SODIUM CARBONATE (0.41 ml, 0.82 mmol) via syringe and heated in a 105° C. oil bath for 2 hrs at which time LC-MS indicated a complete reaction. Let cool. Workup: EtOAc, water, brine, dried over Na2SO4, filtered and concentrated. Purified by chromatography: ISCO, 24 g silica Gold, 0-6% MeOH/DCM to give desired product as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([NH:23][C:24]4[S:25][C:26]5[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=5[N:28]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:33].[ClH:33].[NH:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([NH:23][C:24]4[S:25][C:26]5[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=5[N:28]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCNC3)ccc21
Yield: 258.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (R)-pyrrolidin-3-ylamide dihydrochloride (45 mg) was prepared by following General Procedure L starting from (R)-3-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (55 mg) in 4M HCl in dioxane (1 mL).
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.[CH:11]12[O:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]2>O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[OH:17]
Reactant: COc1ccccc1Br
Reactant: C1CCC2OC2C1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccccc1[C@@H]1CCCC[C@H]1O
Temperature: -30 °C
Yield: 61.5 %

Procedure:
A mixture of 3.24 g (0.1 35 mol) of magnesium and 20 ml of tetrahydrofuran was charged into a three-necked flask of 300 ml and stirred. Then, a solution of 25.3 g (0.135 mol) of o-methoxyphenylbromide in 80 ml of tetrahydrofuran was added dropwise at a temperature of 60° C. or less. After the dropping was stopped, the mixture was cooled to -30° C., 0.65g of cuprous chloride was added, and the mixture was stirred for 10 minutes. To the mixture, a solution of 13.3 g (0.135 mol) of cyclohexene oxide in 15 ml tetrahydrofuran was added dropwise. After the dropping was stopped, the temperature was raised to 0° C., and the mixture was stirred for three hours at 0° C. After the temperature was raised to room temperature, the mixture was charged into a separatory funnel and extracted with 600 ml of methylene chloride, and the organic layer was washed with 600 ml of saturated ammonium sulfate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled away under reduced pressure. The concentrate was distilled under reduced pressure to obtain 17.11 g (0.083 mol ) of (±)-trans-2-(2-methoxyphenyl)-1-cyclohexanol.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][C:11]#[N:12].N1C=CC=CC=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[CH2:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:8][N:9]([CH2:10][C:11]#[N:12])[S:25]([CH2:24][C:23]1[CH:29]=[CH:30][CH:31]=[C:21]([C:20]([F:19])([F:32])[F:33])[CH:22]=1)(=[O:27])=[O:26]
Reactant: CNCC#N
Reactant: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CC#N)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
In this example 21 ml (0.15 mole) of triethylamine was added over a 5 minute period to a cooled solution containing 16 g (0.15 mole) of the hydrochloride salt of methylaminoacetonitrile in 150 ml of methylene chloride. The mixture was stirred at 20° C. for 15 minutes and then 7.9 g (0.1 mole) of pyridine was added. Then 25.9 g (0.1 mole) of 3-trifluoromethylbenzylsulfonylchloride dissolved in about 50 ml methylene chloride was added to the reaction mixture. The reaction mixture was maintained at 20° C. during the addition and then refluxed for three hours. The mixture was cooled to room temperature and washed once with 200 ml of water and then washed twice with 100 ml of aqueous 5 wt. % hydrochloric acid. The washed mixture was dried over magnesium sulfate and evaporated under vacuum affording 28.2 g of the title compound as a solid residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16]C=O)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([Br:49])(Br)(Br)[Br:46]>ClC(Cl)C.ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[C:45]([Br:49])[Br:46])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ncccc1CN1CCC(CC=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ncccc1CN1CCC(C=C(Br)Br)CC1
Reaction time: 1 h
Yield: 61.5 %

Procedure:
3.0 g of 1-[(2-methoxy-3-piridyl)methyl]-4-piperidine acetaldehyde, 5.4 ml of triethylamine, 20.1 g of triphenylphosphine and 12.9 g of carbon tetrabromide were dissolved in 77 ml of dichloroethane at 0° C., and the mixture was stirred for one hour. Dichloromethane was added to the reaction solution, the mixture was washed with an aqueous saturated sodium bicarbonate, and then it was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (hexane:ethyl acetate=20:1), to give 2.9 g of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:32][C:33]([O:35][CH:36](I)[CH3:37])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:36]([O:35][C:33]([O:32][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:34])[CH3:37])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(I)OC(=O)OC1CCCC1
Agent: [Na+]
Product: CC(OC(=O)OC1CCCC1)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 86.7 %

