Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[O:6]C(=O)[CH:4]=1.[CH3:14][O-:15].[Mg+2].[CH3:17][O-:18].Cl>>[F:10][C:9]([F:12])([F:11])[C:7](=[O:6])[CH2:8][C:3](=[O:2])[CH2:4][C:14]([O:18][CH3:17])=[O:15]
Reactant: C[O-]
Reactant: COc1cc(C(F)(F)F)oc(=O)c1
Agent: Cl
Agent: [Mg+2]
Product: COC(=O)CC(=O)CC(=O)C(F)(F)F
Yield: 25 %

Procedure:
A solution of 4-methoxy-6-trifluoromethylpyran-2-one (10 g, 52 mmol) in a methanolic magnesium methanolate solution (8.5% Mg(OMe)2, 62.8 g, 61 mmol) was heated under reflux for 2 hours. Concentrated aqueous HCl (25.5 g, 250 mmol) was added to the reaction solution, and the mixture was heated under reflux for a further 2 hours, then cooled and concentrated in vacuo to about 20% of the initial volume. The residue was mixed with 10 mL each of methylene chloride and water. The organic phase was separated off, washed with water, dried over sodium sulfate and concentrated. Kugelrohr distillation at 0.04 mbar and about 160° C. afforded methyl 6,6,6-trifluoro-3,5-dioxohexanoate (2.8 g, 13 mmol, 26%) as a pale yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCCCO1
Temperature: 0 °C
Reaction time: 16 h
Yield: 110 %

Procedure:
2-(Tetrahydro-2H-pyran-2-yl)ethanol (465 mg) was dissolved in dry DCM (10 mL) and triethylamine (996 mg) was added. The stirred solution was cooled in an ice bath under nitrogen and methanesulphonyl chloride (359 mg) was added dropwise over 5 mins. The reaction was allowed to warm to room temperature as the ice bath melted and was left for 16 h. The mixture was then shaken with saturated sodium bicarbonate solution and the aqueous layer was extracted with DCM (×2). The combined organic extracts were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound as a brown oil (718 mg).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:14]([I:17])=[C:13]2[C:9]=1[CH:10](O)[N:11](C(C)(C1C=CC=CC=1)C)[C:12]2=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[O:1]([C:8]1[CH:16]=[CH:15][C:14]([I:17])=[C:13]2[C:9]=1[CH2:10][NH:11][C:12]2=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(Oc3ccccc3)c2C1O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(Oc3ccccc3)ccc(I)c21
Yield: 73 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-phenoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (700 mg, 1.44 mmol) was dissolved in nitromethane (28 mL), and the solution was treated with trifluoroacetic acid (1.10 mL, 14.4 mmol) and triethylsilane (0.460 mL, 2.88 mmol), followed by purification by slurry using diisopropylether to obtain 4-phenoxy-7-iodoisoindolinone (369 mg, yield 73%).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38](O)=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].C([N:52]([CH2:55][CH3:56])[CH2:53]C)C.C(Cl)(=O)C(C)(C)C.[CH3:64][NH:65][CH:66](NC)CC>C(Cl)Cl>[F:49][C:2]([F:48])([F:1])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:52]([CH3:53])[CH2:55][CH2:56][CH2:64][NH:65][CH3:66])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7]
Reactant: CCN(CC)CC
Reactant: CCC(NC)NC
Reactant: O=C(O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
The compound (800 mg, 1.15 mmol) obtained in Example 1j was dissolved in methylene chloride (6 mL), triethylamine (0.240 mL, 1.73 mmol) and pivaloyl chloride (0.156 mL, 1.27 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added dropwise to a solution of N,N′-dimethylpropanediamine (588 mg, 5.75 mmol) in methylene chloride (19 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=30:1→10:1, v/v) to give the title compound (566 mg; yield, 63%) as a light yellow solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH2:10][C:11]2[NH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:14]([CH3:16])[N:15]=2)=[CH:5][CH:4]=1.C[O-].[Na+].[C:27](OC)(=[O:30])[C:28]#[CH:29]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[CH:29]=[CH:28][C:27](=[O:30])[N:15]3[C:14]([CH3:16])=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:12][C:11]=23)=[O:23])=[CH:7][CH:8]=1
Reactant: C#CC(=O)OC
Reactant: Cc1nc(CC(=O)c2ccc(F)cc2)[nH]c1-c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1c(-c2ccccc2)[nH]c2c(C(=O)c3ccc(F)cc3)ccc(=O)n12

