Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C([Li])CCC.[C:35]1([C:41]2[N:42]=[C:43]([CH2:52]Br)[O:44][C:45]=2[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Na+].[I-]>C1COCC1.O.C(OCC)(=O)C>[C:35]1([C:41]2[N:42]=[C:43]([CH2:52][O:1][C@H:2]3[C:11]4[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:8]=[CH:9][CH:10]=4)[CH2:5][CH2:4][CH2:3]3)[O:44][C:45]=2[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2O)(c1ccccc1)c1ccccc1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [I-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2OCc1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.6 %

Procedure:
To a solution of (1R)-1-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.5 g) in THF (20 ml) were added n-butyllithium (2.8 ml, 1.5M solution in hexane), (4,5-diphenyloxazol-2-yl)methyl bromide (1.8 g) and NaI (1.2 g) at -78° C. under N2. The solution was warmed to the room temperature and stirred for 6 hours. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-(4,5-diphenyloxazol-2-yl)methyloxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.65 g). MS (m/z): 636 (M+ +1) IR (Neat): 3400 cm-1NMR (CDCl3, δ): 1.09 (9H, s), 1.6-2.2 (4H, m), 2.6-3.2 (2H, m), 4.65 (1H, m), 4.75 (1H, d, J=13.2 Hz), 4.84 (1H, d, J=13.2 Hz), 6.31 (1H, d, J=8 Hz), 6.75 (1H, t, J=8 Hz), 6.98 (1H, d, J=8 Hz), 7.2-7.8 (10H, m)
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[CH3:20][N:21]=[C:22]=[S:23].C(Cl)(Cl)Cl.CO.N>CO>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:22]([NH:21][CH3:20])=[S:23])[N:11]=1
Reactant: CN=C=S
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNC(=S)NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 3 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.3 g.) and methyl isothiocyanate (0.18 g.) in methanol (6 ml.) was allowed to stand at room temperature for 3 hours. The residue obtained on evaporation of the solvent was subjected to preparative thin layer chromatography using chloroform/methanol/ammonia 90:10:0.5 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (100 ml.). Evaporation of the solvent gave B 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylthioureido)butyl]thiazole as a straw-coloured gum. The n.m.r. spectrum d6 dimethylsulphoxide using tetramethylsilane as internal standard included the following resonances (ε): 2.75 (3H, doublet), 4.04 (2H, multiplet) and 6.34 (1H, singlet). On addition of D2O the multiplet at ε 4.04 collapsed to a quartet.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)Cl>[Br:18][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[Cl:1])[NH:8][N:9]=1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Clc1ncnc2[nH]nc(Br)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a suspension of 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (1.1 g, 7.1 mmol) in CHCl3 (50 mL) was added NBS (1.49 g, 8.4 mmol) The mixture was stirred at room temperature for 5 hours, cooled to 0 C and the solids were isolated by vacuum filtration, rinsed with cold CHCl3, and air dried. The solid was purified by column chromatography on silica (50% EtOAc/hexanes) to give 3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.3, 77%.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([S:27]C(=O)C)[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([SH:27])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)SC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCC(S)CC1COc1c(F)ccc(F)c12
Reaction time: 4 h
Yield: 34.8 %

