Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1C=CC=C2C=1C(=O)N(C1C=CC=CC=1)C([C@@H](NC1N=CN=C3C=1N=CN3)CC)=N2.[N+:32]([C:35]1[CH:43]=[CH:42][C:41](C)=[CH:40][C:36]=1[C:37]([OH:39])=O)([O-:34])=[O:33].FC1C=CC=C([N+]([O-])=O)C=1C(O)=O.[F:58][C:59]1[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[C:60]=1[NH2:61].NC1C=CC=CC=1>>[F:58][C:59]1[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[C:60]=1[NH:61][C:37](=[O:39])[C:36]1[C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:2]
Reactant: Nc1c(F)cccc1F
Reactant: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Solvent: Nc1ccccc1
Product: Cc1cccc([N+](=O)[O-])c1C(=O)Nc1c(F)cccc1F

Procedure:
Compound 118a was prepared following the preparation procedure described above with respect to compound 107, but 2-nitro-5-methylbenzoic acid was substituted for 2-fluoro-6-nitrobenzoic acid and 2,6-difluoroaniline was substituted for aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:44][C:45]1[S:46][C:47]([CH3:51])=[C:48]([CH3:50])[N:49]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:44][C:45]2[S:46][C:47]([CH3:51])=[C:48]([CH3:50])[N:49]=2)=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Cc1nc(N)sc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4nc(C)c(C)s4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 138.8 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (84 mg) was dissolved in chloroform (2.5 ml) and triethylamine (0.50 ml) to prepare a solution. A solution of triphosgene (38 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 2-amino-4,5-dimethylthiazole hydrochloride (42 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated and was evaporated to dryness. Diethyl ether was then added to the solid, and the solid was collected by filtration. Further, the collected solid was washed with methyl alcohol to give the title compound (86.4 mg, yield 68%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12](O)=O.C1CCC(N=C=NC2CCCCC2)CC1.[N:30]1[C:34]2[CH:35]=[CH:36][C:37]([C:39]([NH:41][NH2:42])=O)=[CH:38][C:33]=2[NH:32][CH:31]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:52])=CC=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]1[S:52][C:39]([C:37]2[CH:36]=[CH:35][C:34]3[NH:30][CH:31]=[N:32][C:33]=3[CH:38]=2)=[N:41][N:42]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1cccc(CCC(=O)O)c1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1cccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)c1Cl

Procedure:
The compound was synthesized starting from 3-(2-Chlor-3-methoxyphenyl)propionic acid (215 mg; 1 mmol), DCC (206 mg; 1 mmol), Benzimidazol-5-carbohydrazide (176 mg; 1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 2; yield: 0.015 g (4.1%); MS m/z: 371.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.20-3.24 (m, 2H); 3.42-3.46 (m, 2H); 3.84 (s, 3H); 6.98-7.04 (m, 2H); 7.22-7.26 (m, 1H); 7.78-7.80 (m, 1H); 7.86-7.89 (m, 1H); 8.20 (br s, 1H); 8.72 (s, 1H); HPLC (METHOD [A]): rt 13.13 min (97.8%)
Reaction SMILES: [CH2:1]([S:3]([C@@H:6]1[N:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:13])[C@H:7]1[CH2:14][CH2:15][CH2:16][N:17](C(OCC1C=CC=CC=1)=O)[C:18]([NH:20]C(OCC1C=CC=CC=1)=O)=[NH:19])(=[O:5])=[O:4])[CH3:2].[ClH:41]>[Pd].CO.C(OCC)(=O)C>[ClH:41].[CH2:1]([S:3]([C@@H:6]1[N:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:13])[C@H:7]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)[C@H]1[C@H](CCCN(C(=N)NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCS(=O)(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 62 %

