Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH:17]=[CH2:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](Cl)=[O:14])=O.C(N(CC)CC)C.[C:28]([CH:33]([CH:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[OH:36])[OH:34])([O:30][CH2:31][CH3:32])=[O:29]>CCOCC>[CH2:16]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:36][CH:35]([CH:33]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[OH:34])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:14])[CH:17]=[CH2:18]
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: C=CCN(C(=O)C(F)(F)F)c1ccccc1CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCNc1ccccc1CC(=O)OC(C(=O)OCC)C(O)C(=O)OCC

Procedure:
A mixture of 2-[N-trifluoroacetyl-(allylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl O-[2-(allylamino)phenylacetyl]tartrate as a white, crystalline solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1C=CC=CC=1)C(O)=O)=O)(C)(C)C.[C:20]([O:24][C:25]([NH:27][C@H:28]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@H:40]2COC(C)(C)[O:41]2)=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].N1(C(=O)CCl)CCC1>>[N:8]1([C:40](=[O:41])[CH2:39][O:38][C:35]2[CH:36]=[CH:37][C:32]([C@@H:28]([NH:27][C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:26])[C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[CH2:9][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C(CCl)N1CCC1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCC(=O)N2CCC2)cc1

Procedure:
Prepared by the same method as described in example 1 except that (i) 4-iodoaniline was used in place of 4-bromoaniline in step 2 and (ii) (R)-[4-(2-azetidin-1-yl-2-oxo-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid was used in place of (R)-tert-butyloxycarbonylamino-4-methoxyphenylglycine. (R)-[4-(2-Azetidin-1-yl-2-oxo-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid was prepared by a method similar to that used for the preparation of (R)-tert-butyloxycarbonylamino-4-methoxyphenylglycine in example 1 except that 1-azetidin-1-yl-2-chloro-ethanone was used in place of iodomethane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=3[CH3:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C1C=CC=CN=1)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=3[CH3:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=S)c1cc(-c2nc(-c3ccc(N)cc3)cs2)c(C)s1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=S)c1cc(-c2nc(-c3ccc(NS(C)(=O)=O)cc3)cs2)c(C)s1
Temperature: 25 °C
Reaction time: 192 h
Yield: 66.4 %

Procedure:
Methyl 4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (200 mg, 0.55 mmol) was dissolved in dry dichloromethane (20 mL). To this, N-methyl morpholine (150 μL, 1.38 mmol) and dimethylaminopyridine (6.1 mg, 0.055 mmol) were added, the mixture was cooled on an ice bath, and methanesulfonyl chloride (43 μL, 0.55 mmol) was added dropwise. The mixture was then stirred for 8 days at room temperature. The mixture was partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (20 mL). The aqueous layer was extracted with dichloromethane (3×20 mL), and the combined organic layers were washed with saturated sodium bicarbonate (20 mL), brine (2×20 mL), and dried over anhydrous sodium sulfate. The solvent was remove in vacuo. Column chromatrography on silica gel (100 g) eluting with dichloromethane:methanol 99/1 (v:v), gave methyl 4-(4-{4-[(methylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (155 mg, 64%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ9.92 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 8.40 and 6.90 (AB quartet, 2H, J=8.7 Hz), 3.87 (s, 3H), 3.05 (s, 3H), 2.76 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix m/z): Calcd. for C17H16N2O4S4441.0 (M+H), found 441.2.
Reaction SMILES: Br[CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:3](=[O:21])[O:4][C@H:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][C:7]([O-:9])=O.C([Mg]Cl)(C)(C)C>>[CH2:22]([C:2]1[C:3](=[O:21])[O:4][C@H:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][C:7]=1[OH:9])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCC[C@H](CC(=O)[O-])OC(=O)C(Br)CCCCCC
Agent: CC(C)(C)[Mg]Cl
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Yield: 78 %

