Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]=[CH2:13]>[Pd]>[CH2:12]=[CH:13][C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C
Reactant: Nc1ccccc1S(=O)(=O)O
Agent: [Pd]
Product: C=Cc1ccccc1S(=O)(=O)O
Yield: 87 %

Procedure:
Although the use of supported palladium catalysts is mentioned in EP-A 0 508 264 A1 page 4, lines 2 to 3, it is only referred to in one case, namely in the reaction of aniline-2-sulfonic acid with ethylene to give styrene-2-sulfonic acid (Example 6). However, as a comparison with Example 4 carried out using Pd(OAc)2 shows, the yield decreases significantly when a palladium-containing supported catalyst (10% Pd on charcoal) is used (Example 4: 87% yield; Example 7: 74% yield). In both examples, the reaction is carried out using a base which is used in excess based on aniline-2-sulfonic acid. As the experimental findings prove (see comparative trial in the experimental part), the procedure practised in the examples of EP-A 0 508 264 to prepare the aryldiazonium salts in situ and then to further process them, cannot generally be applied to preparation of a cinnamic ester by a palladium-containing supported catalyst. The comparative trial verifies that the desired cinnamic ester is not even formed in small amounts. These experimental findings do not let it be expected that palladium-containing supported catalysts are suitable for the preparation of the cinnamic acids and cinnamic esters according to the invention.
Reaction SMILES: S(=O)(=O)(O)O.[P:6]([CH2:10][N:11](CC(O)=O)[CH2:12][C:13]([OH:15])=[O:14])([OH:9])([OH:8])=[O:7]>O>[P:6]([CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])([OH:9])([OH:8])=[O:7]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a suitable reaction vessel was added 150 grams of 5% fuming sulfuric acid and the sulfuric acid heated to 90° C. To the fuming sulfuric acid was added over a one hour period 70 grams of N-(phosphonomethyl) imino-diacetic acid. The reaction mixture was heated at 100° C. for 2 hours at which time a nuclear magnetic resonance spectra indicated that no N-(phosphonomethyl) imino-diacetic acid starting material was present. Water (200 mls.) was added at a temperature of approximately 50° C. and then the reaction mixture vacuum distilled to 100° C. at 17 to 18 inches of mercury. The reaction mixture was then cooled to 30° C. and 375 mls. of 80% isopropanol was added. The isopropanol mixture was then chilled for 2 hours and filtered and the filter cake was washed with 80% isopropanol and 50 mls. of water and dried, yielding 35 grams of N-phosphonomethyl glycine of 93.5% purity. The filtrates and wash were combined and then stripped to 105° C. at 17 to 18 inches of mercury. The stripped material was cooled to 40° C. and 50% sodium hydroxide (235 grams) was added to the mixture to bring the pH to 2.45 at less than 60° C. This mixture was then distilled at atmospheric pressure to 105° C. The residue was cooled to 50° C. and methanol (200 mls.) was added and then the mixture was cooled to 10° C. The cooled mixture was stirred for one hour, filtered and the filter cake was washed with an additional 50 mls. of methanol. The residue was slurried in methanol (200 mls.), cooled to 15° C. and isopropylamine (7.0 grams) was added. This mixture was stirred for 1/2 hour, filtered and the residue was washed with methanol (100 mls.). The methanolic filtrates were combined and methanol was distilled off to a temperature of 70° C. To the residue was added 40 mls. of water and the residual methanol was then removed under vacuum until the pot residue temperature reached 75° C. There was obtained from this residue an additional 38 grams of N-phosphonomethyl glycine as an isopropylamine, salt solution having an assay of 33.8% N-phosphonomethyl glycine.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[N:17]\[S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])=[CH:12][CH:11]=1.[Cl-].[NH4+]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:2]([F:4])([F:3])[F:1])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
Add neat (trifluoromethyl)trimethylsilane (109 mL, 0.74 mol) to a stirred solution of tetrabutylammonium acetate (88 g, 0.29 mol) and (N—Z)—N-[(4-bromophenyl)methylene]-(R)-2-methyl-propane-2-sulfinamide (85 g, 0.29 mol) in DMF (1.2 L) at 0° C. Stir the mixture at 0-5° C. for 90 min Add a saturated aqueous ammonium chloride solution (1.2 L) and extract with EtOAc (4×400 mL). Combine the organic extracts; sequentially wash the extracts with water then brine (2×1 L); dry over MgSO4; filter; and concentrate the filtrate under reduced pressure. Triturate the residue with hexane (200 mL) for 10 min; filter; and dry under reduced pressure to afford the title compound as a yellow solid (81 g, 76% yield, >98 de). MS (m/z): 358 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.C(N(CC)CC)C.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1)[CH3:21]>C1COCC1.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: C#Cc1ccc(OCC)cc1
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1ccc(C#Cc2ccc(C(=O)OC)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
To methyl 4-bromo-2-fluorobenzoate (1.29 g, 5.54 mmol) in THF (10 mL)-triethylamine (5 mL) solvent were added 1-ethoxy-4-ethynylbenzene (1.24 mL, 8.30 mmol), copper(I) iodide (106 mg, 0.544 mmol) and bis(triphenylphosphine)palladium(II) chloride (195 mg, 0.277 mmol), and the mixture was stirred under an argon stream at room temperature for 15 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3 to 17:3) to give the title compound (1.38 g, yield 84%) as an oil.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3](OCC)=O.[H-].[Na+].BrC1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[N+:22]([O-])=O.C(OCC)(=O)C>CS(C)=O>[CH2:2]1[C:1](=[O:9])[NH:22][C:16]2[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:3]1=2
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(Br)cc2N1
Temperature: 0 °C
Yield: 85 %