Procedure:
The compound is prepared as described in example 25 with 300 mg (0.91 mmol) of 1-(4-fluorophenyl)-2-(4-methyl-5-phenyl-1H-imidazol-2-yl)ethanone hydrochloride (example LI), 90 mg (1.80 mmol) of sodium methylate and 76 mg (0.91 mmol) methyl propiolate.
Reaction SMILES: [CH:1]12[O:7][C:6]1([C:8]1[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:19][C:18]=4[CH:28]=3)=[CH:10][N:9]=1)[CH2:5][CH2:4][O:3][CH2:2]2.S(=O)(=O)(O)[OH:36].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O>[OH:7][CH:1]1[C:6]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:19][C:18]=4[CH:28]=3)=[CH:10][N:9]=2)([OH:36])[CH2:5][CH2:4][O:3][CH2:2]1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C45CCOCC4O5)nc3)cc(-c3ccccn3)c2s1
Reactant: O=S(=O)(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C4(O)CCOCC4O)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Yield: 42 %

Procedure:
Compound iii (20 mg; 0.042 mmol) was dissolved in THF-H2O (10:1, 11 mL). Conc. sulfuric acid (20 μL) and p-toluenesulphonic acid (0.7 mg, 4 mmol) were added and the mixture stirred at RT. The mixture was concentrated in vacuo and purified over silica (0-100% 0.1% FA (aq)-MeCN) yielding Compound 8 (8.8 mg, 42%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][C@@H:8]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH2:13][CH2:12]1)=[O:10].C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:7][C@@H:8]([CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH2:15][CH2:16]1)=[O:10])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)C(=O)N(C2CCN(C(=O)[C@@H](N)CCc3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)N(C2CCN(C(=O)[C@H](CCc3ccccc3)NC(=O)CCl)CC2)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of chloroacetyl chloride (120 microL, 1.49 mmol) in dichloromethane (5 mL) was slowly added a mixture of (S)-1-(1-(2-amino-4-phenylbutanoyl)piperidin-4-yl)-3,3-dimethylindolin-2-one hydrochloride (600 mg, 1.36 mmol, EXAMPLE 1, Step 4) and triethylamine (420 microL, 2.99 mmol) in dichloromethane (4 mL) at 0° C. After 5 min, the reaction was quenched with water and the mixture was diluted with ethyl acetate to separate. The organic layer was washed with water (×2) and brine, dried over sodium sulfate and concentrated to give the title compound. The product was diluted with 6.0 mL of tetrahydrofuran to give 0.226 mol/L tetrahydrofuran solution assuming 100% conversion. The stock solution was used for the next step without further purification.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:17])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])C.C1COCC1.O>CO>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]([NH:9][CH2:8][C:7]([OH:17])=[O:6])=[O:11]
Reactant: CCOC(=O)CNC(=O)c1cccs1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
LiOH.H2O (110 mg, 2.63 mmol) was added to a solution of [(thiophene-2-carbonyl)-amino]-acetic acid ethyl ester (140 mg, 0.66 mmol) in a mixture of MeOH (5 mL), THF (2.5 mL) and H2O (2.5 mL). The resulting mixture was stirred for 3 hrs at room temperature. The MeOH and THF were evaporated and the resulting residue was diluted with water (2 mL), acidified with citric acid and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford [(thiophene-2-carbonyl)-amino]-acetic acid in 70% yield. LC-MS purity: 92%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)(Cl)Cl.