Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[C:27]([F:30])([F:29])[F:28])[CH2:22]Br.O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][C:21]2[CH:24]=[CH:25][C:26]([C:27]([F:28])([F:29])[F:30])=[C:19]([F:18])[CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)c(F)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (8.9 g, 42.3 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.69 g, 42.3 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-fluoro-4-(trifluoromethyl)benzyl bromide (9.0 g, 42.3 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) and recrystallized from diisopropyl ether-hexane to give ethyl 3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-oxopropionate (10.8 g, 66%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].C1[CH2:12][O:11]CC1.[Li].CCCCCCC.C1C[O:24]CC1.C(C1C=CC=CC=1)C>>[C:6]([C:2]1[S:1][C:5]([C:12]([OH:11])=[O:24])=[CH:4][CH:3]=1)#[N:7]
Reactant: N#Cc1cccs1
Reactant: C1CCOC1
Agent: [Li]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: N#Cc1ccc(C(=O)O)s1
Reaction time: 0.17 h
Yield: 22 %

Procedure:
In a 500 mL receiving flask are placed thiophene-2-carbonitrile (5.0 mL, 53.8 mmol) and THF (270 mL) and cooled in an acetone/solid CO2 bath. Lithium disopropylaoide (40.3 mL, 80.7 mmol, 2.0M solution in heptane/THF/ethylbenzene) is added in a slow stream via syringe. The solution is stirred for 10 min then quenched with an excess of dry ice. The reaction mixture is warned in a water bath and the THF removed in vacuo. The slurry is taken up in 1N NaOH and extracted with ether (3×). The aqueous layer is then acidified to pH<6 with conc. HCl, whereupon a brown precipitate forms. This precipitate is filtered off and to the resulting eluent is added 1N HCl which results in precipitation of the product. The product is collected by filtration then triturated with CH2Cl2Purification over silica gel (1:2.5:100 formic acid:MeOH:CH2Cl2) provides the product as a solid (1.79 g, 22%). 1H NMR (400 MHz, CDCl3) δ 14.10, 8.00, 7.80.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:19][SH:20].O>CN(C)C=O>[F:11][C:6]1[C:3]2[CH:4]=[C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])[S:20][C:2]=2[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(F)cc(F)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a suspension of 2,4,6-trifluorobenzaldehyde (5.00 g, 31.2 mmol) and potassium carbonate (5.61 g, 40.6 mmol) in N,N-dimethylformamide (63 mL) was added ethyl thioglycolate (3.40 g, 28.3 mmol) at 0° C. The mixture was stirred at room temperature overnight, and then heated to stir at 60° C. for 6 hours. The mixture was cooled to room temperature, and then to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→93:7) to give ethyl 4,6-difluoro-1-benzothiophene-2-carboxylate (1.95 g, 29%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]([C:27]1[N:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH-].[Na+].Cl>CO.O>[OH:1][C:2]([C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(O)c3ccc(C(=O)O)cn3)s2)c1
Temperature: 100 °C
Yield: 93.8 %

Procedure:
The product of Step 2 (366 mg, 0.710 mmol) was taken up in MeOH (8.0 ml) in a microwave vial, and sodium hydroxide (1.0 M in H2O, 1.42 ml, 1.42 mmol) was added. The reaction was heated to 100° C. for 10 min in the microwave. The colorless solution was adjusted to a pH of 3-4 with 1 N HCl, diluted with water, and extracted with 15% IPA/CHCl3 (2×). The combined organic layers were dried (MgSO4), filtered and evaporated to a yellow solid that was triturated with CH2Cl2/hexanes, filtered, and dried to provide the title compound (334 mg, 0.666 mmol, 94% yield) as a pale yellow powder. MS ESI: [M+H]+ m/z 502.1. 1H NMR (500 MHz, DMSO-d6) δ 13.53-13.21 (s, 1H), δ 10.24 (s, 1H), 8.99 (d, J=2.0, 1H), 8.82 (d, J=4.9, 1H), 8.29 (dd, J=2.2, 8.3, 1H), 7.98-7.90 (m, 2H), 7.85 (d, J=8.3, 1H), 7.45 (s, 1H), 7.27 (d, J=4.9, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 2.29 (s, 3H), 1.98 (s, 3H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1sccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1sccc1Cl)C2
Yield: 115 %

