Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:54][C:55]([O:57][CH3:58])=[O:56]>C(Cl)Cl>[F:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18]([C:15]1[N:13]2[N:14]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:54][C:55]([O:57][CH3:58])=[O:56])[CH2:3][CH2:4]3)[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]2=[N:17][CH:16]=1)=[O:19]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 5C (40 mg, 0.057 mmol) in CH2Cl2 (1 mL) was added DIEA (0.043 mL, 0.248 mmol) and methyl 2-bromoacetate (9.68 mg, 0.063 mmol). The solution was heated to 50° C. overnight. The volatiles were removed via a stream of nitrogen. The resulting dark brown oil was taken up in TFA (0.75 mL) and heated to 65° C. for 2 h, and then cooled to room temperature. The volatiles were removed under a stream of nitrogen and the crude material was diluted with 1 mL of THF and purified via preparatory HPLC using a YMC ODS C-18 30×250 mm column with 10-100% B (Solvent A: 10% aq MeOH with 0.1% TFA; Solvent B: 90% aq. MeOH with 0.1% TFA) and a linear gradient over 60 min at 25 mL/min, monitoring at 220 nm, and a total run time of 70 min. (Rt of desired=46.365 min) Appropriate fractions were concentrated and lyophilized overnight to afford methyl N-(trans-4-((3-((3-fluoro-4-pyridinyl)carbamoyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)glycinate (23 mg, 0.030 mmol, 52.5% yield). HPLC Rt=3.335 minutes. (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA. [M+H]=534.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([Mg]Br)#[CH:11]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[C:10]#[CH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1cccc(Br)n1
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(Br)n1
Temperature: -78 °C

Procedure:
6-Bromo-2-pyridine carboxaldehyde (3.00 g, 16.13 mmol) was dissolved in THF (50 mL) and cooled to −78° C. Ethynylmagnesium bromide (0.5 M in THF, 45.2 mL, 22.58 mmol) was added, and the reaction was allowed to warm to room temperature over 2 h. It was then quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (50% EtOAc/hexanes) afforded the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[NH2:17].[N:18]([O-])=O.[Na+]>>[Cl:1][C:2]1[C:3]2[N:17]=[N:18][N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: O=N[O-]
Reactant: Nc1nc(Cl)c(N)c(NCc2ccccn2)n1
Agent: [Na+]
Product: Nc1nc(Cl)c2nnn(Cc3ccccn3)c2n1

Procedure:
A solution of 6-chloro-N4-pyridin-2-ylmethyl-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNO2, following the general procedure 2. 1HNMR (CDCl3): δ 8.60–8.59 (m, 1H), 7.71–7.67(m, 1H), 7.29–7.25 (m, 1H), 7.22–7.20 (m, 1H), 5.81 (s, 2H), 5.48 (s, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Br[C:12]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:22]>O>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:13](=[O:22])[N:14]2[CH2:2][C:3](=[O:4])[N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:19][CH:18]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1ccc(Cl)cc1
Reactant: O=C(CCl)N1CCCCC1
Solvent: O
Product: O=C(CN1C(=O)C(Cc2ccc(Cl)cc2)(NC2CCCCC2)c2ccc(Cl)cc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of 2-chloro-1-piperidin-1-yl-ethanone (41 mg, 31 mmol) and KI (43 mg, 0.26 mmol) in dimethylformide (5 mL) was added rac-3-bromo-6-chloro-3-(4-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.26 mmol) prepared in example 76c. After stirring at room temperature for 2 h, water (10 mL) was added and the crude was extracted with ethyl acetate (3×20 mL). The combined organic solution was concentrated in vacuo. The residue was purified with preparative HPLC to give rac-6-chloro-3-(4-chloro-benzyl)-3-cyclohexylamino-1-(2-oxo-2-piperidin-1-yl-ethyl)-1,3-dihydro-indol-2-one as a white solid. MS: 514 (M+H)+.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][CH:10]1[C:20]([O:22]CC)=[O:21])=[O:8])(=O)C.[OH-].[K+]>CO.O>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:11][CH:10]1[C:20]([OH:22])=[O:21])=[O:8]
Reactant: CCOC(=O)C1SC(c2ccccc2)=NN1C(=O)CCSC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1SC(c2ccccc2)=NN1C(=O)CCS
Temperature: 25 °C
Yield: 33.3 %

