Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6])[CH:15]=[CH2:14]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cc(C(=O)O)ccc1OC

Procedure:
The reaction of methyl 3-hydroxyl-4-methoxybenzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-Allyloxy-4-methoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.63 (s, —CO2H); 7.54 (d-like, 1 arom. H); 7.43 (m, 1 arom. H); 7.04 (m, 1 arom. H); 6.02 (m, —CH═CH2); 5.39, 5.23 (2 d-like, CH═CH2); 4.57 (d-like, CH2—CH═CH2); 3.81 (s, OCH3). 13C-NMR (100 MHz, d6-DMSO): 167.04 (—C═O); 152.87; 147.07; 133.59; 123.40; 122.86; 117.60; 113.62; 111.23; 68.88; 55.69.
Reaction SMILES: C([BH3-])#N.[Na+].F[C:6]1[C:14](F)=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:16])[NH:10]2.[OH2:17]>C(O)(=O)C>[OH:17][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([CH3:16])[NH:10]2
Reactant: Cc1cc2c(F)c(F)ccc2[nH]1
Reactant: O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1Cc2c(O)cccc2N1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
750 mg of sodium cyanoborohydride are gradually added to a solution of 1 g of 4,5-difluoro-2-methylindole in 20 ml of acetic acid under argon cooled to a temperature of about 5° C. The reaction mixture is stirred at ambient temperature for 3 hours and 5 ml of water are added. The mixture is then concentrated under reduced pressure and the residue is taken up in ethyl acetate, then treated with 60 ml of a saturated sodium hydrogen carbonate solution. After stirring for 1 hour and then settling out, the organic phase is separated and the aqueous phase is extracted with 50 ml of ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with an 80/20 v/v heptane/ethyl acetate mixture. 0.37 g of 4-hydroxy-2-methylindoline is thus obtained in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[N:47]=[CH:48][S:49][CH:50]=1>>[CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:46]3[N:47]=[CH:48][S:49][CH:50]=3)=[CH:17][CH:18]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4]
Reactant: Brc1cscn1
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(-c2cscn2)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 4-bromothiazole. MS (ESI): mass calcd. for C32H28N4O3S, 548.18; m/z found, 549.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.17 (d, J=1.6, 1H), 8.59 (d, J=8.5, 1H), 8.18-8.14 (m, 2H), 8.07 (d, J=8.1, 1H), 7.96 (d, J=8.2, 2H), 7.92-7.84 (m, 1H), 7.79 (d, J=8.4, 1H), 7.69 (t, J=7.4, 1H), 7.60 (d, J=9.4, 1H), 7.42 (s, 1H), 7.35 (d, J=8.3, 2H), 7.30 (d, J=9.4, 1H), 5.82 (s, 2H), 5.58 (s, 2H), 3.53 (s, 2H), 1.31 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][NH:4][S:5]([C:8]1[CH:19]=[C:12]2[C:13]([O:15]C(=O)[NH:17][C:11]2=[CH:10][CH:9]=1)=O)(=[O:7])=[O:6].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)C>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:13](=[O:15])[C:12]2[C:11](=[CH:10][CH:9]=[C:8]([S:5](=[O:6])(=[O:7])[NH:4][CH2:3][CH:2]([CH3:1])[CH3:20])[CH:19]=2)[NH2:17])[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: CC(C)CNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: CCO
Product: CC(C)CNS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-[N-(2-methylpropyl)-sulfamoyl]-isatoic anhydride with 1-methylpiperazine yields 5-[N-(2-methylpropyl)-sulfamoyl]-anthranilic acid (4-methyl)-piperazide with a melting point of 162°-163° (from ethanol; melting point of the hydrochloride: 254°-255°).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:12].C(N(CC)CC)C.Cl[C:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:12][C:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=1
Reactant: COc1nsc(Cl)n1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(OC)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
A solution of N-L-leucyl-L-proline methyl ester hydrochloride (5.6 g, 20 mmol, prepared according to the procedure by Jones, J. B. et al. in J. Med. Chem. 1995, 38, 3078) and triethylamine (5.6 mL, 40 mmol) in DMF (60 mL) was stirred at room temperature for 15 min. Then, a solution of 5-chloro-3-methoxy-[1,2,4]thiadiazole (1.51 g, 10 mmol) in DMF (10 mL) and tetrabutylammonium bromide (150 mg) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water and extracted into ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (7/3 and 6/4) afforded N-(3-methoxy-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester (1.92 g, 53.9%) as as an off-white foam. 1H-NMR (CDCl3) δ7.10 (d, J=8.5 Hz, 1H, NHCH), 4.74 (m, 1H, NHCH), 4.57 (dd, J=8.6, 4.6 Hz, 1H, CHCO2), 3.92 (s, 3H, OMe), 3.85 (m, 1H), 3.69 (s, 3H, OMe), 3.62 (m, 1H), 2.17-2.23 (m, 1H), 1.95-2.07 (m, 4H), 1.77-1.82 (m, 1H), 1.59-1.66 (m,1H), 0.97 (d, J=6.5 Hz, 3H, Me), 0.94 (d, J=6.7 Hz, 3H, Me); MS (m/z) 357 (M+ +1), 228, 200, 130, 101, 70.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:28](Br)[CH:29]=[CH2:30]>>[CH2:30]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH:29]=[CH2:28]
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: C=CCBr
Product: C=CCOc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 356 and allyl bromide, white powdery 3-[2-(4-allyloxy-3-difluoromethoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:26])[NH:14][C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:26])[N:14]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CCc2ccccc2)[nH]c1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
Using a similar procedure to that of Example 1.d., above, 3-benzyloxycarbonylamino-6-phenethylpyrid-2-one (1.64 g) was suspended in dry dimethylformamide (20 mL) and to this suspension was added NaH (0.22 g of a 60% mineral oil dispersion). The mixture was stirred for 1.5 h, at which point all solids were in solution. tert-Butyl bromoacetate (0.92 g) was added, and the mixture was stirred overnight. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (four times). The extracts were washed with brine, dried and evaporated. The residue was purified by chromatography, eluting with methanol:dichloromethane (0:100 then 3:97), to give tert-butyl (3-benzyloxycarbonylamino-2-oxo-6-phenethyl-1,2-dihydro-1-pyridyl)acetate (0.578 g); TLC: Rf =0.17, dichloromethane; MS: m/z=463(M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.Cl.[CH3:12][N:13]([CH3:32])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30].I.[NH2:34][C:35]1[C:36]([C:43]([NH:45][C:46](=[NH:49])SC)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1>C(O)C>[CH3:32][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:46]([NH2:49])=[N:45][C:43]([C:36]1[C:35]([NH2:34])=[N:40][C:39]([NH2:41])=[C:38]([Cl:42])[N:37]=1)=[O:44]
Reactant: CN(C)CCCNC(=O)CCCCCCCCCCCN
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)CCCNC(=O)CCCCCCCCCCCNC(N)=NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
Diisopropylethylamine (0.23 mL, 1.31 mmol) was added to a suspension of 12-amino-dodecanoic acid (3-dimethylaminopropyl)amide dihydrochloride (5) (0.081 g, 0.22 mmol) in absolute ethanol (5 mL). The mixture became homogeneous. It was stirred at 70° C. (oil bath) for 5 min and then 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.093 g, 0.24 mmol) was added in one portion. The reaction mixture was stirred at this temperature for 3 hours and cooled to room temperature. The solvent was then removed by rotary evaporation, the residue dissolved in small volume of methanol, and this solution passed through an ion exchange resin column (Dowex 550A OH type). The resin was rinsed with methanol and the methanol solution was concentrated in vacuo. The resulting residue was purified by Biotage silica gel column chromatography, eluting with a gradient of 1% to 10% of 9:1 methanol/ammonium hydroxide in dichloromethane, to give 12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]dodecanoic acid (3-dimethylaminopropyl)amide 6 (0.070 g, 63%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.25 (m, 14H), 1.50 (m, 6H), 2.01 (t, 2H), 2.11 (s, 6H), 2.20 (t, 2H), 3.02 (m, 2H), 3.12 (t, 2H), 6.80 (br, 3H), 7.75 (m, 1H). m/z (ESI) 512 [C23H42ClN9O2+H]+. mp 82-84° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([NH2:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Cl:1][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=1)[C:9]([NH2:17])=[O:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)c1ccccc1
Solvent: CC#N
Product: NC(=O)c1cccc(Cl)c1