Procedure:
In the same manner as in Example 81, 187 mg of the title compound was prepared from 162 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 148 mg of 1-(cyclopentyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:23]2C=CC=[CH:25][CH:24]=2)=[CH:4][CH2:3]1.CC1(C)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C#CC)=CC1>>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:23]#[C:24][CH3:25])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Agent: CC#CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Product: CC#CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 75 mg (0.20 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-2-yl)ethynyl]benzoate (Compound 92) was converted to the title compound (pale yellow solid) using 42 mg (2 ml, 1.0 mmol) of LiOH (0.5M aqueous solution).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][S:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][CH2:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=[O:22])=[CH:12][CH:11]=1)=[O:7])C>CO>[C:6]([CH2:8][S:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][CH2:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([OH:23])=[O:22])=[CH:12][CH:11]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)CSc1ccc(OCc2ccsc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSc1ccc(OCc2ccsc2C(=O)O)cc1
Yield: 96.3 %

Procedure:
An aqueous sodium hydroxide (19.2 g, 480 mmol) solution was added to a methanol (250 mL) solution of the compound obtained in Example 19 (35.1 g, 96 mmol), and the mixture was refluxed while heating for 2 hours. After allowing the mixture to cool in the air, the solvents were distilled off under a reduced pressure, and water was added to the residue. The solution was neutralized with hydrochloric acid, and the precipitated crystals were separated by filtration and dried, to give 30.0 g (97%) of the captioned compound.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16](OCC)=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.Cl.[NH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])[C:8](=[O:15])[C:9]2([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(F)c(F)c2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)c(F)c2C(C)(C)C1=O
Temperature: 85 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
A mixture of ethyl 7,8-difluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.46 g, 1.6 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.39 g, 2.3 mmol) in 2 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.60 g, 4.7 mmol). The mixture was warmed to 85° C. and stirred for 15 hours, M+Na=404, M−1=380. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give the title compound (0.53 g) as a pale yellow solid. MS (m/z)=404 (M+Na)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:27]=[C:21]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][N:20]3[N:19]=2)[C:3]1=[O:28].[C:29]([C:33]1[CH:34]=[C:35]2[C:40](=[C:41]([F:43])[CH:42]=1)[C:39](=[O:44])[N:38]([C:45]1[N:52]=[CH:51][CH:50]=[C:49](Cl)[C:46]=1[CH:47]=[O:48])[N:37]=[CH:36]2)([CH3:32])([CH3:31])[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:29]([C:33]1[CH:34]=[C:35]2[C:40](=[C:41]([F:43])[CH:42]=1)[C:39](=[O:44])[N:38]([C:45]1[N:52]=[CH:51][CH:50]=[C:49]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:27]=[C:21]5[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][N:20]5[N:19]=4)[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=3)[C:46]=1[CH:47]=[O:48])[N:37]=[CH:36]2)([CH3:32])([CH3:30])[CH3:31]
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 65.2 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 128d (193 mg, 0.50 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (180 mg, 0.50 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (17 mg, 0.025 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), acetonitrile (6 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 1 h. Analysis of the reaction mixture by LCMS showed completed conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (10 mL). The aqueous layer was separated and extracted with dichloromethane (3×10 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 128e (190 mg, 65%) as a yellow solid. MS-ESI: [M+H]+ 583.3
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH2:10]([N:12]([CH2:28][CH3:29])[C:13](=[O:27])[C:14]1[C:19]([CH2:20]O)=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[Si:23]([CH3:26])([CH3:25])[CH3:24])[CH3:11]>C(Cl)Cl>[CH2:10]([N:12]([CH2:28][CH3:29])[C:13](=[O:27])[C:14]1[C:19]([CH2:20][F:7])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[Si:23]([CH3:26])([CH3:25])[CH3:24])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN(CC)C(=O)c1c(CO)ccc(F)c1[Si](C)(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)c1c(CF)ccc(F)c1[Si](C)(C)C
Temperature: 0 °C
Yield: 83.5 %

Procedure:
A solution of DAST (400 mg, 2.5 mmol) and the compound of Example 54 (660 mg, 2.2 mmol) in CH2Cl2 (30 mL) was stirred for 2 h at 25° C. The solution was poured into ice water (50 mL) and extracted with CH2Cl2. The organic extracts were combined, washed with brine, dried (MgSO4), concentrated, and purified by RC with 1:9 ethyl acetate/hexanes to give 550 mg of the title compound as a yellow oil, an 83% yield.
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]([C:14]3[S:18][C:17]([C:19]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[O:20])=[C:16]([CH3:29])[CH:15]=3)[C:10]2=[O:30])=[CH:6][CH:5]=1)(=[O:3])N.[OH-].[K+].C(O)(=[O:37])C>C(O)C.O>[CH3:29][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:9]([CH2:8][C:7]3[CH:31]=[CH:32][C:4]([C:1]([OH:3])=[O:37])=[CH:5][CH:6]=3)[C:10]2=[O:30])[S:18][C:17]=1[C:19](=[O:20])[NH:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(C(N)=O)cc3)C2=O)sc1C(=O)NCc1cccnc1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 0 °C
Yield: 50 %