[CH3:16][S:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:16][S:17]([CH:18]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A solution of 10.7 grams (0.0525 mole) of m-chloroperbenzoic acid in 150 ml. of chloroform was slowly added to a cool solution (5°-7° C.) of 14.1 grams (0.050 mole) of bis(p-chlorophenyl)methyl methyl sulfide in 500 ml. of chloroform, and the resulting solution stirred for two hours at a temperature of 5° C., while a white precipitate formed. The mixture after warming to ambient temperature and holding at this temperature for a two hour period was then mixed with a solution having 20 grams of potassium carbonate in 200 ml. of water. The chloroform phase was then removed and washed with 100 ml. of water, and the chloroform distilled off; the vacuum distillation leaving 14.7 grams of a crude product which was recrystallized twice from 2,2,4-trimethylpentane-benzene (2:1) mixture to yield 11.7 grams (78 percent) of the white colored solid of bis(p-chlorophenyl)methyl methyl sulfoxide with a melting point of 109.5°-110.5° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1.C(OCC)(=O)C>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[NH:16][C:14]1[N:15]=[C:10]([CH2:9][OH:8])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Nc2nccs2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cccc(Nc2nccs2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.48g of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-thiazol-2-ylpyridin-2-amine was dissolved in 100 ml of tetrahydrofuran. Under cooling with ice, a tetrabutylammonium fluoride-tetrahydrofuran solution (1.0 M, 20.2 ml) was added followed by stirring at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and then washed with phosphate buffer (pH 6.8). The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to give the title compound.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C[C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[N:29]2)=[N+]=[N-].[OH-].[Na+].[OH-].[NH4+:37]>C1COCC1.C(OCC)(=O)C>[N:37]1[C:24]2[C:25](=[C:30]([NH:29][CH3:28])[CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:27][CH:1]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=NCc1cccc2ncccc12
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Triphenylphosphine (172 mg, 0.65 mmol) was added to the solution of 5-azidomethyl-quinoline (109 mg, 0.59 mmol) in THF (3 mL) at 0° C. After 5 min of stirring, the reaction mixture was warmed to room temperature and stirred at that temperature 16 h. The reaction mixture was diluted with ammonium hydroxide (0.55 mL) and stirred for 3 h. The mixture was then treated with 2M NaOH (0.8 mL) and stirred for another 1 h. The solution was diluted with ethyl acetate and the organic phase was separated, dried over Na2SO4, concentrated. The resulting residue was purified by silica gel prep TLC using 10:1:0.3 CH2Cl2:MeOH:Et3N as an eluant to afford 105 mg of quinolin-5-yl-methylamine as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[N-:30]=[N+:31]=[N-:32].[Na+].CC(C)=O>O>[N:30]([CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(CN=[N+]=[N-])S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After removing acetone under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, with a saturated sodium bicarbonate queous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small amount of ether was added to the residue. Precipitated crystals were filtered off and the solvent was distilled off from the filtrate. The crystalline residue was purified by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-azidomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (150 mg). This substance was crystallized by adding a small amount of a mixture of ether and petroleum ether and the crystals were recrystallized from ether to give pure compound, mp 105° to 106° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CN(C)[C:15]1[CH:23]=CC(C(Cl)=O)=C[CH:16]=1.C(Cl)C=C.CN(C)C1C=CC(C([O-])=O)=CC=1.[Na+]>CN(C)C=O>[CH2:23]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=1)[CH:15]=[CH2:16]
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C=CCCl
Product: C=CCOC(=O)c1ccc(N(C)C)cc1
Yield: 60 %