Procedure:
A solution of thioacetic acid S-[10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yl]ester (420 mg, 0.888 mmol) in MeOH (8 mL) was treated with 1N NaOH (2 mL) followed by THF (3 mL). After 4 h, the reaction mixture was concentrated in vacuo, diluted with 1N HCl and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo. Flash chromatography (2→20% EtOAc/Hex) gave the disulfide of the title compound (133 mg, 17%): 1H NMR (CDCl3 400 MHz) δ 7.62 (d, J=8.8 Hz, 4H), 7.51 (d, J=8.8 Hz, 4H), 7.07 (m, 2H), 6.41 (m, 2H), 5.24 (dd, J=11.0, 2.9 Hz, 2H), 4.11 (d, J=11.0 Hz, 2H), 3.48 (m, 2H), 3.14 (d, J=13.2 Hz, 2H), 2.55 (m, 2H), 2.42 (m, 2H), 1.92-1.52 (m, 8H); followed by the title compound (169 mg, 44%): 1H NMR (CDCl3 400 MHz) δ 7.60 (dd, J=8.8, 1.5 Hz, 2H), 7.48 (dd, J=8.8, 1.5 Hz, 2H), 7.08 (m, 1H), 6.42 (m, 1H), 5.25 (dd, J=11.7, 2.2 Hz, 1H), 4.11 (d, J=11.0 Hz, 1H), 3.11 (m, 1H), 2.95 (d, J=12.5 Hz, 1H), 2.40-2.38 (m, 2H), 2.04-1.82 (m, 3H), 1.49 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:40][CH3:41])[CH2:4][N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:39])[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[S:32][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:30][CH:29]=2)[CH2:23][CH2:22]1)[C:6](=O)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][CH:3]([O:40][CH3:41])[CH2:4][N:5]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18](=[O:39])[C:19]([CH2:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[S:32][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:30][CH:29]=3)[CH2:25][CH2:26]2)=[C:6]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(=O)N(CC(OC)OC)c1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(CC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c(=O)c2ccccc2n1CC(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The compound prepared in Example 324 (0.390 g) was suspended in methanol (7 mL) and potassium carbonate (0.093 g) added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to afford the crude material, which was partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (eluant: 5% (9:1 methanol/concentrated ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.340 g) having the following physical properties.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:19]=3[CH:18]=2)(=[O:16])=[O:15])[CH2:10][C:9]1=[O:27])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:19]2[CH:18]=[C:17]([S:14]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:9](=[O:27])[CH2:10]3)(=[O:15])=[O:16])[S:21][C:20]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1=O
Yield: 99.7 %

Procedure:
[4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine-1-yl]acetic acid tert-butyl ester (500 mg, 1.13 mmol) is dissolved in 1 mL of trifluoroacetic acid and 3 mL of CH2Cl2. The solvents are azeotropically removed with toluene. [4-(6-chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine-1-yl]acetic acid (438 mg) is isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1.C([O-])(=O)C.[Na+].C(O)C.[N:37]#[C:38]Br>ClCCl.C1(C)C=CC=CC=1.[OH-].[Na+]>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:8]=1)[C:38]#[N:37]
Reactant: FC(F)(F)c1cc(CNCc2cc(C(F)(F)F)ccc2Cl)cc(C(F)(F)F)c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Yield: 74 %

Procedure:
To the mixture of the compound from Step B (10 gm), 5.6 gm of sodium acetate 100 mL of ethanol was added over 15 minutes 15.5 mL of cyanogen bromide 3M in dichloromethane. The reaction mixture was stirred at ambient temperature until reaction completion. When the reaction was judged complete, it was diluted with 200 mL of toluene and 200 mL of sodium hydroxide. The layers were separated and the organic layer dried with magnesium sulfate, filtered and concentrated to an oil. 7.8 gm (74% yield). The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 7.84 (s, 2H), 7.56 (s, 3H), 7.66 (m, 4H), 7.48 (s, 2H), 4.39 (s, 2H), 4.36 (s, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C(O)(=[O:15])C>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:15])[CH2:7][C:8]2([CH3:12])[CH3:11]
Reactant: CC(=O)O
Reactant: CC1(C)CCc2ccc(Br)cc21
Product: CC1(C)CC(=O)c2ccc(Br)cc21
Temperature: 60 °C
Yield: 76 %