Procedure:
A solution of the product of step (b) (2.6g) in methanol (20ml) was cooled to 0° under nitrogen and treated dropwise with a solution of potassium hydroxide (1.42g) in water (8ml). The mixture was allowed to warm to room temperature over 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was acidified with 2N HCl and the organic phase separated, washed with water and dried. Evaporation yielded an oil which slowly crystallised to give the title product (0.7g) as white crystals. mp 145°-6°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([Mg]Br)[CH2:17][CH:18]=[CH2:19].C(O)(=O)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([OH:15])[CH2:19][CH2:18][CH:17]=[CH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCOCCCCc1ccccc1
Reactant: C=CCC[Mg]Br
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCCC(O)CCOCCCCc1ccccc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A solution of Intermediate 13 (0.55 g, 2.66 mmol) in THF (5 mL) was cooled to −30° C. To this solution a 0.5 M solution of 3-butenylmagnesium bromide (5.8 mL, 2.92 mmol) in THF was added, and the resulting mixture was stirred 2 hours at −30° C. The reaction was allowed to reach room temperature; acetic acid (0.1 mL) was added and concentrated. Purification by column chromatography with silica gel and methylene chloride/acetone (20:1) as eluent afforded the title compound (410 mg, 54%) as oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>O1CCCC1.CCCCCC>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[F:20])[OH:24])[CH3:2]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(OCC)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccccc1C(O)c1ccccc1F
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A solution of 345 g of 2-bromobenzaldehyde diethyl acetal in 3 l of dry tetrahydofuran was cooled to −40° C. In one portion, 913 ml of a 1.6 M solution of butyllithium in hexane were added under vigorous stirring. The resulting solution was stirred for 0.5 h at −25° C., after which a solution of 140 ml of 2-fluorobenzaldehyde in 350 ml tetrahydrofuran was added drop-wise. In a period of 4 h, the mixture was allowed to reach room temperature. The resulting mixture was pored upon ice-water and extracted several times with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure to yield 404 g of 2-(diethoxymethyl)-α-(2-fluorophenyl)-benzenemethanol as an oil, M.S. (C.I.) (M/Z): 305 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][C:35]=3[O:42][CH3:43])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)(=[O:14])=[O:13]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
Reactant: COc1cc(F)ccc1B(O)O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4OC)ncnc3c2)c(OC)c1