Procedure:
N-Chlorosuccinimide (2.4 parts) is added to a solution of the primary benzamide (from method D or E) in dry acetonitrile, and the mixture is refluxed for 1 hour. This is partitioned between ether and aqueous Na2S2O3 and the organic layer is washed with 10% NaOH followed with brine, dried (MgSO4), filtered through silica gel, and concentrated to give the crude 5-chlorobenzamide.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=1)=[O:4].[NH3:14]>CO.O>[C:10]([C:8]1[CH:9]=[C:5]([C:3]([NH2:14])=[O:4])[NH:6][CH:7]=1)#[N:11]
Reactant: N
Reactant: N#Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Solvent: CO
Solvent: O
Product: N#Cc1c[nH]c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-trichloroacetylpyrrole-4-carbonitrile (20 g, 84.2 mmol) in methanol is treated with ammonia (51 mL), stirred at room temperature for 30 minutes and diluted with water. The aqueous mixture is filtered to obtain the title product as a white solid (7.0 g, mp 253°-256° C.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][O:22][CH2:21]1>C1COCC1>[CH2:1]([O:8][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:24]([CH2:23][O:22][CH2:21][C:20]([OH:27])=[O:26])=[O:25])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COCC(=O)O1
Reactant: NCCCCCCCNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)COCC(=O)NCCCCCCCNC(=O)OCc1ccccc1
Yield: 85.2 %

