Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1Br.[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO.CCOC(C)=O.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]>[Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:13]=[CH2:14]
Reactant: C=C[B-](F)(F)F
Reactant: O=C1OCc2c1ccc(Br)c2Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1Br)COC2=O
Temperature: 60 °C

Procedure:
4,5-Dibromo-2-benzofuran-1(3H)-one (3.00 g, 10.3 mmol), Potassium vinyltrifluoroborate (12.7 g, 20.6 mmol) and Pd(dppf)Cl2 (839 mg, 1.03 mmol) in TEA (2.7 mL) and EtOH (15 mL) were added to a flask containing a stir bar. The flask was then heated at 60° C. for 2 h. TLC showed clean and complete reaction. The organic residue was dissolved in EtOAc (500 mL) and the solution was washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting organic residue was subjected to purification over silica gel to give 4-bromo-5-ethenyl-2-benzofuran-1(3H)-one.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:15][S:16]([O:2][C@H:3]1[CH2:7][CH2:6][N:5]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4]1)(=[O:18])=[O:17]
Reactant: O[C@H]1CCNC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 62.9 %

Procedure:
The crude (S)-3-hydroxyl-pyrrolidine hydrochloride 11b (124 mg, 1 mmol) was dissolved in 15 mL of dichloromethane, followed by addition of triethylamine (303 mg, 3 mmol). The reaction solution was cooled down to 0° C., followed by addition of methanesulfonyl chloride (264 mg, 2.30 mmol), then warmed up to room temperature and stirred for another 2.5 hours. The resulting solution was mixed with 10 mL of dichloromethane, 1M citric acid was added dropwise to adjust the pH to 4˜5, the organic phase was dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-1-(methylsulfonyl)pyrrolidin-3-yl methanesulfonate 11c (153 mg) as a yellow solid, which was directly used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn].[Cl-].[CH2:24]([C:31]1[O:32][C:33]([CH3:37])=[C:34]([CH3:36])[CH:35]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C:31]1[O:32][C:33]([CH3:37])=[C:34]([CH3:36])[C:35]=1[C:6]([C:5]1[CH:9]=[C:10]([CH2:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:8])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCc1cc(C(=O)O)cc(CC)c1OC
Reactant: Cc1cc(Cc2ccccc2)oc1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Sn]
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OC