Procedure:
A microwave vial was charged with 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Intermediate KKKK; 0.040 g, 0.084 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (0.021 g, 0.126 mmol), tetrakis(triphenylphosphine)palladium(0) (9.69 mg, 8.39 μmol), and potassium carbonate (0.058 g, 0.419 mmol). Dioxane (0.419 mL) and water (0.140 mL) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (12 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-(4-fluoro-2-methoxyphenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was concentrated and purified via column chromatography (12 g silica gel column, gradient elution 0 to 10% MeOH:DCM) to afford 4-(4-fluoro-2-methoxyphenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.01 (br. s., 1H), 9.45 (s, 1H), 8.38 (br. s., 1H), 8.06-7.76 (m, 2H), 7.49 (t, J=7.2 Hz, 1H), 7.31 (d, J=4.1 Hz, 1H), 7.21 (d, J=11.2 Hz, 1H), 7.01 (t, J=7.1 Hz, 1H), 6.90 (d, J=4.3 Hz, 1H), 3.70 (br. s., 3H). m/z (ESI) 417.2 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:12]2=[CH:13][NH:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]2[C:10](=[O:22])[N:9]([CH3:23])[C:8]1=[O:24].CN([CH:28]=[O:29])C>>[CH3:6][N:7]1[C:12]2=[C:13]([CH:28]=[O:29])[NH:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]2[C:10](=[O:22])[N:9]([CH3:23])[C:8]1=[O:24]
Reactant: CN(C)C=O
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]cc2n(C)c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C=O)c2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (1.081 mL, 11.60 mmol) was added slowly to a solution of 1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (2.96 g, 11.60 mmol) in DMF (40 mL) at 0° C. The mixture was stirred at 0° C. for 15 mins. The reaction was quenched with 2M HCl(aq), diluted with EtOAc, and the mixture stirred overnight. The mixture was then extracted with EtOAc (3×) and the combined organic phases washed with brine, dried over sodium sulphate and evaporated under vacuum. The residue was triturated with diethyl ether/hexane to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].Br[C:10]1[N:11]=[CH:12][C:13]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:14][C:15]=1[Cl:16]>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:13]1[C:12]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:11][CH:10]=[C:15]([Cl:16])[N:14]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Nc1cnc(Br)c(Cl)n1)c1cccc(Cl)c1Cl
Reactant: OCc1ccccn1
Product: O=S(=O)(Nc1nc(Cl)cnc1OCc1ccccn1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyridine-2-methanol (0.22 g) and N-(3-bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].[CH3:13]I>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:13])[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4]
Reactant: CCCC1CCC(C(=O)OC)C1
Reactant: CI
Solvent: C1CCOC1
Product: CCCC1CCC(C)(C(=O)OC)C1

Procedure:
Under an atmosphere of nitrogen, 3 ml. of a 1.4M solution of n-butyllithium in n-hexane were added to a solution of 0.643 ml. of diisopropylamine in 3 ml. of dry tetrahydrofuran at -78° C., and the solution was stirred at that temperature for 15 minutes. To the lithium diisopropylamide solution thus obtained was added dropwise a solution of 300 mg. of 1-methoxycarbonyl-3-propylcyclopentane in 5 ml. of dry tetrahydrofuran and the mixture was stirred at -78° C. for 30 minutes. To the solution was added a solution of 0.216 ml. of methyl iodide in 5 ml. of dry tetrahydrofuran and the mixture was stirred at -78° C. for one hour. The reaction mixture was quenched with an aqueous solution of ammonium chloride and extracted with diethyl ether. The extract was washed with 1N hydrochloric acid, an aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 330 mg. of the title compound having the following physical characteristic:
Reaction SMILES: N1[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C1C[O:12][CH2:11]C1>[Pd]>[CH3:8][CH:2]1[CH2:7][CH2:6][CH:5]([CH:11]=[O:12])[CH2:4][CH2:3]1
Reactant: C1CCOC1
Reactant: Cc1cccc(C)n1
Agent: [Pd]
Product: CC1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
A mixture of the compound prepared in step 115.6 (8.8 g, 54.7 mmol) and Pd/C 10% (5.8 g, 54.7 mmol) in THF (150 mL) and 2,6-lutidine (11.7 g, 109 mmol) was stirred for 15.5 h at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite. The crude was dissolved in CH2Cl2 and extracted with 1N HCl then with a saturated aqueous NaHCO3 solution. The organic layer was dried (Na2SO4), filtered and concentrated.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11](=[O:17])[NH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:18][N:12]1[C:13]2[C:8](=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]1=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc2c(-c3ccccc3)nccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2c(-c3ccccc3)nccc21
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A mixture containing 22.2 g of 5-phenyl-1,6-naphthyridin-2(1H)-one, 13.18 g of anhydrous potassium carbonate and 300 ml of dimethylformamide was heated with stirring on a steam bath for 1 hour and to this mixture was added 6.9 g of methyl iodide. The resultig mixture was heated with stirring for an additional 6 hours, allowed to cool and the solvent removed by distillation under reduced pressure. To the residue was added 100 ml of 20% acetic acid and the resulting pale yellow solid was collected, washed with water, dried, recrystallized from methanol and dried at 90° C. to yield 16.4 g of 1-methyl-5-phenyl-1,6-naphthyridin-2(1H)-one, m.p. 190°-192° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CS(C)=O>[O:7]([C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([NH2:10])[C:12]=1[C:13]#[N:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1c(N)cccc1Oc1ccccc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Phenol (2.06 g, 22 mmol) was dissolved in dry dimethyl sulfoxide (25 mL), and sodium hydride (0.53 g, 22 mmol) was added in portions, and the mixture stirred for 1 hour under argon. 2-Amino-6-fluorobenzonitrile (2.72 g, 20 mmol) was added and the mixture heated to 110° C. overnight. The solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (5×), brine (1×) dried over anhydrous Na2SO4 filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–20% ethyl acetate in hexane to give the title compound as a white amorphous solid. Recrystallization from carbon tetrachloride, hexane gave a white crystalline solid. mp 66–67° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>ClCCl.N1C=CC=CC=1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:6][C@@H:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[O:23])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
2.0 g (9.3 mmol) L-phenylalanine methylester hydrochloride and 1.73 g (9.3 mmol) 4-nitrobenzoyl chloride were dissolved in a mixture of 10 ml dichloromethane and 5 ml pyridine and stirred over night at room temperature. The mixture was evaporated in vacuo, while a colorless solid precipitated, which was filtered by suction, recrystallized from ethanol, washed with diisopropylether, and dried in vacuo to give the title compound in colorless needles, m.p. 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[S:16][C:15]([C:17]([O:19]CC)=[O:18])=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]#[N:30])[CH:23]=1.C(=O)(O)[O-].[Na+]>COCCOC.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:3]=[C:4]([C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[N:14][C:13]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]#[N:30])[CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
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
Solvent: O
Product: N#Cc1cc(-c2nc(C(=O)O)sc2-c2cccc(Cl)c2)ccc1F