Procedure:
Esters of p-dimethylaminobenzoic acid can be prepared by several methods. U.S. Pat. No. 2,202,865 describes the preparation of esters by reacting p-dimethylaminobenzoyl chloride with alcohols. Another method is by reacting an alkali salt of p-dimethylaminobenzoic acid with an alkene halide. Either method can be used but the latter is preferred. For example, if allyl chloride is added to sodium p-dimethylaminobenzoate in a suitable solvent such as dimethylformamide using a quaternary ammonium salt catalyst, allyl-p-dimethylaminobenzoate is obtained in yield of about 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:36]=[C:37]([NH:40][C:41](=[O:43])[CH3:42])[S:38][CH:39]=3)=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:36]=[C:37]([NH:40][C:41](=[O:43])[CH3:42])[S:38][CH:39]=2)=[CH:33][CH:34]=1
Reactant: CC(=O)Nc1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cs1
Reactant: Cc1cc(-c2c(O)c3cc(I)c(Cl)cc3[nH]c2=O)on1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(-c2ccc(-c3cc4c(O)c(-c5cc(C)no5)c(=O)[nH]c4cc3Cl)cc2)cs1
Temperature: 80 °C
Yield: 84.9 %

Procedure:
To a solution of 7-chloro-4-hydroxy-6-iodo-3-(3-methylisoxazol-5-yl)quinolin-2(1H)-one (Intermediate 99) (125 mg, 0.311 mmol) in 1,4-dioxane (4 mL) and water (2 mL) were added N-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)acetamide (Intermediate 31) (118 mg, 0.342 mmol), cesium carbonate (152 mg, 0.466 mmol) and tetrakis(triphenylphosphine)palladium (3.59 mg, 3.11 μmol). The reaction mixture was heated at 80° C. for 16 h. After cooling the reaction mixture was filtered, evaporated to dryness. The resulting residue was acidified with HCl 1N. The precipitate was filtered and dried to give the title compound N-(4-(4-(7-chloro-4-hydroxy-3-(3-methylisoxazol-5-yl)-2-oxo-1,2-dihydro quinolin-6-yl)phenyl)thiazol-2-yl)acetamide (130 mg, 0.264 mmol, 85% yield) as a grey solid. LCMS: (M+H)+=493; Rt=2.37 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH2:10]([NH:13][OH:14])[CH2:11][CH3:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:3]2[O:2][C:11]([CH:10]=[N+:13]([CH2:5][CH2:6][CH3:7])[O-:14])=[CH:12][CH:4]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: CCCNO
Product: CCC[N+]([O-])=Cc1ccc(Sc2ccc(OC)cc2)o1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 4-methoxybenzenethiol and N-n-propylhydroxylamine. The title compound was isolated in 76.6% yield as slightly yellowish crystals, m.p. 63.0° C. (Rf =0.17 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=1)=[O:4].[OH-].[Na+].Cl>CO.O>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:35][CH:36]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 50 °C
Yield: 83.1 %

Procedure:
A solution of 6-[4-(2-methoxycarbonylphenyl)benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.141 g) in MeOH/H2O (5/1 mL) containing NaOH (0.087 g) was heated at 50° C. for 2 h. The reaction mixture was cooled in ice and acidified with 0.5 N HCl. It was extracted with EtOAc and the extract was washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: CHCl3/MeOH: 100/1 to 50/1, Chromatotron) afforded the titled compound (114 mg). MS (m/z) 531 (M++Na).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[O:10].[C:11]1([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-:26].[K+].[K+]>CN(C)C=O>[C:11]1([CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([C:5]3[CH:6]=[CH:7][CH:2]=[C:3]([C:9]([OH:10])=[O:26])[C:4]=3[F:8])[CH2:23][CH2:24]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(N2CCN(CCc3ccccc3)CC2)c1F
Yield: 59.6 %

Procedure:
Combine 2,6-difluorobenzenaldehyde (7.48 g, 52.3 mmol) and 1-(2-phenylethyl)-piperazine (10.94 g, 57.5 mmol)[evolution of heat]. Add dry dimethylformamide (55 mL) and potassium carbonate (7.95 g, 57.5 mmol). With stirring, heat the reaction at 75°-85° C. for 7 hours under nitrogen. Add ice water (200 mL) and extract the reaction with ether (250 mL). Wash the organic extract with brine (2×50 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to yield a brown oil which solidifies on standing. Purify by flash chromatography (ethyl acetate:hexane, 50:50, TLC Rf =0.3, then 100:0) to provide 4-(2-phenylethyl)-1-(3-carboxy-2-fluorophenyl)-piperazine (10.24 g) as a yellow solid, mp 85.5°-87.5° C.; 1H NMR (CDCl3) δ 10.28 (1H, s), 7.45 (1H, dt, J=6.4, 8.2 Hz), 7.33-7.21 (5H), 6.86 (1H, d, J=8.1 Hz), 6.75 (1H, dd, J=8.2, 10.4 Hz), 3.16 (4H, m), 2.85 (2H, m), 2.76-2.66 (6H); 13C NMR (CDCl3) δ 187.48, 187.41, 165.96, 162.51, 155.62, 155.57, 140.10, 135.66, 135.50, 128.74, 128.67, 128.49, 128.41, 126.11, 116.98, 116.88, 114.28, 114.24, 109.45, 109.16, 77.20, 60.28, 53.53, 53.43, 53.06, 52.97, 33.57; 19F NMR (CDCl3) δ -115.980 (dd, J=32, 51 Hz); IR (CHCl3 solution) 2832, 1688, 1609, 1472, 1450, 1236, 1005, 754 cm-l ; CI/MS (CH4) 313(100%), 221(52%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[C:23]([C:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1)#[CH:24]>>[OH:29][C:25]1([C:23]#[C:24][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:22]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#CC1(O)CCC1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#CC3(O)CCC3)cc1-2
Yield: 46.2 %

Procedure:
10-bromo-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with 1-ethynylcyclobutanol as described in General Procedure F without making critical modifications to afford 48 mg (46.2%) of 10-[2-(1-hydroxycyclobutyl)ethynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=381.2.