Procedure:
To a solution of 6-bromo-1,1-dimethyl-2,3-dihydro-1H-indene (3.6 g, 16 mmol) in acetic acid (50 mL) was added to a solution of CrO3 (9.6 g, 96.0 mmol) in 50% aqueous acetic acid (50 mL). This solution was heated for 3 h at 60° C. At completion, the reaction mixture was quenched by the addition of isopropanol (20 mL). The quenched reaction was partitioned between EtOAc (200 mL) and a 0.25 M aqueous NaOH (100 mL). The layers were separated and the organics were extracted with EtOAc (2×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. After purification by flash chromatography over silica gel (50% EtOAc/hexanes eluent), 5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (2.91 g, 76% yield) was isolated as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65 (s, 1H), 7.47-7.58 (m, 2H), 2.58 (s, 2H), 1.42 (s, 6H); MS (EI) m/z=240.1 [M+1]+.
Reaction SMILES: Br[CH2:2][CH3:3].[Mg].C#C.[F:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[CH:10][CH:9]=1.C([Mg]Br)#C.Cl>O1CCCC1>[F:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]([OH:17])[C:2]#[CH:3])=[CH:10][CH:9]=1
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Reactant: CCBr
Agent: C#C
Agent: C#C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(Oc2ccc(F)cc2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
14 g (0.13 mol) of bromoethane were slowly added dropwise, while stirring, to 2.4 g (0.1 mol) of magnesium filings in 70 ml of anhydrous tetrahydrofuran at 30°-40° C. and the mixture was then stirred for a further 30 minutes at 50° C. The Grignard solution thus prepared was transferred into a dropping funnel under nitrogen and was added dropwise to a saturated solution of acetylene in 40 ml of anhydrous tetrahydrofuran, the solution having been saturated at 20° C. During the addition further acetylene was passed in continuously, and this was continued for a further 30-45 minutes after the end of the dropwise addition. 10.8 g (0.05 mol) of 3-(4-fluorophenoxy)-benzaldehyde, dissolved in 50 ml of absolute tetrahydrofuran, were added dropwise to the suspension of ethynyl magnesium bromide, thus prepared, at 25°-30° C., and the mixture was then warmed to 40° C. for 4 hours. Thereafter the reaction batch was cooled to 10° C. and poured into 500 ml of ice-water, and the resulting precipitate was dissolved by adding concentrated hydrochloric acid. The mixture was then extracted twice with 150 ml of ether at a time, the ether phases were dried over sodium sulfate and the ether was then distilled off in vacuo. 7.3 g (61% of theory) of 3-(4-fluorophenoxy)-α-ethynyl-benzyl alcohol were obtained as a yellow oil of boiling point 160°-180° C./3 mm Hg. ##STR27##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[NH2:25])[CH3:2].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([SiH](CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[NH:25][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=1)[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1N
Agent: CC[SiH](CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.5 %

Procedure:
A solution of 1.03 g (2.80 mmol) of N-(5-(4-cyanobenzyloxy)-2-aminobenzoyl)-b-alanine ethyl ester, 394 mg (2.80 mmol) of p-chlorobenzaldehyde, and 20 mg of p-toluenesulfonic acid in 30 mL of toluene was heated at reflux through a Dean-Stark trap for 45 min. The solvent was removed in vacuo and the residue was dissolved in 15 mL of trifluoroacetic acid. Triethylsilane (1.34 mL, 8.40 mmol) was added and the mixture was stirred at room temperature for 12 h, concentrated in vacuo, and partitioned between 1N aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. Chromatography (silica gel-60, 2:3 ethyl acetate/hexane) gave 820 mg (59%) of N-(5-(4-cyanobenzyloxy)-2-(4-chlorobenzylamino)benzoyl)-b-alanine ethyl ester as a colorless solid. 1H NMR (300 MHz, CDCl3) d 7.66 (2H, d, J=7.8 Hz, NC-Ar-H2), 7.51 (2H, d, J=7.8 Hz, NC-Ar-H2), 7.27 (4H, s, ClArH4), 6.98 (1H, d, J=2.0 Hz, O-Ar-H), 6.89 (1H, dd, J=2.0, 9.3 Hz, O-Ar-H), 6.78 (1H, b, N-H), 6.66 (1H, d, J=9.3 Hz, O-Ar-H), 5.03 (2H, s, ArCH2O), 4.32 (2H, s, ClArCH2), 4.17 (2H, q, J=7.3 Hz, OCH2CH3), 3.65 (2H, bq, J=5.7 Hz, NHCH2CH2), 2.62 (2H, t, J=5.7 Hz, NHCH2CH2), 1.28 (3H, t, J=7.3 Hz, OCH2CH3); Exact mass (FAB, M+H+) calcd for C27H27ClN3O4 : 492.1690; Found: 492.1681.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:24])[C@H:15]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH2:16])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[C@@H:15]([NH:16][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:12]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)o1)C(=O)OCC
Yield: 72 %