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2, using 3,5-diethyl-4-methoxybenzoic acid (10.66 g, 51.3 mmol), oxalyl chloride (4.90 mL, 56.3 mmol), N,N-DMF (2 drops), tin TV chloride (6.60 mL, 56.3 mmol) and 2-benzyl-4,5-dimethylfuran (11.4 g, 61.3 mmol) to give 22.0 g, of the title compound. 1H NMR δ1.13 (t, 6 H), 1.83 (s, 3 H), 2.19 (s, 3 H), 2.61 (q, 4 H), 3.74 (s, 3 H), 3.82 (s, 2 H), 7.05 (d, 2 H), 7.23-7.27 (m, 3 H), 7.42 (s, 2 H). mass spectrum (EI), m/z 376 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][C:24]([NH2:28])([C:26]#[CH:27])[CH3:25]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:28][C:24]([CH3:25])([CH3:23])[C:26]#[CH:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: C#CC(C)(C)N
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: C#CC(C)(C)NCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 6, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 1,1-dimethylpropargylamine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(1,1-dimethyl-prop-2-ynyl)-amine as colorless oil, MS: 443 (MH+, 1Br).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O.O1CCOCC1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of D-threonine (5.0 g, 0.042 mol) in water (50 mL) and dioxane (50 mL) containing triethylamine (8.9 mL, 0.063 mol) at room temperature is added 4-methoxybenzenesulfonyl chloride (9.54 g, 0.046 mol). The reaction mixture is stirred overnight at room temperature. Most of the dioxane is evaporated off, and the pH is adjusted to pH=2 with 1N HCl. The mixture is then extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated in vacuo to provide N-[4-methoxybenzenesulfonyl]-(D)-threonine.
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][CH:17]([CH3:28])[CH2:18][NH:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1C(N)=O.CO>ClCCl>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][CH:17]([CH3:28])[CH2:18][N:19]1[C:20]2[N:21]=[CH:22][NH:23][C:24]=2[C:4](=[O:5])[NH:6][C:7]1=[S:8]
Reactant: CCOC(=O)N=C=S
Reactant: CC(CNc1nc[nH]c1C(N)=O)OCc1ccccn1
Solvent: ClCCl
Solvent: CO
Product: CC(Cn1c(=S)[nH]c(=O)c2[nH]cnc21)OCc1ccccn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.246 mL, 2.18 mmol) was added to a suspension of 4-{[2-(pyridin-2-ylmethoxy)propyl]amino}-1H-imidazole-5-carboxamide (0.500 g, 1.82 mmol, obtained from Example 20(c)) in dichloromethane (10 mL). After 0.5 h, methanol (2 mL) was added. The solvent was removed in vacuo and acetone (5 mL) and another portion of ethoxycarbonyl isothiocyanate (0.246 mL, 2.18 mmol) were added. After o.n. stirring, the reaction was concentrated in vacuo. To the residue was added 1 N NaOH (10 mL) and the resulting solution was heated for 4 h at 100° C. After cooling to r.t., 2 N HCl was added until pH˜6. The mixture was concentrated in vacuo. The product was purified by preparative HPLC resulting in 54.3 mg (9% yield) of the title compound.
Reaction SMILES: CO[C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([OH:19])=[O:18].OC1C(OC2C=CC=CC=2)=CC=CC=1CC(O)=O>C(OC(=O)C)(=O)C.I>[O:9]([C:8]1[C:3]2[O:19][C:17](=[O:18])[CH2:16][C:4]=2[CH:5]=[CH:6][CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1c(CC(=O)O)cccc1Oc1ccccc1
Agent: I
Agent: O=C(O)Cc1cccc(Oc2ccccc2)c1O
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2cccc(Oc3ccccc3)c2O1
Yield: 51.6 %