Procedure:
Under ice cooling, diethyl malonate (500 g) was added dropwise into a suspension of sodium hydride (125 g) in dimethyl sulfoxide (800 ml). After the solution became homogeneous, the resultant mixture was heated to 100° C. and a solution of 2,5-dibromonitrobenzene (500 g) in dimethyl sulfoxide (400 ml) was added dropwise thereinto followed by stirring the resultant mixture at 100° C. for 5 hr. Then the reaction solution was diluted with ice water (2 l), mixed with ethyl acetate (8 l), and the layers were separated. The organic layer was washed successively with water (2 l) four times and brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was diluted with ethanol (2.5 l) followed by the addition of tin (380 g). Under ice cooling, conc. hydrochloric acid (1.5 l) was added dropwise into the reaction mixture. After the completion of the addition, the resultant mixture was heated under reflux for 3 hr and diluted with ice water (8 l). The resulting crystalline precipitates were collected by filtration, washed with water and hexane, and air dried at 50° C. for 24 hr to give the title compound (321 g) (yield: 84%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[C:17]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][CH:36]([N:39]5[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]5)[CH2:35][CH2:34]4)=[C:29]([CH3:46])[CH:28]=3)[C:18]([C:23]([NH2:25])=[O:24])=[N:19][C:20]=2[CH2:21][CH3:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C>[OH-].[Pd+2].[OH-].C(O)(=O)C>[CH2:21]([C:20]1[N:19]=[C:18]([C:23]([NH2:25])=[O:24])[C:17]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)=[C:29]([CH3:46])[CH:28]=2)=[N:16][C:15]=1[NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:22]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1NC1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1NC1CCNCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
To a mixture of 5-[(1-benzylpiperidin-4-yl)amino]-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (Example 507) (1.31 g), ethanol (26 mL) and acetic acid (13 mL), palladium hydroxide (0.65 g) was added and stirred under a hydrogen atmosphere at room temperature for 3 days. After the catalyst was separated by filtration, the solvent was concentrated and partitioned using chloroform and saturated aqueous sodium hydrogen carbonate. The organic layer was concentrated to give 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(piperidin-4-ylamino)pyrazine-2-carboxamide (0.73 g) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:19]([O:18][C:16]([N:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[CH3:9])[CH2:12][CH2:11]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Cl)ccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 20 %