Procedure:
A mixture of 5-(3-(4-carbamoylbenzyl)-2-oxoimidazolidin-1-yl)-3-methyl-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide (0.16 g, 0.36 mmol) and 5 N aqueous potassium hydroxide solution (5.0 mL, 25.0 mmol) in ethanol (5 mL) was stirred at reflux for 2 h, cooled to 0° C. and acidified with glacial acetic acid to pH˜6. The mixture was diluted with water (25 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ether in hexanes to afford the title compound as a colorless solid in 50% yield (0.08 g): mp 120° C. (dec.): 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.46 (s, 1H), 8.30 (t, J=5.8 Hz, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.44-7.32 (m, 2H), 6.24 (s, 1H), 4.47 (s, 2H), 4.39 (d, J=5.8 Hz, 2H), 3.88-3.79 (m, 2H), 3.51-3.43 (m, 2H), 2.37 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 167.0, 162.9, 155.5, 148.8, 147.8, 142.5, 141.7, 139.0, 135.0, 130.0, 129.6, 127.7, 123.4, 119.9, 113.8, 112.1, 46.8, 42.5, 41.5, 15.7: MS (ES+) m/z 450.4 (M+1).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[CH2:11][C:10](=O)[CH2:9]1>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]([S:5]([N:7]=[C:10]1[CH2:11][O:8][CH2:9]1)=[O:6])([CH3:4])[CH3:3]
Reactant: O=C1COC1
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1COC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
2-Methylpropane-2-sulfinamide (3.36 g, 27.77 mmol, 1 eq) and Ti(OEt)4 (12 ml, 55.54 mmol, 2 eq) were added to a solution of oxetan-3-one (2 g, 27.77 mmol, 1 eq) in THF at 22° C. The reaction mixture was stirred at 50° C. for 5 h. It was cooled to room temperature and poured into saturated brine solution, and then the suspension was filtered through a pad of Cellite. The filtrate was extracted with ethyl acetate, and the organic layer washed with saturated brine solution, dried over Na2SO4 and concentrated. The crude product was purified by silica gel (60-120 mesh) columatography using 30% EtOAc/Petroleum ether. Yield: 0.55 g (45.4%).
Reaction SMILES: O=O.[C:3]([S:6][C@H:7]1[N:10]([C:11](=C(C)C)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:13])[C:9](=[O:27])[C@@H:8]1[Br:28])(=[O:5])[CH3:4].P(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(OCC)(=O)C>[C:3]([S:6][C@H:7]1[N:10]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:13])[C:9](=[O:27])[C@@H:8]1[Br:28])(=[O:5])[CH3:4]
Reactant: COc1ccc(COC(=O)C(=C(C)C)N2C(=O)[C@H](Br)[C@H]2SC(C)=O)cc1
Agent: COP(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)CN2C(=O)[C@H](Br)[C@H]2SC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ozonised oxygen was bubbled through a solution of p-methoxybenzyl 2[(3S, 4R)-4-acetylthio-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (Osborne N. F. et al., J. Chem. Soc. Perkin Trans. 1, 1994, 179) (20.16 g, 0.0456 mol) in ethyl acetate (400 ml) at -65° to -70° C. until a permanent blue solution was obtained. Excess ozone was removed by the passage of oxygen, then trimethyl phosphite (53.8 ml, 0.456 mol) was added dropwise. After 15 min. the solution was allowed to warm to room temperature, then stood for 16 hr. The solvents were evaporated and the residue reevaporated twice from toluene, then dissolved in ethyl acetate (300 ml) and stirred vigorously for 1.5 hr. with a solution of p-toluenesulphonic acid (2 g) in water (100 mol). After dilution with water the organic layer was separated and the aqueous layer further extracted with ethyl acetate. The combined extracts were washed successively with saturated aq. sodium hydrogen carbonate and brine, then dried ((MgSO4) and evaporated. Purification by flash chromatography (silica, ethyl acetate-pet. ether) gave the product as a light brown oil, yield 10.6 g (58%).
Reaction SMILES: [CH:1]([C:4]1[C:5]([NH:17][C:18]([O:20]C(C)(C)C)=O)=[C:6]([NH:9][C:10](OC(C)(C)C)=[O:11])[S:7][CH:8]=1)([CH3:3])[CH3:2].C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[CH:1]([C:4]1[C:5]2[NH:17][C:18](=[O:20])[C:10](=[O:11])[NH:9][C:6]=2[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(NC(=O)OC(C)(C)C)c1NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Product: CC(C)c1csc2[nH]c(=O)c(=O)[nH]c12

Procedure:
A mixture of di-t-butyl 4-isopropylthiophene-2,3-dicarbamate (1.42 g, 3.98 mmol), diethyl oxalate (25 ml, 183 mmol) and glacial acetic acid (25 ml) was refluxed for 2 h. The reaction mixture was cooled on ice for 2 h and the precipitate was filtered off, washed twice with water and finally with ether. Yield 580 mg (69%) of the title compound. M.p.>250° C. 1H-NMR (DMSO-D6, δ) 1.15 (d, 6H), 3.1 (m, 1H), 6.75 (s, 1H), 11.9 (br.s, 2H). MS (70 eV): m/z 210 (100%, g), 195 (97), 182 (42), 167 (52), 154 (12), 139 (29), 122 (13), 97 (19).