Procedure:
A solution of 2-(2-methoxy-3-phenoxyphenyl)acetic acid (2.1 g) in acetic anhydride (10 ml) and hydriodic acid (55-58%, 20 ml) were treated in a similar manner to that of Example 10-(7). To the resultant oily residue containing 2-(2-hydroxy-3-phenoxyphenyl)acetic acid was added acetic anhydride (5 ml), and the mixture was refluxed under heating for 30 minutes and then evaporated. The oily residue (1.5 g) was purified by column chromatography (silica gel, benzene) and crystallization from ethanol to give 7-phenoxy-2,3-dihydrobenzofuran-2-one (950 mg). mp 60°-61° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10]CCCC)=O)=[CH:4][CH:3]=1.[NH3:15]>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:15])=[O:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCCCOC(=O)c1ccc(Cl)nn1
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Cl)nn1
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of the chloro pyridazine compound from the previous step (51 g, 0.238 mole) in THF (375 ml) was treated with methanolic ammonia (saturated, 80 ml). The reaction was allowed to stand at ambient temperature overnight. The precipitate was filtered and dried to give 6-chloropyridazine-3-carboxamide as a pink solid (18.2 g, 49%). [Further material could be obtained by evaporating the filtrate (at reduced pressure) and treating the residue with THF (100 ml) and methanolic ammonia (40 ml). The product was isolated as before to give a pink solid (17.4 g). Total yield (35.6 g, 95%)].
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]([CH3:24])[C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=O)=[CH:9][CH:8]=1.[Cl-].[NH4+]>C1COCC1>[CH3:5][N:6]([CH3:24])[C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:1][CH3:2])=[CH:9][CH:8]=1
Reactant: CC[Mg]Br
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
Into a reactor was introduced 102 mL (82.0 mmol; 0.80 M THF solution) of ethylmagnesium bromide under a nitrogen atmosphere. The contents were cooled to 0° C. Thereto was gradually added dropwise a solution prepared by mixing 20.0 g (74.5 mmol) of 4,4′-bis(dimethylamino)benzophenone and 40 mL of THF. This mixture was stirred at room temperature for 5 hours. Saturated aqueous ammonium chloride solution was added to the resultant reaction mixture, and the metal salt yielded was removed by Celite filtration. The organic layer was separated from the filtrate and then extracted with toluene. Thereafter, the solvent was removed under reduced pressure. The concentrate was dissolved in 150 mL of toluene, and 0.1 g of p-toluenesulfonic acid monohydrate was added thereto. Azeotropic dehydration was conducted with toluene refluxing. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. This concentrate was purified by column chromatography to obtain 13.6 g (65%) of light-yellow crystals. 1H-NMR (CDCl3) δ 1.77 (d, J=7.0 Hz, 3H), 2.92 (s, 6H), 2.98 (s, 6H), 5.94 (q, J=7.0 Hz, 1H), 6.58-6.79 (m, 4H), 7.02-7.18 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (11.2 g, 30.0 mmol), morpholine (26.0 mL, 294.0 mmol), copper(I) iodide (3.4 g, 18.0 mmol), N,N-dimethylglycine hydrochloride (3.4 g, 24.0 mmol), and potassium carbonate (12.4 g, 90.0 mmol) in dimethyl sulfoxide (65 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (200 mL×2), washed with saturated aqueous ammonium chloride solution (50 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (9.1 g, 80%) as a white solid: MS (ESI) M+1=381.0.
Reaction SMILES: [S:1](=[O:39])(=[O:38])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[C:20]([CH3:29])([CH3:28])[CH2:19]3)[CH:12]=2)[CH2:7][C@@H:6]1[O:30][Si](C(C)(C)C)(C)C)[NH2:2]>Cl.C(O)C>[S:1](=[O:39])(=[O:38])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[C:20]([CH3:28])([CH3:29])[CH2:19]3)[CH:12]=2)[CH2:7][C@@H:6]1[OH:30])[NH2:2]
Reactant: CC1(C)C[C@H](Nc2cc(O[C@@H]3C[C@@H](COS(N)(=O)=O)[C@@H](O[Si](C)(C)C(C)(C)C)C3)ccn2)c2ccc(Cl)cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)C[C@H](Nc2cc(O[C@@H]3C[C@@H](COS(N)(=O)=O)[C@@H](O)C3)ccn2)c2ccc(Cl)cc21
Yield: 71.2 %

