Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9](CC3C=CC(OC)=CC=3OC)[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(=O)OC(C)(C)C)[N:3]=1.CC1(C)C(C)(C)OB([C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CNC2=O
Temperature: 80 °C
Yield: 43.9 %

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (300 mg, 0.546 mmol), 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (172 mg, 0.820 mmol), and trans-dichloro-bis(triphenylphosphine)palladium-II (38.4 mg, 0.055 mmol) were dissolved in dioxane (5 mL). An aqueous solution of 2N Na2CO3 (0.5 mL) was added, the cap was sealed, and the mixture was allowed to react at 85° C. for 3 h. The reaction mixture was subsequently diluted with water (5 mL) and extracted into EtOAc (2×30 mL). The organic layer was dried over sodium sulfate and evaporated. The resulting residue was treated with TFA (4 mL) and heated at 80° C. for 1 h to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The product was reconstituted in DMSO (8 mL) and was then purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-45% gradient, 0.035% TFA). The pure fractions were combined and evaporated to a minimal volume. Saturated aq NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (3×25 mL). The organic layers were combined, dried over sodium sulfate, and evaporated to give the title compound as a pale yellow solid (83 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.80 (m, 8H), 3.18 (br s, 1H), 3.86-4.11 (m, 1H), 4.39 (s, 2H), 6.60 (d, J=6.57 Hz, 1H), 7.13 (dd, J=5.05, 3.79 Hz, 1H), 7.60 (dd, J=5.18, 1.14 Hz, 1H), 8.39 (s, 1H), 9.00 (dd, J=3.79, 1.01 Hz, 1H). [M+H] calc'd for C17H19FN4OS, 347. found, 347.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25]([O:28][CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])[CH:26]=[CH2:27]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:45]1[CH2:46][CH2:47][CH:42]([C:40]([C:32]2[N:31]([CH2:30][CH2:29][O:28][CH2:25][CH:26]=[CH2:27])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=2)=[O:41])[CH2:43][CH2:44]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Reactant: C=CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: C=CCOCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3ccccc3)c3ccccc3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(1-(2-allyloxyethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[I:13]Cl.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:6][C:7]=1[I:13]
Reactant: CNC(=O)Cc1ccc(N)cc1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
4-Amino-N-methyl-benzeneacetamide (6) (6.56 g, 0.04 mol) was dissolved in CH3CN (200 mL) and ICl (7.14 g dissolved in 60 mL of CH3CN, 0.044 mol) was added dropwise with vigorous stirring. After stirring at RT for 3 h, saturated aqueous Na2CO3 (50 mL) was added and the reaction was concentrated in vacuo. The residue was dissolved in EtOAc and extracted with saturated aqueous Na2CO3. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product (7) (7.38 g, 63.6%) was isolated from the concentrate by trituration with CH2Cl2 /EtOAc and washing with Et2O. This material was found to be pure by NMR analysis.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)/[CH:14]=[CH:15]/[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)#[N:6]>CN(C)C=O>[NH:1]1[C:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)/[CH:14]=[CH:15]/[C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:6][N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCCNc1cccc(/C=C/c2nc3ccccc3s2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=C/c1nc2ccccc2s1)\c1cccc(NCCCc2nnn[nH]2)c1
Temperature: 120 °C
Yield: 34.5 %