Procedure:
A methanol/ethyl acetate (2.5 mL/2.5 mL) solution of compound 22 (380 mg, 0.66 mmol) and 1N HCl (0.66 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material. The suspension was filtered through a pad of Celite, and the solution was concentrated to afford 140 mg (62%) of the product as a yellow foam.
Reaction SMILES: C(OC(C)C)(=O)C.[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:18][C:17](=[CH2:33])[C:16]1=[O:34])=[O:14])([CH3:11])([CH3:10])[CH3:9].[H][H]>[Pt]>[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH2:18][C@@H:17]([CH3:33])[C:16]1=[O:34])=[O:14])([CH3:11])([CH3:9])[CH3:10].[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH2:18][C@H:17]([CH3:33])[C:16]1=[O:34])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: [H][H]
Reactant: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Agent: [Pt]
Solvent: CC(=O)OC(C)C
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Isopropyl acetate (1 ml) is added to a mixture of 100 mg (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) and 10% platinum on carbon (10 mg). Hydrogen gas (ambient pressure) is applied to the mixture. The mixture is stirred at ambient temperature and pressure for 4 h. The mixture is then filtered over Celites and washed with isopropyl acetate (2×0.5 ml). The mixture is then concentrated in vacuo to give (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 33:67 (3-a, R1=Boc: 3-b, R1=Boc) as determined by hplc. Spectroscopic data in described in WO/2008/083967, for example, Examples 14 and 18.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=2[O:23]C)[CH:12]=[CH:13][CH:14]=1)(C)(C)C.[N:26]([Sn](CCCC)(CCCC)CCCC)=[N+:27]=[N-:28].C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16]([OH:23])=[CH:17][CH:18]=[C:19]([C:21]3[NH:22][N:28]=[N:27][N:26]=3)[CH:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccc(C#N)cc1-c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NCc1cccc(-c2cc(-c3nnn[nH]3)ccc2O)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
tert-Butyl(5′-cyano-2′-methoxy-biphenyl-3-yl-methyl)-carbamate (0.73 g, 2.16 mmol), prepared as in Reference 19, and azidotributyltin (0.9 mL, 3.2 mmol) was dissolved in toluene (5 mL) and the solution was refluxed for 14 hours. The mixture cooled to room temperature and then workup with ethyl acetate and 1N HCl gave a slurry. The slurry was dried by rotovap and then triturated with hexanes. The solids were collected by filtration and treated with hydrobromic acid (48% aqueous, 15 mL). The mixture was refluxed for 14 hours at 120° C. and then diluted with water (50 mL). The dilution was dried by lyophilization to give 3′-aminomethyl-5-(1H-tetrazol-5-yl)-biphenyl-2-ol (0.4 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35]OS(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O.[NH3:42]>CO>[NH2:42][CH2:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Reactant: N
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CN)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 9 h
Yield: 41 %

Procedure:
400 mg (0.687 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one was dissolved in 50 mL of an about 6N solution of ammonia in methanol and the solution was stirred at room temperature for 9 hours. Water was added to the reaction solution and the mixture was extracted twice with chloroform. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 142 mg of 7-aminomethyl-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 41%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3[C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:19][CH:18]=2)[CH:7]=[CH:8][CH:9]=1)#[N:3]>[N+](C)([O-])=O>[C:2]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3[C:17]2[CH:29]=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[CH:7]=[CH:8][CH:9]=1)#[N:3]
Reactant: CC(C)(C)OC(=O)c1ccc(N2C[C@@H]3C[C@H]2CN3c2cccc(C#N)c2)cc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: N#Cc1cccc(N2C[C@@H]3C[C@H]2CN3c2ccc(C(=O)O)cc2)c1
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To a saturated mixture of HCl (gas) and nitromethane (25 mL) was added title compound 247 (0.85 g, 2.264 mmol). The clear solution was stirred 2 h then concentrated. The beige residue was triturated with ether overnight and filtered to afford title compound 248 (315 mg, 39%) as a beige solid. LRMS (ESI): (calc.) 319.13. (found) 320.3 (MH)+.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[CH2:11][CH:10]2[CH:7]([C:8](=[O:12])[CH2:9]2)[CH:6]1[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH3:3].S(Cl)(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([S:4][C:5]1[CH2:11][CH:10]2[CH:7]([C:8](=[O:12])[CH2:9]2)[C:6]=1[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH3:3]
Reactant: CCCSC1CC2CC(=O)C2C1C(=O)OC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSC1=C(C(=O)OC)C2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 33 mg of crude methyl 3-(1-propylthio)-7-oxobicyclo[3.2.0]heptan-2-carboxylate, prepared by the procedure of Paragraph A, in 2 mL of methylene chloride at -40° under argon was added 24 mg of sulfuryl chloride. This solution was stirred for 15 min at -40° and then cooled to -70°. Triethylamine was added until the solution was basic to pH paper, and the solution was allowed to warm slowly to room temperature. The reaction mixture was partitioned between methylene chloride and brine, and the organic layer was dried over sodium sulfate and concentrated to dryness. The crude product was purified by preparative thin layer chromatography on three 20×10×0.05 cm silica gel plates, eluting with ether-petroleum ether (1:1), to afford after crystallization from ether 7.5 mg (23%) of methyl 3-(1-propylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylate: NMR (220 MHz; CDCl3): δ 1.05 (3 H, t, J=7), 1.68 (2H, m), 2.87 (2H, t, J=7), 2.9-3.0 (3H, m), 3.3-3.45 (2H, m), 3.78 (3H, s), and 4.51 (1H, m); HRMS: Calcd for C12H16O3S, 240.0819; found, 240.0807.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])(C)(C)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31](C(O)=O)=[C:30]([O:38][CH3:39])[CH:29]=1>>[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:11]2)=[O:7])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCNC(=O)c2ccccc2)C1