Procedure:
To the solution of 21 (350 mg, 1.324 mmol) in THF (4 mL) was added diglycolic anhydride (161 mg, 1.39 mmol) in one portion. The resultant mixture was stirred at ambient temperature for 12 h. After removed THF under reduced pressure, the residue was crystallized by EtOAc/hexane to give 429 mg white solid as first crop, in 85% yield. 1H NMR (400 MHz, DMSO-d6): δ12.79 (brs, 1H), 7.81 (t, J=5.52 Hz, 1H), 7.34-7.29 (m, 5H), 7.21 (t, J=5.46 Hz, 1H), 5.00 (s, 2H), 4.10 (s, 2H), 3.94 (s, 2H), 3.08 (q, J=6.56 Hz, 2H), 2.97 (q, J=6.28 Hz, 2H), 1.42-1.37 (m, 4H), 1.24 (m, 6H). 13C NMR (100 MHz, CDCl3): 171.43, 168.53, 156.06, 137.30, 128.27, 127.65, 70.18, 67.88, 65.04, 40.22, 38.08, 29.65, 29.00, 28.38, 26.28, 26.14. mp 74-74.5° C. IR v (Diamond, cm−1): 3374, 3331, 1726, 1688, 1608, 1548, 1249, 1236, 1135, 956, 701. MS (ESI) found 381.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:4]=1/[CH:5]=[CH:6]/[S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1)(=[O:9])=[O:8].[OH-].[Na+:33]>C(O)C>[Na+:33].[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:4]=1/[CH:5]=[CH:6]/[S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([NH:17][CH2:18][C:19]([O-:21])=[O:20])[CH:16]=1)(=[O:8])=[O:9]
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(NCC(=O)O)c2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(NCC(=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
(E)-2-(5-((2,4,6-Trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid (15 g, 0.032 mol) is dissolved in ethanol (150 ml) and 1N NaOH (1.28 g in 33 ml of water, 0.032 mol) is added, adjusted pH to 7.5-8.0 and stirred at room temperature for 1 h. The reaction is cooled to 0° C., and the precipitated solid is collected by filtration, washed with cold ethanol, and finally with hexane and dried under vacuum to give (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid sodium salt (13 g, 84%).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:17]=[CH:16][CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12]C)=[O:10])[C:2]([CH3:5])([CH3:4])[CH3:3].C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:26])C>>[CH2:1]([N:6]1[C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9](=[O:10])[O:11][C:12]1=[O:26])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1NCC(C)(C)C
Product: CC(C)(C)Cn1c(=O)oc(=O)c2cccnc21

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 30A for the product of Example 3A (0.182 g, 89%). 1H NMR (300 MHz, CDCl3) δ 1.12 (s, 9H), 4.28 (s, 2H), 7.25 (dd, J=6.99, 4.04 Hz, 1H), 8.41 (dd, J=7.91, 2.02 Hz, 1H), 8.69 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:31][C:32]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:33]=1[C:34](O)=[O:35]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:8]2([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:34]([C:33]4[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:32]=4[CH3:31])=[O:35])=[CH:25][CH:24]=3)=[O:7])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4cc([N+](=O)[O-])ccc4C)cc3)C(=O)O)CCCC2)cc1
Yield: 72.1 %