Procedure:
A solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)oxy]cyclopentyl}methyl sulfamate (0.0287 g, 0.0000481 mol) in 3.0% (V/V) HCl in ethanol (25.0 ml) was stirred for 4 hrs. The reaction was concentrated and dissolved in 50 ml EtOAc and 1.00 ml triethylamine. The solution was washed with water, concentrated, and the residue was isolated by preparative plate chromatography (5% MeOH/EtOAc) to afford the title compound (16.5 mg, 71%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ: 7.92 (d, 1H, J=5.8 Hz), 7.22-7.20 (m, 1H), 7.17-7.14 (m, 2H), 6.16 (dd, 1H, J=6.0 Hz, J=2.3 Hz) 5.85 (d, 1H, J=2.0 Hz), 5.30 (m, 1H), 4.92 (m, 1H), 4.70 (d, 1H, J=8.5 Hz), 4.50 (dt, 1H, J=5.0 Hz, J=1.9 Hz), 4.40 (dd, 1H, J=7.3 Hz, J=2.5 Hz), 4.28 (dd, 1H, J=7.3 Hz, J=2.5 Hz), 2.60 (bs, 1H), 2.50 (q, 1H, J=7.0 Hz), 2.31-2.25 (m, 1H), 2.18-2.12 (m, 1H), 1.95-1.87 (m, 2H), 1.79 (m, 1H), 1.25 (s, 6H). LC/MS: Rt=1.81 min, ES+ 482 (AA standard).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C(O)(=O)C>[CH3:3][N:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1[CH:6]=[CH:7][C:8]([Br:1])=[CH:9][CH:10]=1
Reactant: BrBr
Reactant: CC(C)CCN(C)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCN(C)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A solution of 58 g of bromine in 60 ml of acetic acid was added dropwise at about 15° C. over one hour to a mixture of 64 g of the product of Step A in 300 ml of acetic acid and the mixture was stirred at 80° C. for 8 hours and was poured into iced water. The mixture was extracted with methylene chloride and the organic phase was washed with aqueous sodium bicarbonate, with water, dried and evaporated to dryness. The residue was distilled to obtain 70 g of N-methyl-N-(3-methylbutyl)-4-bromo-aniline boiling at 119° C. at 0.5 mm Hg.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[O:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:39])([F:38])[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:27]=[C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:28])[N:18]1[CH2:17][C@@H:16]([NH:15][C:12]([C:9]1[O:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:38])([F:37])[F:39]
Reactant: Cn1nccc1-c1coc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1coc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (54 mg, 0.28 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (108 mg, 0.28 mmol)[prepared in Preparation 6] and N,N-diisopropylethylamine (0.24 ml, 1.40 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (158 mg, 0.34 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (100 mg, 0.14 mmol, 50% yield) as a white solid: LCMS (ES) m/e 523 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:20])[N:8]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[C:25](Cl)=[O:26]>>[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[C:25]([N:13]1[C:9]2=[N:10][C:11]3[C:6]([C:7](=[O:20])[N:8]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]1=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)=[O:26]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Product: COc1ccc2c(=O)n3c4ccccc4n(C(=O)c4cc(C)cc(C)c4)c3nc2c1

Procedure:
6-(3,5-Dimethylbenzoyl)-3-methoxybenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-methoxybenzimidazo[2,1-b]quinazolin-12(6H)one and 3,5-dimethylbenzoyl chloride.
Reaction SMILES: O=[C:2]([C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[CH:10][CH:9]=1)[CH3:7])[CH2:3][CH:4]=O.O.[NH2:25][NH2:26]>CCO.C1COCC1>[NH:25]1[C:2]([C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)=[CH:10][CH:9]=2)[CH3:7])=[CH:3][CH:4]=[N:26]1
Reactant: NN
Reactant: C[C@@H](C(=O)CC=O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1ccn[nH]1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a cooled (−78° C.) solution of the ester (1.16 g, 3 mmol) in dry CH2Cl2 (20 ml) under argon atmosphere DIBAH (1M in hexanes, 3.6 ml) was added dropwise over 15 min via syringe; once the addition was complete, the resulting solution was stirred at −78° C. for 1 h. The reaction was quenched pouring the cold solution into a saturated NH4Cl solution (10 m). 1M HCl (10 ml) was added and the biphasic mixture was stirred vigorously for 10 min. The layers were separated and the organic one was washed with brine while the aqueous was extracted with Et2O (2×10 ml). The collected organic extracts were dried over anhydrous Na2SO4 and concentrated to afford of (4R)-3-oxo-4-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)pentanal (728 mg) as a white waxy solid, used without further purification. To a solution of the aldehyde (728 mg) in EtOH/THF (2:1, 15 ml), hydrazine monohydrate (0.495 ml, 10.2 mmol) was added and the mixture refluxed for 30 min. After cooling at room temperature, the mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (3×25 ml). The collected organic extracts were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to give N-{4-[(1R)-1-(1H-pyrazol-5-yl)ethyl]phenyl}-4-(trifluoromethyl)-1,3-thiazol-2-amine (421 mg, 1.24 mmol) as a colourless oil (61%). 1H-NMR (CD3OD): δ 9.40 (bs, 1H, NH); 7.50 (d, 1H, J=2.5 Hz); 7.40 (d, 2H, J=7 Hz), 7.35 (d, 2H, J=7 Hz), 7.15 (s, 1H), 6.15 (d, 1H, J=2.5 Hz), 3.80 (q, 1H, J=7 Hz), 1.60 (d, 3H, J=7 Hz).
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][C@:13]1([NH:39][CH:40]=[O:41])[C:37](=[O:38])[N:15]2[CH:16]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C:17](=[CH2:20])[CH2:18][S:19][C@H:14]12.[Br:42]C(Br)(C(OCC)=O)C(OCC)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[NH2:12][C@:13]1([NH:39][CH:40]=[O:41])[C:37](=[O:38])[N:15]2[C:16]([C:21]([O:23][CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:17]([CH2:20][Br:42])[CH2:18][S:19][C@H:14]12
Reactant: C=C1CS[C@H]2N(C(=O)[C@]2(N)NC=O)C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@]1(NC=O)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@@H]21
Yield: 69.5 %