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) as starting compound was reacted and treated in the same manner as in Example 1 using benzoyl chloride (0.47 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.83 g) to give 4 -amino-N-(1-(2-benzoylaminoethyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=O)[CH:6]=[C:5]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:4]=[CH:3]1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([C:5]2[CH:6]=[C:7]3[C:2](=[CH:3][CH:4]=2)[NH:1][C:33](=[O:35])[CH:34]=[C:8]3[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=[O:25])=[CH:23][CH:22]=1
Reactant: NC1C=CC(C(=O)c2ccc(Cl)cc2)=CC1C(=O)c1cccc(I)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(I)c3)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
[6-Amino-3-(4-chloro-benzoyl)-cyclohexa-2,4-dienyl]-(3-iodo-phenyl)-methan-one (60 g, 130 mMol) was dissolved in anhydrous toluene (450 mL) under an atmosphere of dry N2. To this solution was added 180 mL of triethylamine (NEt3), 50 mL of acetic anhydride (Ac2O) and 1.60 g (13.0 mMol) of 4-dimethylaminopyridine (DMAP). The reaction mixture was then heated to reflux and stirred at this temperature for 20 hours. The reaction mixture was cooled to ambient temperature and the precipitate was collected via suction filtration. The solid was washed with ethyl ether (Et2O) and dried under vacuum to give of the titled compound (63 g) which was used without further purification.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[O-]CC.[Na+].[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18]>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:22]([OH:23])=[C:16]([CH3:15])[C:17](=[O:18])[NH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: NNc1cccc(Br)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)n(-c2cccc(Br)c2)[nH]c1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
To a suspension of 1-(3-bromophenyl)hydrazine hydrochloride (1.0 g, 4.47 mmol) in ethanol (8.9 mL) was added dropwise 2.0 M sodium ethoxide in ethanol (0.77 mL, 9.84 mmol, 2.2 eq.). Diethyl 2-methylmalonate (0.85 mL, 4.92 mmol, 1.1 eq.) was then added. The reaction mixture was stirred at 90° C. for 16 hours and then quenched with 2 N aqueous hydrochloric acid (50 mL). The reaction was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure. Purification using MPLC (Biotage) eluted with 3:1 v/v ethyl acetate-hexane gave the desired product as a white solid (125 mg, 0.46 mmol, 10.4% yield). MS LC-MS (ES MH+=269/271); TLC (Rf=0.10, 50% ethyl acetate-hexane).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].[Br:24][C:25]1[CH:26]=[C:27]([CH2:32][OH:33])[CH:28]=[C:29]([F:31])[CH:30]=1.O>CN(C)C=O>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:32][O:33][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(F)cc(Br)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cc(F)cc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
Imidazole (3.3 g) and tert-butyl-diphenylchlorosilane (10.0 g) were added to a solution of (3-bromo-5-fluorophenyl)methanol (5.0 g) in dimethylformamide (50 ml), and the mixture was stirred over night at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [(3-bromo-5-fluorobenzyl)oxy](tert-butyl)diphenylsilane (9.5 g).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[S:16])=[CH:13][CH:12]=1>CCO>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]2[S:16][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:1][N:17]=2)=[CH:13][CH:12]=1
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: -20 °C
Yield: 23 %