Procedure:
At room temperature, 231 mg (1.48 mmol) of (3-chlorophenyl)boronic acid are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under reflux for 1 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 353 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O:11][C:12](=O)[C@@H:13]1[O:15][C@H:14]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.O>CS(C)=O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:14]2[O:15][C@H:13]2[C:12]([NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:11])=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2O[C@H]2C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a mixture of sodium hydride (62.5% oil dispersion, 0.46 g) and dimethyl sulfoxide (3 ml) is added a solution of aniline (1.02 g) in dimethyl sulfoxide (1 ml) at room temperature under nitrogen atmosphere, and the mixture is stirred for 30 minutes. To the mixture is added a solution of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionic acid methyl ester (2.08 g) in dimethyl sulfoxide (4 ml) at room temperature over a period of 15 minutes. The mixture is further stirred at the same temperature for one hour, and thereto is added water (50 ml). The precipitated yellow crystals are collected by filtration, and recrystallized from ethyl acetate (60 ml) to give (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxy-N-phenylpropionamide (1.50 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C:9]1=[O:22])(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C:9]1=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccnc(C#N)c2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CN2CC[C@H](N)C2=O)ccn1
Reaction time: 18 h

Procedure:
To a solution of [1-(2-cyano-pyridin-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acid tert-butyl ester (3.34 g, 10.6 mmol) in 50 mL of CH2Cl2 is added 5 mL of TFA. The reaction mixture is stirred for 18 hours and then concentrated to give the title compound (3.40 g, 10.3 mmol) as a white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:19]=[CH:18]/[CH2:17][CH2:16][C:15]([O:21][CH2:22][CH3:23])=[O:20])[CH3:9]
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Reactant: C=CCCC(=O)OCC
Product: CCOC(=O)CC/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Yield: 82 %

Procedure:
By using (2R)-2-{[(1R)-1-(2-bromo phenyl)ethoxy]methyl}oxirane described in WO 2004/094362 and ethyl pent-4-enoate, the reaction was carried out in the same manner as the method described in Example 4(4c) to give the title compound as a colorless oily substance (yield 82%).