Procedure:
A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (24 mg) in dry tetrahydrofuran (5 ml) was added over 5 min to a solution of diphenylmethyl 7β-amino-7α-formamido-3-methylenecepham-4-carboxylate (prepared above)(739 mg) in dry tetrahydrofuran (30 ml) containing diethyl dibromomalonate (999 mg) at -70° C. under argon. After 25 min the mixture was added to a mixture of ethyl acetate (150 ml) and 5% (w/v) aqueous citric acid (100 ml). The phases were separated and the organic phase washed with water (3×100 ml), brine (100 ml), then dried (anhyd. MgSO4), filtered and the filtrate evaporated to give a yellow solid. Trituration with dichloromethane (15 ml) followed by filtration provided the title compound (609 mg) as a white solid, m.p. 151°-153° C. (decomp.) (Found: C, 52.33; H, 4.00; N, 8.37; S, 6.50; Br, 15.59%. C22H20N3O4SBr requires C, 52.59; H, 3.98; N, 8.37; S, 6.38; Br, 15.94%). υmax (KBr) 3370, 3280, 3150, 1795, 1720, and 1670 cm-1 ; δH (250 MHz, d8 -THF) (major rotamer) 2.70 (2H, broad s, exch. D2O), 3.46 and 3.58 (2H, ABq, J 16.8 Hz), 4.34 and 4.42 (2H, ABq, J 10.0 Hz), 5.21 (1H, s), 6.95 (1H, s), 7.1-7.6 (10H, m), 8.15 (1H, d, J 1.0 Hz, becomes s on D2O exch.), and 8.17 (1H, broad s, exch. D2O); m/z (positive xenon F.A.B.; 3-nitrobenzyl alcohol-NaOAc) MNa;, 524.
Reaction SMILES: O[C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][CH:14]=1)([C:4]1[N:5]([CH2:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:7][CH:8]=1)[CH3:3].[CH2:30]([SiH](CC)CC)[CH3:31].B(F)(F)F.CCOCC>>[CH3:12][O:11][CH2:10][CH2:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[CH:2]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:17][CH:18]=1)[CH2:3][CH2:30][CH3:31]
Reactant: COCCn1cccc1C(C)(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Reactant: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Product: CCCC(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)c1cccn1CCOC

Procedure:
The title compound was prepared from N-(4-{1-hydroxy-1-[1-(2-methox-yethyl)-1H-pyrrol-2-yl]-ethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 1) using triethylsilane and boron trifluoride diethyl etherate as described in Example 88 of U.S. application Ser. No. 10/354,922, now U.S. Pat. No. 7,071,358, and provided below as Preparative Example B.
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3](OC)=[O:4].[NH2:18][NH2:19]>CO>[F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3]([NH:18][NH2:19])=[O:4]
Reactant: NN
Reactant: COC(=O)C(F)(F)c1ccc2ncccc2c1
Solvent: CO
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1

Procedure:
A solution methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (400 mg, 1686 μmol) and anhydrous hydrazine (2153 μl, 67453 μmol) in MeOH (4 mL) was stirred for 1 h at 23° C. The solvents were then removed under reduced pressure to provide product as a white solid. MS (ESI pos. ion) m/z: 238 (MH+). Calc'd exact mass for C11H9F2N3O: 237.