Procedure:
To 5 ml of dimethylformamide were added 390 mg of sodium azide and 638 mg of 2-[trans-3-(3-cyanopropylamino)styryl]benzothiazole, and the mixture was heated to 120° C. for 7 hours. After cooled to room temperature, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent was evaporation under reduced pressure. The concentrate was purified through silica gel column chromatography by use of ethyl acetate to obtain 250 mg (yield 35%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1.[CH:28]([O:41][C:42]([NH:44][C:45]1[NH:46][C:47](=[O:58])[C:48]2[N:49]=[CH:50][N:51]([CH2:54][C:55](O)=[O:56])[C:52]=2[N:53]=1)=[O:43])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:55](=[O:56])[CH2:54][N:51]4[CH:50]=[N:49][C:48]5[C:47](=[O:58])[NH:46][C:45]([NH:44][C:42]([O:41][CH:28]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)=[O:43])=[N:53][C:52]4=5)[CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2cc(Cl)ccc2s1
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4cc(Cl)ccc4s3)C(=O)C2)c(=O)[nH]1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(5-chloro-benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.62 (brs, H), 11.25 (brs, 1H), 8.42–8.39 (m, 1H), 7.96 (s, 0.6H), 7.82 (s, 0.4H), 7.78 (m, 1H), 7.46 (d, 4H), 7.39 (t, 4H), 7.31 (t, 2H), 6.87 (s, 1H), 5.17 (s, 1.2H), 5.06 (s, 0.8H), 4.53 (s, 0.8H), 4.29 (s, 1.22H), 4.25 (t, 1.2H), 4.08–4.06 (m, 2H), 3.87 (t, 0.8H).
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.[CH:14]([O:16][CH2:17][CH3:18])=[CH2:15].N1C=CC=CC=1>ClCCl>[CH2:17]([O:16][CH:14]=[CH:15][C:3](=[O:4])[C:2]([F:7])([F:1])[CH3:6])[CH3:18]
Reactant: CC(F)(F)C(=O)O
Reactant: C=COCC
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC=CC(=O)C(C)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a cooled (0° C.) solution of 2,2-difluoropropionic acid (prepared according to the procedure described in U.S. Pat. No. 5,859,051) (2.20 g, 20.0 mmol) in dichloromethane (15 ml) was added oxalyl chloride (2.79, 22.0 mmol) dropwise over 10 min. The mixture was stirred at 0° C. for 10 min then allowed to warm to ambient temperature overnight. The mixture was cooled to −10° C. and added via a cannula to a cooled (−10° C.) solution of ethyl vinyl ether (1.59 g, 22.0 mmol) and pyridine (1.74 g, 22.0 mmol) in dichloromethane (50 ml). The mixture was stirred at −10° C. for 10 min then at ambient temperature for 5 h. The brown solution was diluted with dichloromethane (30 ml) and washed with ice-cold 1M sulphuric acid (2×50 ml) and ice-cold water (2×50 ml), dried over anhydrous sodium sulfate and evaporated to give crude 1-ethoxy-4,4-difluoropent-1-en-3-one (3.28 g, 100%) as an orange oil: δH (400 MHz, CDCl3) 1.38 (3H, t, J 7), 1.71 (3H, t, J 19), 4.05 (2H, q, J 7), 5.94 (1H, dt, J 12 and 1), 7.81 (1H, d, J 12).
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1OCC(F)(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1OCC(F)(F)F
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Subsequently, ammonium chloride (0.5 g) and iron powder (2.5 g) were added to a mixed solvent of water (40 ml) and ethanol (120 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(2,2,2-trifluoroethoxy)benzonitrile (80.5 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (70 g), melting point: 98–100° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH2:17])=[S:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:17][C:15]1[S:16][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]=2[N:14]=1
Reactant: NC(=S)Nc1ccccc1Oc1ccccc1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(Oc3ccccc3)cccc2s1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
To a mixture of 1-(2-phenoxyphenyl)thiourea (53.4 g) in chloroform (100 ml) was added dropwise a solution of bromine (35.0 g) in chloroform (50 ml) with stirring under ice-cooling during 40 minutes. After refluxing for 1 hour and 40 minutes, the mixture was cooled to ambient temperature. To the resultant mixture was added water and then the mixture was alkalified with 5% sodium hydroxide aqueous solution. The chloroform layer was washed with water, dried over magnesium sulfate, concentrated under reduced pressure to give crystals, which were recrystallized twice from isopropyl alcohol to give 2-amino-4-phenoxybenzothiazole (25.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][C@H:9]1[C:18](O)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[OH:19][CH2:18][C@@H:9]1[CH2:10][CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC[C@H]1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1c2ccccc2CC[C@H]1CO
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(S)-1-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (5 g, 18.03 mmol) was dissolved in tetrahydrofuran (40 ml) and the mixture was cooled. Boron hydride-tetrahydrofuran complex (27 ml, 1 mol/l in tetrahydrofuran) was cautiously added dropwise at 0° C. and the mixture was then stirred at room temperature for 15 h. The reaction mixture was cooled again and water (8 ml) was slowly added dropwise at 0° C. Potassium carbonate (4.21 g, 30.65 mmol) was then added and the mixture was stirred for 30 min. After phase separation the aqueous phase was extracted with diethyl ether (2×30 ml) and the combined organic phases were washed with saturated sodium chloride solution (30 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/ethyl acetate 2/1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH2:14][CH2:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:29]([O-:31])=[O:30])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:29]([O:31][C:5]([CH3:11])([CH3:6])[CH3:4])=[O:30])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: CCO[C@H]1C[C@@H](c2nc3c([nH]2)-c2cc4c(cc2CC3)-c2ccc(Cl)cc2CO4)N(C(=O)[O-])C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 143.7 %