Procedure:
A mixture of 7-(3-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.3 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.27 ml), water (0.27 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was washed with ethyl acetate, and to the mixture was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added a solution of 4N hydrochloric acid-ethyl acetate (0.4 ml), and the mixture was concentrated under reduced pressure. The resulting crystals were recrystallized from ethanol-water to give 7-(3-chloro-2-thienyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 74) (0.23 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:17][C:11]1([C:14]([O:16][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (5.0 g, 20.55 mmol) in methanol (60 mL) and toluene (100 mL) was added a 2M solution of trimethylsilyldiazomethane (20 mL) in hexanes (the addition was accompanied by effervescence and a small exotherm). The resulting pale yellow solution was allowed to stir at ambient temperature for 1 hr. The solvent was removed under reduce pressure to give the title compound as a pale yellow oil (5.28 g 20.55 mmol, 100%); 1H NMR (CDCl3) δ 1.20 (s, 3H), 1.34-1.39 (m, 2H), 1.44 (s, 9H), 2.03-2.07 (m, 2H), 2.96-3.03 (m, 2H), 3.70 (s, 3H), 3.72-3.77 (m, 2H); MS m/e MH+. 257
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](OC)=[O:6].C[O-].[Na+].Cl.[CH:21]([NH2:23])=[NH:22]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:5]([OH:6])=[N:22][CH:21]=[N:23][C:3]=2[OH:2])=[CH:10][CH:11]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1ncnc(O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
A solution of 2-(4-chlorophenyl)-malonic acid dimethyl ester (18.90 g) in methanol (200 ml) was added dropwise at 0° C. to a solution sodium methylate (14.60 g) in methanol (150 ml). The mixture was stirred for 1 h at 0° C. before formamidine hydrochloride (7.66 g) was added. The suspension was stirred at rt for 20 h. The solvent was removed and the residue was suspended in 2 N aq. HCl (200 ml). The pH of the suspension was carefully adjusted to 4–5 by adding 10 M NaOH (20 ml), stirring was continued for 30 min. The white precipitate was collected, washed with water and diethyl ether and dried to give 5-(4-chlorophenyl)-pyrimidine-4,6-diol (16.44 g) as a white powder. LC-MS: tR=2.75 min, [M+H]+=222.96, [M−H]−=220.92.
Reaction SMILES: [NH2:1][N:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]1=[NH2+:10].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[Cl:24][CH2:25][C:26](OC)=O.C(=O)([O-])[O-].[K+].[K+]>CCO>[Cl:24][CH2:25][C:26]1[N:10]=[C:3]2[C:4]([CH3:9])=[CH:5][CH:6]=[C:7]([CH3:8])[N:2]2[N:1]=1
Reactant: Cc1ccc(C)n(N)c1=[NH2+]
Reactant: COC(=O)CCl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(C)n2nc(CCl)nc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
A suspension of 1-amino-3,6-dimethylpyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (crude product from the previous step, 8.2 mmol), methyl 2-chloroacetate (1.78 g, 16.4 mmol) and potassium carbonate (2.26 g, 16.4 mmol) in EtOH (30 mL) was stirred at 80° C. for 16 h. After cooled to room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluting with 20% v/v EtOAc in PE) to give the title compound (920 mg, yield 36%, 2 steps). ESI MS: m/z 196, 198 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.24 (d, J=7.2 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 4.85 (s, 2H), 2.74 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[O:31][CH3:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[O:31][CH3:32])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:14])=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)N3CCNCC3)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) piperazine-1-carboxylic acid tert-butyl ester gave, after treatment with TFA and neutralisation, the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:19]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:19])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2nc3ccccc3[nH]2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(Br)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
2-(3-bromophenyl)-1H-benzimidazole (7.8 g, 28.6 mmol) was completely dissolved in dry THF (300 ml), then NaH 60% m/m (1.49 g, 37.2 mmol) was added portionwise to the clear yellow solution. The light brown suspension was stirred 1 h rt, then CH3I (2.5 ml, 40.0 mmol) was added dropwise. The reaction mixture was stirred rt overnight. The reaction was quenched with H2O (300 ml), and extracted with EtOAc (2×450 ml). The organic extracts were dried over MgSO4, filtered and evaporated, to afford the compound as a brown-yellow solid (7.4 g, 70%).
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][C:24]2=[O:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31].O>O1CCCC1>[OH:29][C:24]1([CH2:31][C:30]([O:33][CH2:34][CH3:35])=[O:32])[C:25]2[C:20](=[C:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1(O)CCCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc21
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (17 ml) in THF (tetrahydrofuran) (210 ml) was added n-butyllithium (67 ml, 1.6N in hexane) at -78° C. under N2. The solution was stirred for 30 minutes at 0° C. and then cooled to -78° C. To the solution was added ethyl acetate (12 g) and the mixture was stirred for 30 minutes at the same temperature to give Li-enolate solution. A solution of 5-t-butyldiphenylsilyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene (10 g) in THF (50 ml) was cooled to -78° C., the above Li-enolate solution (35 ml) was added, and stirred for 1 hour at the same temperature. 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 1-hydroxy-1-ethoxycarbonylmethyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (8.0 g). 2.72 (2H, t, J=6.6 Hz), 2.90 (2H, t, J=8.0 Hz), 4.30 (2H, t, J=7.0 Hz), 5.78 (1H, t, J=4.4 Hz), 6.33 (1H d, J=8 Hz), 6.6-6.9 (2H, m), 7.1-7.8 (20H, m) MS m/z: 624 (M+ +1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/B(O)O)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:2]2[CH:3]=[C:4]([N:8]3[C:12]([CH3:13])=[C:11]([C:14]([N:16]4[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]4)=[O:15])[C:10]([CH3:26])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(Br)c3)c2C)C1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(/C=C/c4ccc(Cl)cc4)c3)c2C)C1
Yield: 67 %