Procedure:
A solution of ethyl formylchloroacetate (1.45 g, 9.6 mmol; obtained according to Panizzi, L. Gazz. Chim.Ital., 1946, 76, 56) and 4-chlorothiobenzamide (1.76 g, 9.6 mmol) in EtOH (50 mL) was refluxed for 48 h. The reaction mixture was then cooled to -20° C. and the solid formed was filtered and dried to give ethyl 2-(4-chlorophenyl)thiazole-5-carboxylate (0.59 g, 23%): mp 144°-145° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.40 (s, 1H, thiazole), 7.92 (dt, Jt =1.8, Jd =8.6, 2H, arom), 7.44 (dt, Jt =1.8, Jd =8.6, 2H, arom), 4.39 (q, J=7, 2H, OCH2), 1.40 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H10ClNO2S: C 53.84; H 3.76; N 5.23; S 11.97. Found: C 54.22; H 3.52; N 5.25; S 11.46.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:2][CH:3]([CH3:18])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1)=[O:26]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCc1ccc(CC(C)N)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NC(C)Cc1ccc(CCC(=O)O)cc1

Procedure:
By the reaction of ethyl β-[4-(2-aminopropyl)-phenyl]-propionate hydrochloride (m.p. 115°-117° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained β-{4-[2-(5-chloro-2-methoxybenzamido)-propyl]-phenyl}-propionic acid; m.p. 125°-126° C., after recrystallization from isopropanol/water.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][CH3:25])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3].[CH3:26][S:27](Cl)(=[O:29])=[O:28].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][CH3:25])=[CH:12][CH:13]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(N)ccc32)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(NS(C)(=O)=O)ccc32)cc1
Reaction time: 6 h
Yield: 88 %

Procedure:
To a stirred solution of 2-[4-(5-amino-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step 4, 1.18 g, 3.50 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.40 mL, 5.25 mmol) and pyridine (0.42 mL, 5.25 mmol) at room temperature. After stirring for 6 h, the mixture was poured into 10% aqueous citric acid (100 mL) and extracted with ethyl acetate (100 mL). The aqueous layer was made basic with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL) and dried (MgSO4), and concentrated to afford 1.28 g (88%) of the title compound as brown amorphous: 1H-NMR (CDCl3) δ 8.47 (1H, s), 7.66 (1H, d, J=1.7 Hz), 7.50 (2H, d, J=8.4 Hz), 7.42 (1H, dd, J=2.0, 8.8 Hz), 7.41 (2H, d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 4.39 (2H, t, J=7.0 Hz), 3.09 (2H, t, J=6.8 Hz), 3.00 (2H, q, J=7.7 Hz), 2.36 (2H, q, J=7.7 Hz), 1.42 (3H, t, J=7.7 Hz), 1.15 (3H, t, J=7.5 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClC(Cl)Cl>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCc1ccc(CO)o1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnccc1NCc1ccc(CO)o1
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A mixture of 15.9 parts of 4-chloro-3-nitropyridine, 12.7 parts of 5-(aminomethyl)-2-furanmethanol, 13.3 parts of N,N-diethylethanamine and 745 parts of trichloromethane was stirred for 3 hours at reflux temperature. After cooling, the reaction mixture was washed with K2CO3 (aq.), dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 17.76 parts (71.3%) of 5-[[(3-nitro-4-pyridinyl)amino]methyl]-2-furanmethanol; mp. 134.9° C. (interm. 19).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13](=[O:14])[N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:18])[CH2:24][CH2:23]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCCCC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and piperidine (21 μL, 2.0 equiv) in dimethylformamide (0.5 mL) and dichloromethane (0.5 mL) at 0° C. was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0° C. for 4 h. The reaction was concentrated and purified by column chromatography (95:5:1 to 90:10:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 55 mg (93%) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ 0.75-1.70 (m, 9H), 1.70-1.95 (m, 4H), 2.51 (s, 3H), 2.72-3.04 (m, 3H), 3.11 (m, 4H), 3.19-3.58 (m, 4H), 3.98-4.49 (m, 2H), 5.47 (dd, J=7.3, 7.3, 1H), 7.07 (s, 1H), 7.17 (m, 1H), 7.27 (m, 1H), 7.43 (m, 2.5H), 7.58 (d, J=7.3, 1H), 7.65 (bs, 0.5H), 7.96 (s, 1H). Mass spec.: 542.29 (MH)+.