Procedure:
To a solution of (2S,4S)-2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.99 g, 1.9 mmol) in CH2Cl2 (18 mL) was added MnO2 (4.52 g, 52.0 mmol). The resulting slurry was stirred at room temperature for 18 h. The reaction was filtered through celite, washed with CH2Cl2, and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 75% EtOAc (w/5% MeOH)/Hexanes) to afford tert-butyl (2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.71 g, 72%).
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:43])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1.[OH-].[K+]>C1COCC1.CO>[C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31](/[CH:30]=[CH:29]/[C:28]([NH:27][C:5]2[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[CH:8]=[CH:9][C:4]=2[C:3]([OH:44])=[O:2])=[O:43])=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)/C=C/c1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)/C=C/c3ccc(-c4ccccc4)cc3)c2)cc1
Yield: 68.5 %

Procedure:
The desired product was prepared using a procedure similar to Step 7 of example 34. Thus, 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.148 g, 0.251 mmol) was reacted with 1N KOH (0.50 ml) in THF/MeOH (6 ml/4 ml) to give 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid (0.099 g, 0.172 mmol, 68%) as a white solid, mp 169-171° C. 1H NMR (DMSO-d6) δ 1.26 (s, 9H), 2.13-2.17 (m, 2H), 4.18 (t, J=6.4 Hz, 2H), 4.27 (t, J=6.3 Hz, 2H), 6.75 (dd, J=2.6, 8.9 Hz, 1H), 6.89 (d, J=15.6 Hz, 1H), 7.38-7.43 (m, 3H), 7.46-7.54 (m, 4H), 7.67 (d, J=15.6 Hz, 1H), 7.70-7.76 (m, 4H), 7.83 (d, J=8.2 Hz, 2H), 7.96 (d, J=8.9 Hz, 1H), 8.23 (s, 1H), 8.38 (d, J=2.4 Hz, 1H), 11.75 (s, 1H), 13.3 (s, 1H); IR (solid) 2960, 1680, 1610, 1580, 1540 and 1200 cm−1; [ES(−)], m/z 575 (M−H)−; Anal. Calcd. for C36H36N2O5: C, 74.98; H, 6.29; N, 4.86, Found: C, 74.57; H, 6.32; N, 4.89.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[NH:14][C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:14]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1CCc1ccco1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCc1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
Triton B (1.94 mL, 4.3 mmols) was added dropwise to a stirred, cooled (-30° C.) solution of (3S,4R)-3-benzyloxycarbonylamino-4-[2-(2-furyl)ethyl]azetidin-2-one (1.35 g, 4.3 mmols) in N,N-dimethylformamide (15 mL). Stirring was continued for 0.25 hr. at -30° C. The mixture was allowed to warm to 0° C. during about 0.25 hr and then was recooled to -30° C. when a solution of t-butyl bromoacetate (0.764 mL, 4.73 mmols) in DMF (3 mL) was added dropwise. Stirring was continued at -30° C. for 0.25 hr., 1hr at 0° C. and then for 2 hr at ambient temperatures, when additional t-butyl bromoacetate (0.3 mL) was added. The mixture was stirred for an additional 1hr and was poured into H2O. The mixture was extracted twice with ethyl acetate. The extracts were washed twice with H 2 O, followed by saturated NaCl and then dried over MgSO4. The ethyl acetate was removed and the residue flash chromatographed on SiO2 (40 g) with methylene chloride-methanol (98:2) to afford 1.47 g (80% yield) of the title compound as a viscous oil which crystallized. Recrystallization from ethyl acetate-hexanes afforded colorless crystals, mp 82-84° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>C(Cl)(Cl)Cl>[C:16]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])(=[O:19])[CH:17]=[CH2:18]
Reactant: O=C1CCC(=O)N1O
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-hydroxysuccinimide (NAS) (1.15 g, 10.0 mmol) and triethylamine (1.53 ml) in chloroform (15 ml), acryloyl chloride (0.99 g, 11.0 mmol), cooled at 0° C., was added dropwise, under mechanical stirring, over a period of 30-min. After an additional stirring of 20 min at 0° C., the solution was washed with ice-cold water (8 ml for 2 times), dried on Na2SO4 and then filtered. 2,5-Di-tert-butylhydroquinone (0.5 mg) (polymerization inhibitor) was added to the chloroform solution, which was concentrated to a volume of 3 ml, using a rotary evaporator and filtered. Ethyl acetate (3 ml) and n-hexane (2 ml) were slowly added while stirring to the chloroform solution, which was left at 0° C. for several hours. The precipitate, a colorless solid, was separated by filtration and washed with an ice-cold solution of ethyl acetate/n-hexane (4/1) and then washed only with n-hexane.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH2:12]>C1C=CC=CC=1>[CH3:11][NH:12][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccccc1
Product: CNC(=O)Cc1ccccc1