Procedure:
2-Bromo-5-chlorotoluene (0.82 g, 4 mmol) and tert-Butyl 1-piperazine carboxylate (0.89 g, 2.32 mmol) were added to a solution of tri-t-butyl phosphine (0.033 g, 4 mmol %), tris(dibenzylideneacetone) dipalladium(0) (0.075 g, 2.0 mmol %) and cesium carbonate (1.95 g, 6.0 mmol) in toluene and heated to 80° C. overnight. The reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified on silica gel (gradient elution from 20% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound in 20% yield. ESI-MS m/z: 311 (M+1), UV retention time: 3.49 min.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[CH2:17]([S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[CH3:18]>>[CH2:17]([S:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:6]3=[N:7][C:8]([C:11]4[O:12][C:13]([CH3:16])=[N:14][N:15]=4)=[CH:9][CH:10]=[C:5]3[O:4][CH:3]=2)=[CH:22][CH:21]=1)[CH3:18]
Reactant: CCSc1ccc(B(O)O)cc1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Product: CCSc1ccc(-c2coc3ccc(-c4nnc(C)o4)nc23)cc1
Yield: 12 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[3,2-b]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole, using [4-(ethylthio)phenyl]boronic acid instead of (4-fluorophenyl)boronic acid, and using [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex instead of tetrakis(triphenylphosphine)palladium(0), the title compound (yield 12%) was obtained as colorless crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH3:21])([CH3:18])[CH2:13]1.[CH2:22](Br)[CH:23]=C>>[CH2:21]([O:20][CH2:19][C:14]1([CH3:18])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)[CH2:13]1)[CH:22]=[CH2:23]
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Reactant: C=CCBr
Product: C=CCOCC1(C)CCCN(CC2COc3ccccc3O2)C1

Procedure:
The procedure described above for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine was repeated except that allyl bromide was used instead of methyl iodide.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl.O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccc(Br)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1-(6-bromopyridin-2-yl)ethanone (2.9636 g, 14.82 mmol) in methanol (40 mL) at 0° C. was charged with sodium borohydride (1.682 g, 44.4 mmol) and then allowed to warm to room temperature. After 2.5 hours, the reaction mixture was diluted with dichloromethane (60 mL) and water (60 mL) and the layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield the title compound.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([OH:20])=O)=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:26][N:27]1[C:31]([NH2:32])=[CH:30][C:29]([CH3:33])=[N:28]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:32][C:31]4[N:27]([CH3:26])[N:28]=[C:29]([CH3:33])[CH:30]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2ccccc2Sc2ccc3nc(NC(=O)C4CC4)cn3n2)n(C)n1
Yield: 69.2 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (150 mg, 0.42 mmol), 1,3-dimethyl-1H-pyrazol-5-amine (130 mg, 1.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (130 mg, 70%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]2[CH:46]=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[N:38]=[C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]4[CH:46]=3)=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: Cc1cccc2nc(CCl)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5c(C)cccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Yield: 77 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 0.8 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.22 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 minutes upon which 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (218 mg, 1.2 mmol) was added. The mixture was heated at for 4 h (the reaction was monitored by TLC) upon which the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (280 mg, 77.7%,) as a light yellow solid. 1H NMR: 500 MHz, DMSO-d6: δ 7.95 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (d, 3H), 7.15 (d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.2 (s, 2H) 3.85 (s, 3H), 2.6 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=455.6. HPLC: (97.3%, Condition-A).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:16][C:15]=1[O:33][CH3:34].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]3)=[CH:16][C:15]=2[O:33][CH3:34])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
Zinc chloride (1.0 M in Et2O) (8.56 mL, 8.56 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.06 mL, 7.85 mmol) in 1:1 DCE/t-BuOH (10 mL) at 0° C. under nitrogen. The mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate (I26) (1.97 g, 7.13 mmol) in 1:1 DCE/tBuOH (30 mL) was added. A solution of triethylamine (600 μL, 0.432 mmol, 1.1 eq) in 1:1 DCE/t-BuOH (10 mL) was next added drop-wise at 0° C. The reaction mixture was vigorously stirred for a further 30 minutes at 0° C. after the final addition and then at room temperature for 24 hours. The solvent was removed in vacuo to afford a brown oily residue which was purified by column chromatography on silica gel (0-45% EtOAc in petroleum benzine 40-60° C.) to give a pale yellow oil which solidified upon standing. This was triturated sequentially with water, 1:1 water/MeOH and MeOH and the precipitate was filtered to afford a white solid. The solid was recrystallised from water to give the title compound (I34) (0.92 g, 30%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 6.86 (dd, J=8.4, 1.7 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.25 (s, 2H), 3.91 (s, 3H), 2.81 (t, J=11.8 Hz, 2H), 2.64 (tt, J=12.1, 3.6 Hz, 1H), 1.83 (d, J=13.5 Hz, 2H), 1.69-1.57 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 7.00 min; m/z=487.0 [M+H]+, 431.0 [M-tButyl+H]+, 485.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH2:15][OH:16])[C:13](=[O:17])[C:12]([CH3:19])([CH3:18])[C:11]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH2:15][OH:16])[C@H:13]([OH:17])[C:12]([CH3:18])([CH3:19])[C:11]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)C(=O)C(CO)N(c2ccc(C#N)c(Cl)c2)C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(Cl)c2)[C@H](CO)[C@@H]1O