Procedure:
In analogy to the procedure described in Example 14C], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone (Example 28A]) and trans-2-(4-chlorophenyl)vinylboronic acid gave the title compound in 67% yield as light brown foam. MS: 477.3 (MH+, 1 Cl).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:39])[NH:29][C:30]3[C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[S:33][CH:34]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:33]1[CH:34]=[C:30]([NH:29][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:17]=[CH:16][C:15]([S:12]([NH:11][CH:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:40])=[O:5])(=[O:14])=[O:13])=[CH:20][CH:19]=3)=[CH:22][CH:23]=2)=[O:39])[C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]1=2
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3csc4ccccc34)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3csc4ccccc34)cc2)cc1)C(=O)O
Reaction time: 4 h
Yield: 66 %

Procedure:
2-[4′-(Benzo[b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (180 mg, 0.31 mmol) was dissolved in methylene chloride under N2 atmosphere, added with TFA (2 mL) at 0° C. and stirred for 4 hrs. Solvent was evaporated and the product dried under high vacuum to give 2-[4′-(Benzo[b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 66% yield (108 mg).
Reaction SMILES: Cl[C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].CC1C=C(C)C=C(C)N=1.Cl>CO>[CH3:17][O:18][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1cccc2c1nnn2C1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CO
Product: COc1cccc2c1nnn2C1CCCCC1