Procedure:
Dissolved 15 g(0.1 mol) of phenylacetyl chloride in 100 ml of benzene. While stirring on a magnetic stirrer, introduced methylamine into the benzene solution at 20°-30° C. Followed the procedure of compound 3-1 for the purification of the product to yield N-methyl phenylacetamide as light yellowish crystal. Yield, 12 g (80%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.[NH2:55][C:56]1[O:57][CH:58]=[CH:59][N:60]=1>CN(C)C=O>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([NH:55][C:56]2[O:57][CH:58]=[CH:59][N:60]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ncco1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncco1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 47 %

Procedure:
A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.23 mmol), 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 60 mg, 0.21 mmol), N,N-diisopropylethylamine (73 μL, 0.42 mmol), and 2-aminooxazole (27 mg, 0.31 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide (34.9 mg, 47%) as a white solid: mp 134-136° C.; EI-HRMS m/e calcd for C17H18Cl2N2O2 (M+) 352.0745, found 352.0750.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1>O1CCCC1.CCCCCC>[Br:8][C:4]1[CH:3]=[C:2]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cccc(Br)c2)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a solution of 1,3-dibromo-benzene (2.36 grams, 10 mmol) in tetrahydrofuran at −78° C. was added a 1.6M solution of n-butyllithium (6.3 ml, 10 mmol) in hexane and stirred for 4 hours. Cyclobutanone (700 mg, 10 mmol) was then added in one portion. After stirring for 2 hours at −78° C., the reaction was quenched with 2N hydrochloric acid. The reaction was warmed to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give 2.5 grams of crude product which was purified on silica gel eluting with 50% methylene chloride in hexane to give 1.5 grams of the titled compound.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[CH3:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1>CCO>[CH3:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]([O:14][CH2:1][CH3:2])=[O:13])[CH2:7]1
Reactant: C[C@H]1CCN[C@H](C(=O)O)C1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@@H](C)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of dry EtOH (65 mL) and acetyl chloride (6.52 mL added dropwise at 0° C.) was added (2S, 4S)-4-methyl pipecolic acid (2.8 g, 19.6 mmol at room temperature. The reaction was stirred at room temperature for 16 hrs and then concentrated it vacuo to give the title compound, (3.01 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1c(O)cccc1O
Yield: 96.5 %

Procedure:
2-Nitroresorcinol (1.00 g, 6.45 mmol) was dissolved in ethanol (10 mL). The solution was then stirred for 6 hours at room temperature in the presence of 10% Pd/C (340 mg, 0.32 mmol) under hydrogen gas atmosphere. Insolubles were removed by filtration, and the solvent was distilled off under reduced pressure, to give 779 mg (yield 97%) of the desired compound in the form of a brown crystalline product.