Procedure:
Using 2-chloro-4-[5-(hydroxymethyl)-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl]benzonitrile (80 mg) and lithium tri(sec-butyl)borohydride-THF solution (0.82 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as colorless crystals (yield: 45.4 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[C:34]([C:35](O)=[O:36])=[CH:33][C:32]2[CH:38]=[CH:39][CH:40]=[CH:41][C:31]1=2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:34]4[S:30][C:31]5[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=5[CH:33]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1cc2ccccc2s1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc3ccccc3s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and benzo[b]thiophene-2-carboxylic acid (27 mg, 0.15 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:9]([Br:28])[CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]1([CH3:42])[CH:34]=[CH:33][C:32]([N:35]([CH2:39][CH2:40]O)[CH2:36][CH2:37]O)=[CH:31][CH:30]=1>>[Br:28][C:9]1[CH:8]=[C:7]([CH2:6][C@H:2]([N:1]2[CH2:40][CH2:39][N:35]([C:32]3[CH:31]=[CH:30][C:29]([CH3:42])=[CH:34][CH:33]=3)[CH2:36][CH2:37]2)[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1Br
Reactant: Cc1ccc(N(CCO)CCO)cc1
Product: Cc1ccc(N2CCN([C@@H](Cc3ccc(OCCc4nc(-c5ccccc5)oc4C)c(Br)c3)C(=O)O)CC2)cc1
Yield: 24 %

Procedure:
Following the procedures described in Example 1, Intermediate 3B was used in place of Intermediate 3A, and 2,2′-(p-tolylazanediyl)diethanol was used in place of 2,2′-(m-tolylazanediyl)diethanol to give (2S)-3-{3-bromo-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-p-tolyl-piperazin-1-yl)-propionic acid as a white solid with the yield of 24% and mp of 203-205° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH2:6][C:7]1[CH:31]=[CH:30][C:10]([N:11]([C:21](=[O:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=[C:9]([CH2:32][CH3:33])[CH:8]=1)(=[O:3])[CH3:2].[C:40]1([C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N+]=[N-])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CC(C)=O>[C:1]([NH:4][CH:5]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH2:6][C:7]1[CH:31]=[CH:30][C:10]([N:11]([C:21](=[O:29])[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([O:16][CH:46]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:15])=[C:9]([CH2:32][CH3:33])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)C(Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)O)c(CC)c1)NC(C)=O
Solvent: CC(C)=O
Product: C=CCOC(=O)C(Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)c(CC)c1)NC(C)=O

Procedure:
To 2-{4-[2-(acetylamino)-3-(allyloxy)-3-oxopropyl][tert-butoxy(oxo)acetyl]-2-ethylanilino}benzoic acid in acetone was added diphenyldiazomethane (until all starting material was consumed as evident by monitoring via TLC). The reaction mixture was concentrated under reduced pressure, purified on silica gel using ethyl acetate as eluent to provide the titled compound. MS (ESI(+)) m/e 705 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.51-8.01 (m, 2H), 7.73-6.86 (m, 16H), 5.93-5.78 (m, 1H), 5.34-5.10 (m, 2H), 4.57-4.40 (m, 3H), 3.10-2.84 (m, 2H), 2.58-2.42 (m, 2H), 1.82-1.77 (m, 3H), 1.22-0.78 (m, 3H), 1.07, 1.05, 1.00 (s, s, s, 9H).