Procedure:
4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (23.4 mg, 0.057 mmol) and 2-methyl-5-nitrobenzoic acid 13 mg, 0.07 mmol) were reacted as described in example 40 to give 23 mg (69%) of N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-[[(2-methyl-5-nitrophenyl)carbonyl]amino]-L-phenylalanine, HR—FAB—MS: obs. mass 560.2413. Calcd. mass 560.2397 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([O:13][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(Br)cc1
Reaction time: 46 h
Yield: 89.3 %

Procedure:
To a suspension of (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (5.02 g, 14.01 mmol) and NaHCO3 (3.53 g, 42.0 mmol) in DMF (20 mL) is added Benzyl bromide (5.10 mL, 42 mmol) at room temperature under nitrogen. After stirring for 46 hours, the reaction is diluted with H2O (200 mL), and then precipitated solid is collected and washed with H2O (500 mL) and then with heptane (200 ml) to give (R)-benzyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (5.61 g, 89%). HPLC retention time=1.56 minutes (condition B); MS (ES+)=392.1 (m-tBu+2); 348.1 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 9H) 2.48 (A of ABX, Jab=15.9 Hz, Jax=5.6 Hz, 1H) 2.54 (B of ABX, Jab=15.9 Hz, Jbx=5.3 Hz, 1H) 2.72-2.88 (m, 2H) 4.11 (br s, 1H) 5.02 (br s, 1H) 5.10 (A of AB, J=12.1 Hz, 1H) 5.16 (A of AB, J=12.1 Hz, 1H) 7.00 (d, J=8.1 Hz, 2H) 7.34-7.39 (m, 7H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH2:21]Br)=[O:5])[CH3:2].[CH2:23]([O:25][C:26](=[O:36])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH2:21][N:28]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(CBr)n(-c2ccccc2)c2ccccc12
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c2ccccc2n1-c1ccccc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 2-bromomethyl-1-phenyl-1H-indole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 503 (M+Na+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH3:22]O>>[CH3:22][O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:14]
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CO
Product: COC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
To a solution in methanol (120 mL) of 4,4-bis(4-hydroxyphenyl)pentanoic acid (Aldrich Chemical Co., 12 g, 42 mmol) was added concentrated H2 SO4 (0.5 mL) and the mixture was heated to reflux for 3 hours. After cooling to room temperature the mixture was concentrated in vacuo and dissolved in ether (300 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×150 mL) and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide a thick oil which was crystallized from ether/hexane to give 4,4-bis(4-hydroxyphenyl)pentanoic acid methyl ester as an off-white color solid (11.8 g, 94%), mp 130° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([O:22]C)=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O>[C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)cnc(Cn2nc3cc(CC(=O)O)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture composed of the above methyl {4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}acetate (69 mg), methanol (2 ml) and a 1 N sodium hydroxide solution (0.22 ml) was stirred at room temperature for 16 hours. A 1 N sodium hydroxide solution (0.5 ml) was added, followed by stirring for three hours. Then, a 1 N sodium hydroxide solution (0.3 ml) was further added, followed by stirring for three hours. A 1 N hydrochloric acid solution (1.5 ml) was added dropwise to the reaction mixture. Then, water was added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. An oil (60 mg, 89%) was obtained as a residue. Although the product contained a by-product, it was directly used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([N+:14]([O-])=O)[CH:8]=1)[CH3:2].[H][H]>[Pd].CO>[NH2:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:8][C:9]=1[NH2:14]
Reactant: CCOCCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOCCOc1ccc(N)c(N)c1

Procedure:
A mixture of 1.8 g. of 4-(2-ethoxyethoxy)-2-nitroaniline and 0.3 g. of 5% palladium-on-charcoal catalyst in 200 ml. of methanol is hydrogenated under ambient conditions. After the uptake of hydrogen is complete, the mixture is filtered and 1,2-diamino-4-(2-ethoxyethoxy) benzene is isolated from the filtrate by evaporation.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([SH:7])[CH:2]=1.[C:9](#[N:12])[CH:10]=[CH2:11].C[O-].[Na+]>>[CH3:8][C:1]1[CH:2]=[C:3]([S:7][CH2:11][CH2:10][C:9]#[N:12])[CH:4]=[CH:5][CH:6]=1
Reactant: C=CC#N
Reactant: Cc1cccc(S)c1
Agent: C[O-]
Agent: [Na+]
Product: Cc1cccc(SCCC#N)c1

Procedure:
β-(3-Methylphenyl)mercaptopropionitrile was prepared according to the procedure of Example 1 using m-toluenethiol (20.0 g; 0.16 moles), acrylonitrile (8.6 g; 0.16 moles) and sodium methoxide (0.5 g).