Procedure:
To improve the yield of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one, U.S. Pat. Nos. 5,274,143 and 5,420,305 disclose a method involving intramolecular cyclization of (R)-3-[2-bromo-1-oxooctyloxy]-tetradecanoate in the presence of zinc to produce (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one in a yield of 61 to 67%, while U.S. Pat. No. 6,545,165 describes intramolecular cyclization of (R)-3-[2-bromo-1-oxooctyloxy]-tetradecanoate in the presence of tert-butyl magnesium chloride to produce (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one in a yield of 78%.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH:6][C:7]([C:9]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=1)=[O:8])[CH2:4][CH3:5].[C@H:23]12[CH2:29][C@H:26]([CH2:27][CH2:28]1)[CH2:25][C:24]2=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:23]12[CH2:29][CH:26]([CH2:27][CH2:28]1)[CH2:25][CH:24]2[N:14]1[CH2:13][CH2:12][C:11]2([C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]([C:7]([NH:6][CH:3]([CH2:2][CH3:1])[CH2:4][CH3:5])=[O:8])=[CH:10]2)[CH2:16][CH2:15]1
Reactant: O=C1C[C@H]2CC[C@@H]1C2
Reactant: CCC(CC)NC(=O)C1=CC2(CCNCC2)c2ccccc21
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: CC(Cl)Cl
Product: CCC(CC)NC(=O)C1=CC2(CCN(C3CC4CCC3C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (F2) (0.020 g, 0.05 mmol), titanium (IV) isopropoxide (0.045 mL, 0.15 mmol) and (1R,4S)-bicyclo[2.2.1]heptan-2-one (3 eq) was stirred at room temperature for 18 h in dichloroethane (0.5 mL). Sodium triacetoxyborohydride (0.011 g, 0.050 mmol) was added and the mixture stirred at room temperature for 1 h. The solvent was evaporated and 6N NaOH (0.5 mL) and methanol (1 mL) was added and then triturated to give a white solid that was washed with methanol (1 mL) and EtOAc (1 mL). The filtrate was concentrated under reduced pressure to afford the crude product which was purified by reverse phase preparative HPLC to afford 1′-(bicyclo[2.2.1]heptan-2-yl)-N-(pentan-3-yl)spiro[indene-1,4′-piperidine]-3-carboxamide (Compound No. 14) (0.013 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 324.1 (M+1), retention time 2.2 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](CNCCN)[N:2]=1.[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:16][CH2:15][CH2:14][N:13]([C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:12])=[S:18]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1cccnn1
Product: CN(C)CCNC(=S)NCCN(C)c1cccnn1

Procedure:
Reacting N-(3-pyridazinylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4][NH2:5].[NH2:14][C:15](N)=[O:16].Cl>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH2:4][NH:5][C:15]([NH2:14])=[O:16]
Reactant: NCc1c(F)cccc1C(F)(F)F
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Product: NC(=O)NCc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To 2-fluoro-6-(trifluoromethyl)benzylamine 1a (51.5 g, 0.267 mmol) in a flask, urea (64 g, 1.07 mmol), HCl (conc., 30.9 mmol, 0.374 mmol) and water (111 mL) were added. The mixture was refluxed for 6 hours. The mixture was cooled to ambient temperature, further cooled with ice and filtered to give a yellow solid. Recrystallization with 400 mL of EtOAc gave 1b as a white solid (46.2 g, 0.196 mmol). MS (CI) m/z 237.0 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.C([CH:22]1[CH2:25][NH:24][C:23]1=[O:26])(=O)C1C=CC=CC=1>CCCCCC.C1COCC1>[C:3]1([C:1]#[C:2][CH:22]2[CH2:25][NH:24][C:23]2=[O:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NCC1C(=O)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NCC1C#Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 500 mL, three necked round bottomed flash with a stirring bar, low temperature thermometer, argon inlet and a septum was added dry THF (100 mL) and ethynylbenzene (60 mmol, 6.1 mL). This solution was cooled to -78° C. and n-butyllithium (60 mmol, 24 mL of a 2.5M solution in hexane) was added with a syringe at such a rate that the temperature was maintained below -50° C. When the addition was complete, the solution was aged 30 min then a solution of 3(R,S)-benzoylazetidinone (15 mmol, 2.87 g) in THF (50 mL) was added slowly with a syringe, maintaining the temperature below -60° C. The resulting solution was aged 1 h at -78° C. then warmed to 0°C. The reaction was quenched at 0°C. by addition of saturated, aqueous NH4Cl solution. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with H2O and brine. Drying (MgSO4), filtration and removal of the solvents in vacuo gave 3(R,S)-phenylethynylazetidinone (15-2) as a crystalline solid, which was used in Step B without further purification. ##STR139##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][Si](C(C)C)(C(C)C)C(C)C)=[CH:12][C:11]=1[O:27][CH2:28][O:29][CH3:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[O:27][CH2:28][O:29][CH3:30]
Reactant: COCOc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1-c1cc(OC)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COCOc1cc(O)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
To a solution of ((2′-fluoro-5′-methoxy-2-(methoxymethoxy)biphenyl-4-yl)oxy)(triisopropyl)silane (3.50 g) in THF (30 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in THF (16 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.30 g) as a colorless oil.
Reaction SMILES: C([S:4][C@H:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH2:8][O:7][CH2:6]1)(=O)C.Cl.C(O)C.C(=O)([O-])O.[Na+]>C(O)C>[SH:4][C@H:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH2:8][O:7][CH2:6]1
Reactant: CCOC(=O)C1=CCOC[C@H]1SC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=CCOC[C@H]1S
Temperature: 25 °C
Reaction time: 40 h
Yield: 91 %