Procedure:
AAG154489 was synthesized as shown in Scheme 3. Compounds 10 was obtained by a Sonogashira coupling of 5a (from scheme 1) with (S)-2-[(5-bromo-furan-2-carbonyl)-amino]-pentanedioic acid diethyl ester 13. Compound 13 (Scheme 3) was synthesized by coupling the commercially available 5-bromo-2-furan-carboxylic acid 12 and L-glutamate diethyl ester hydrochloride in 72% yield. Hydrogenation and saponification of 10 afforded AAG154489.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([NH:20][C:21]([C:23]3[C:24]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH:17]=[CH:16][C:15]=2[Cl:38])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([NH:20][C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][C:24]=3[NH:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH:17]=[CH:16][C:15]=2[Cl:38])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(COc2cc(NC(=O)c3cccnc3NCc3ccc(F)cc3)ccc2Cl)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(OCC2CNC2)c1)c1cccnc1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mL of TFA/CH2Cl2 (1:1) was added 3-(2-chloro-5-{[2-(4-fluoro-benzylamino)-pyridine-3-carbonyl]-amino}-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (270 mg, 0.5 mmol) at 0° C. The solution was stirred for 2 h at RT. The solvents were removed in vacuo. The residue was diluted in 30 mL of EtOAc and washed with 30 mL of saturated aqueous NaHCO3, then brine. The resulting organic phase was dried over MgSO4 and concentrated in vacuo. The title compound was purified by column chromatography (silica gel, 5% 2N NH3 in MeOH/EtOAc) and isolated as a white solid. MS (ES+): 442 (M+H)+. Calc'd for C23H22ClFN4O2-440.90.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cncc(Br)c1

Procedure:
In a manner similar to that described in Preparation 17, 5-bromonicotinic acid and 3-trifluoromethylaniline were converted to the title compound
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.[C:14]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1OS(C(F)(F)F)(=O)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C.[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>[OH:4][C:5]1[CH:6]=[C:7]([C:28]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][C:18]=2[C:14]([CH3:15])([CH3:17])[CH3:16])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(C)(C)C)c1
Reactant: COCOc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cccc(O)c2)c(C(C)(C)C)c1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 6.8 g (37 mmol) of 3-methoxymethoxyphenylboronic acid (described in Example 1(g)) with 11 g (31 mmol) of ethyl 3-tert-butyl-4-trifluoromethanesulphonyloxybenzoate, 37 mL of 2M potassium carbonate and 1.8 g of tetrakis(triphenylphosphine)-palladium, followed by deprotection in ethanol, the desired product is obtained in the form of pink crystals (m.p.=118-120° C.; m=5.3 g; Y=57%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:23]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([CH3:32])=[O:31])[CH:25]=2)=[C:22]([Cl:33])[CH:21]=[CH:20][C:9]=1[C:10]([O:12]C1N(CC)N=CC=1)=O.O>O1CCOCC1>[Cl:7][C:8]1[C:23]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([CH3:32])=[O:31])[CH:25]=2)=[C:22]([Cl:33])[CH:21]=[CH:20][C:9]=1[C:10]([C:25]1[CH:26]=[N:27][N:28]([CH2:24][CH3:23])[C:1]=1[OH:4])=[O:12]
Reactant: CCn1nccc1OC(=O)c1ccc(Cl)c(-c2cc(C(C)=O)nn2C)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1ncc(C(=O)c2ccc(Cl)c(-c3cc(C(C)=O)nn3C)c2Cl)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 135.1 %