Procedure:
A slurry of 1.5 g. of 4-chloro-1-cyclohexylbenzotriazole, 15 g. of sodium methoxide, 10 g. cuprous iodide in 50 ml. of 2,4,6-trimethyl pyridine and 10 ml. of methanol is heated to the reflux temperature for 26 hours. The reaction is cooled and poured into 150 ml. of 10% hydrochloric acid. The product is extracted with ethyl ether and on evaporation of the solvent, 0.5 g. of an oil was obtained which solidified on standing. Recrystallized the crude product from ethyl ether, m.p. 118°-120° C. The analytical sample has a m.p. 133°-134° C.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCN
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 6-aminohexanoic acid, methyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 6 of European Patent Application 136,883 to give (±)-6-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]hexanoic acid, methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:30][CH3:31])[CH2:9][C@@H:10]([C:26]([O:28][CH3:29])=[O:27])[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:30][CH3:31])[CH2:9][C@H:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](CCN1CCN(C(=O)OC(C)(C)C)CC1)C[C@@H](OC)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](CCN1CCNCC1)C[C@@H](OC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-((3S,5R)-5-(4-fluorophenyl)-5-methoxy-3-(methoxycarbonyl)pentyl)piperazine-1-carboxylate in 200 μL DCM was slowly added 2 mL TFA and the resulting solution stirred for 30 min at 25° C. The solvent was evaporated under reduced pressure and the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [CH:1]([N:3]([CH2:16][C:17](=O)[CH3:18])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])=O.C([O-])(=O)C.[NH4+:24].N.C(OCC)(=O)C>C(O)(=O)C>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[N:3]1[CH:16]=[C:17]([CH3:18])[N:24]=[CH:1]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of methyl 4-[formyl-(2-oxopropyl)amino]-3-methoxybenzoate (118 g) and ammonium acetate (172 g) in acetic acid (255 mL) was heated and stirred at 140° C. for one hour. After the reaction was completed, the reaction solution was neutralized with aqueous ammonia under ice-cooling. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then filtered on a silica gel pad, and the filtrate was concentrated under reduced pressure. tert-Butyl methyl ether and heptane were added to the residue, and the precipitated solid was collected by filtration and washed with a solution of 50% tert-butyl methyl ether in heptane. The resulting solid was air-dried overnight to obtain 68.4 g of the title compound. Further, the crystallization mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 22.3 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[N:24]=[C:23]([C:25]([O-:27])=O)[CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]#[N:30]>>[C:29]([CH2:28][C:25]([C:23]1[N:24]=[C:19]([O:18][CH2:17][CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)[CH:20]=[CH:21][CH:22]=1)=[O:27])#[N:30]
Reactant: CC#N
Reactant: O=C([O-])c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)n1
Product: N#CCC(=O)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)n1

Procedure:
CH3CN addition to 6-((1-((benzyloxy)carbonyl)piperidin-4-yl)methoxy)picolinate following the method described in Example 6 gave benzyl 4-(((6-(2-cyanoacetyl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate in which was used in the next step without further purification. Yield (1.53 g, quant).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[CH:17]\I)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[CH:17][C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:13]
Reactant: C#Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccc([N+](=O)[O-])cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-nitro-benzene and (Z)-ethyl-3-iodoacrylate to the title product except using 1.6 mmol of acetylene and 1.8 mmol vinyl iodide. Purification by flash chromatography (20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a yellow solid (350 mg, 89% yield). 1H NMR (400 MHz, CDCl3) δ 8.22-8.19 (d, J=8.9, 2H), 7.68-7.65 (d, J=8.9, 2H), 6.38-6.35 (d, J=11.4, 1H), 6.26-6.23 (d, J=11.4, 1H), 4.29-4.24 (q, J=7.1, 2H), 1.35-1.31 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.38, 147.48, 132.66, 130.32, 129.41, 123.57, 121.67, 97.99, 90.64, 60.64, 14.23. Anal. Calcd. for C13H11NO4: C, 63.67; H, 4.52; N, 5.71; Found C, 63.45; H, 4.44; N, 5.65. m.p.: 76.0°-78.0° C.