Procedure:
To a solution (100 mL) of ethyl (3S)-3-(acetylsulfanyl)-3,6-dihydro-2H-pyran-4-carboxylate (19.5 g) in ethanol was added dropwise hydrochloric acid-ethanol solution (24% w/w, 100 mL) at 0° C. The reaction mixture was stirred at room temperature for 40 hr, and cooled to 0° C. Saturated aqueous sodium hydrogen carbonate solution (750 mL) was added dropwise. The reaction mixture was maintained at 10° C. or lower, and the final pH was adjusted to 7 to 8. After extraction with ethyl acetate (500 mL×2), the extract was washed with water (300 mL×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=5:1) to give the title compound (14.5 g, 91%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1)#[CH:2].I[C:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:25]=2[N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[N:20]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[N:19]=1.O.C(OCC)(=O)C>C1COCC1.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>[CH3:54][O:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][N:20]2[C:21]3=[N:22][CH:23]=[C:24]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:25]([N:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29][CH2:28]4)=[C:26]3[C:18]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]([CH2:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)[CH:7]=3)=[N:19]2)=[CH:48][CH:49]=1
Reactant: C#Cc1cnn(Cc2ccc(OC)cc2)c1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C#Cc3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)cn2)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 118 %

Procedure:
4-Ethynyl-1-(4-methoxybenzyl)-1H-pyrazole (0.068 g, 0.32 mmol) was added to a solution of tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.10 g, 0.16 mmol), Cu(I)I (0.0015 g, 0.008 mmol), PdCl2(PPh3)2 (0.0056 g, 0.008 mmol) and TEA (0.11 ml, 0.80 mmol) in THF (10 mL) and stirred at 40° C. for 18 hours. Water (10 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography (hexane:ethyl acetate=5:1) to give tert-butyl 4-(1-(4-methoxybenzyl)-3-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethynyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.134 g, 95%) as a solid. LCMS (APCI+) m/z 710 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6].C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].[OH-].[Na+]>O.CC(C)=O>[C:24]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6])(=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)Cl
Reactant: Nc1cccc(C(=O)Nc2ccccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)c1cccc(C(=O)Nc2ccccn2)c1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a mixture of 2-aminopyridine (28.2 g), triethylamine (45 ml) and acetone (600 ml), 3-nitrobenzoyl chloride (55.8 g) was gradually added with stirring under ice cooling. The mixture was stirred for 30 minutes under the same condition, then for one hour at room temperature. Thereafter, the reaction solution was poured into 3 liters of water, and the resulting crystal was collected by filtration, washed with water, and recrystallized from methanol to provide 58.5 g of 3-nitro-N-2-pyridylbenzamide as a colorless acicular crystal (yield: 80%, m.p. 156°-157° C.). Hydrogen was bubbled into a mixture of the 3-nitro-N-2-pyridylbenzamide (15.9 g), 10% palladium-carbon (1.5 g) and ethanol (300 ml). After a stoichiometric amount of hydrogen was absorbed, the catalyst was removed, the reaction mixture was concentrated under vacuum, and the residue was recrystallized from ethanol to provide 7.2 g of a colorless acicular crystal of 3-amino-N-2-pyridylbenzamide (yield: 52%, m.p. 113°-115° C.). To a mixture of the 3-amino-N-2-pyridylbenzamide (6.4 g), triethylamine (4.5 ml) and acetone (60 ml), propionic acid chloride (2.8 g) was gradually added with stirring at room temperature. After one hour of stirring, the reaction mixture was poured into 200 ml of water which was then made weakly alkaline by gradually adding a 10% solution of sodium hydroxide. The resulting crystal was collected by filtration, washed with water and recrystallized from methanol to provide 7.0 g of 3-propionyl-N-2-pyridylbenzamide as a colorless acicular crystal (compound 1) (yield: 87%, m.p. 128°-129° C.).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[NH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:17]1([C:23]2[S:27][C:26](B(O)O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>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.O>[NH2:1][CH:2]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:26]3[S:27][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)[CH:14]=2)[NH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(Cc1c[nH]c2ccc(Br)cc12)C(=O)O
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(Cc1c[nH]c2ccc(-c3ccc(-c4ccccc4)s3)cc12)C(=O)O
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 19.4 %