Procedure:
0.076 g (0.6 mmol) of potassium carbonate was added to 0.16 g (0.4 mmol) of (1-ethylpyrazol-5-yl) 2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoate in 3 ml of dioxane and the mixture was heated under reflux for 3 hours and then stirred at room temperature for 12 hours. 50 ml of water were added, the solution was washed with methylene chloride and methyl t-butyl ether, nitrogen was passed through and the pH was adjusted to 1 using 10% strength hydrochloric acid. The precipitate that had formed was filtered off with suction, washed with water and taken up in ethyl acetate. After drying, this organic phase was concentrated. 0.11 g (69% of theory) of 4-[2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoyl]-1-ethyl-5-hydroxy-1H-pyrazole was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[NH:13][CH2:12][CH2:11][S:10]1.Cl.SCCN.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[N:13]([C:25](=[O:27])[CH3:26])[CH2:12][CH2:11][S:10]1
Reactant: Clc1ccc(C2(Cn3cncn3)NCCS2)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: NCCS
Product: CC(=O)N1CCSC1(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 33.5 %

Procedure:
1.58 g of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl methyl)-thiazolidine prepared in the same manner as in Working Example 1 except that β-mercaptoethylamine hydrochloride was used instead of β-mercapto-β-methyl-ethylamine hydrochloride, was mixed with 2.0 g of acetic anhydride, and the mixture was reacted at 120° C. for 4 hours. After the reaction, the reaction product was purified by silica gel column chromatography using a solvent mixture of chloroform and methanol as the developer, whereby 0.6 g of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl methyl)-3-acetyl thiazolidine (Compound No. 48 in Table 1) was obtained.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])#[N:2].[F:14][C:15]1[C:20](O)=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:14][C:15]1[C:20]([O:5][C:4](=[O:6])[C:3]([C:1]#[N:2])=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25]
Reactant: N#CC(=Cc1ccccc1)C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CC(=Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F

Procedure:
9.0 g. (0.05 moles) of α-cyano-β-phenyl-acrylic acid are suspended in 200 ml. of dichloromethane and 9.2 g. (0.05 moles) of pentafluorophenol and 10.02 g. (0.05 moles) of dicyclohexylcarbodiimide in 100 ml. dichloromethane are added. The mixture is heated for 5 hours under reflux, cooled, the precipitated dicyclohexyl urea is filtered off. The solution is washed with 20 ml. of 2n hydrochloric acid and three times with water, dried over magnesium sulfate, evaporated and the residual oily substance is recrystallized from petrolether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[S:17][CH:18]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]=1[C:21]([O:23]CC)=[O:22])C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[K+]>C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C:16]1[S:17][CH:18]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]=1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1scc(-c2ccccc2)c1C(=O)O
Yield: 86.6 %

Procedure:
A mixture of ethyl bis(t-butoxycarbonyl)amino-4-phenylthiophene-3-carboxylate (4.37 g, 9.76 mmol), 40 ml of ethanol, 20 ml of water and 2.19 g of potassium hydroxide was heated at reflux for 3 h. The mixture was cooled and acidified with 2.9 ml of--acetic acid. The precipitate was isolated to give 2.70 g (87%) of 2-t-butoxycarbonylamino4-phenylthiophene-3-carboxylic acid. M.p. 183° C. (dec.). 1H-NMR (DMSO-D6, δ): 1.5 (s, 9H), 6.7 (s, 1H), 7.3 (m, 5H), 11.5 (br.s, 1H).