Procedure:
2-Amino-3-(5-bromo-1H-indol-3-yl)-propionic acid (0.020 g, 0.071 mmol) was added to a 5 ml microwave vial, which contained 5-phenyl-thiophen-2-boronic acid (0.016 g, 0.078 mmol), Na2CO3 (0.015 g, 0.142 mmol), acetonitrile (1.5 ml)/water (1.5 ml) and dichlorobis(triphenylphosphine)-palladium (3 mg, 0.003 mmol). Microwave vial was capped and stirred at 150° C. for 5 min under microwave radiation. Reaction mixture was cooled, filtered through a syringe filter and then separated by a reverse phase preparative-HPLC using YMC-Pack ODS 100×30 mm ID column (MeOH/H2O/TFA solvent system). The pure fractions were concentrated in vacuum. The product was then suspended in 5 ml of water, frozen and lyophilized to give 5 mg of pure product, 2-amino-3-[5-(5-phenyl-thiophen-2-yl)-1H-indol-3-yl]-propionic acid. 1H-NMR (300 MHz, CD3OD): 3.21-3.26 (m, 2H), 4.25 (q, 1H), 7.15-7.35 (m, 8H), 7.58 (d, 2H), 7.82 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:36](=[O:37])[C:30]3[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=3)[C:39]2=[O:38])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3cc(F)cc(F)c3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3cc(F)cc(F)c3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(3,5-difluorophenyl)benzoxazole (70 mg, 0.20 mmol) and 1,2,4-benzenetricarboxylic anhydride (38 mg, 0.20 mmol) the title compound was obtained (72 mg, 68%). 1H NMR (DMSO) δ 13.79(s, 1H), 8.42(dd, 1H), 8.33(s, 1H), 8.23(d, 1H), 8.21(d, 1H), 8.10(d, 1H), 7.90(d, 1H), 7.83(dd, 1H), 7.72(dd, 1H), 7.56(m, 2H), 7.48(d, 1H), 7.26(m, 1H), 4.03(s, 3H). MS 527.3 m/z (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]([O:24][C:25](=[O:40])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C:34]3=[O:39])=[CH:29][CH:28]=2)[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)=[O:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+]>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:24][C:25](=[O:40])[N:26]([C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C:34]4=[O:39])=[CH:31][CH:32]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CNC(=O)c2ccc(Cl)s2)OC(=O)Nc2ccc(N3CCOCC3=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Under an atmosphere of nitrogen a suspension of 1.00 g of toluene-4-sulfonic acid (S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyloxy]-propyl ester (MW=608.09; 1 eq.) in 25 mL tetrahydrofuran was cooled to 0° C. At this temperature 1.6 mL of a 1M solution of lithium t-butoxide in tetrahydrofuran were added dropwise. After stirring at this temperature for 1 hour the resulting slurry was filtered. The cake was rinsed with 14 mL of tetrahydrofuran and 14 mL of water. The wet product was dried at 30° C. in vacuo to yield 0.63 g (MW=435.89; 1.013 eq.) of the title compound (88.5% of theory).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1coc(N2CC(O)C2)n1
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (810 mg, 1.21 mmol) (obtained as described in Reference Example 77(1)) in anhydrous tetrahydrofuran (40 ml) was added a solution of acetic acid (83 μl, 1.45 mmol) and 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (1.45 ml, 1.45 mmol) in an ice bath and the mixture was stirred in an ice bath overnight. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (95:5) as the eluant to afford 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (507 mg, yield 97%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1COCC1>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:16]#[N:17])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 110 °C
Reaction time: 21 h
Yield: 84 %

Procedure:
Under an inert atmosphere a flask is charged with [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethylamine (Example 3) (1.0 g, 3.74 mmol), zinc cyanide (0.235 g, 2 mmol), Pd2(dba)3xCHCl3 (0.194 mg, 5 mol %), dppf (bis-diphenylphosphino ferrocene) (0.207 g, 0.374 mmol, 10 mol %), and DMF (12 mL). The orange slurry is heated to 110° C. and stirred for 21 hours. To the black suspension which has formed, THF (100 mL) is added, and this is extracted with 1 N NaOH (100 mL). The organic layer is washed with water twice (50 mL each), dried and removal of the solvent gives the title product (0.67 g, 84%) as brown solid.