Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:42][CH2:41]1.BrCCCC.O1C2(CCNCC2)OCC1>O>[CH2:46]([N:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:13]([C:9]2[CH:10]=[N:11][C:12]3[C:7]([C:8]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH:26]4[CH2:27][CH2:28][N:29]([CH2:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:30][CH2:31]4)=[O:24])=[CH:21][CH:22]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])=[O:15])[CH2:41][CH2:42]1)[CH2:47][CH2:48][CH3:49]
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Reactant: CCCCN1CCC(N)CC1
Agent: C1CC2(CCN1)OCCO2
Solvent: CCCCBr
Solvent: O
Product: CCCCN1CCC(NC(=O)c2cnc3c(OC)cccc3c2Nc2ccc(C(=O)NC3CCN(Cc4ccccc4)CC3)cc2)CC1

Procedure:
N-(1-Butyl-4-piperidinyl)-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared as a hygroscopic material (0.215 hydrate) by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and 4-amino-1-butylpiperidine as described for Example 17, Step 5. 4-Amino -1-butyl-piperidine can be prepared from 4-bromobutane and 1,4-dioxa-8-azaspiro[4.5]-decane as described in U.S. Pat. Nos. 3,875,165 and 4,816,464: mp 215°-220 ° C.; 1H NMR (Me2SO-d6, 400 MHz) δ 9.50 (s, 1 H), 8.77 (s, 1 H), 8.39 (d, J=7.5 Hz, 1 H), 8.01 (d, J=7.8 Hz, 1 H), 7.70 (d, J=8.6 Hz, 2 H), 7.57 (d, J= 8.4 Hz, 1 H), 7.41 (m, 1 H), 7.18-7.32 (m, 6 H), 6.88 (d, J=8.6 Hz, 2 H), 3.95 (s, 3 H), 3.72-3.76 (m, 1 H), 3.44-3.49 (m, 3 H), 2.68-2.80 (m, 4 H), 2.14-2.19 (m, 2 H), 1.95-2.01 (m, 2 H), 1.71-1.83 (m, 4 H), 1.53-1.60 (m, 4 H), 1,1-1.4 (m, 6 H), 0.8 (t, J=7.24 Hz, 3 H); Karl Fischer, 0.58% H2O.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[C:31]([O:35][C:36]([NH:38][C:39](N1C=CC=N1)=[N:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[NH4+].[Cl-]>[C:44]([O:43][C:41]([NH:40][C:39](=[N:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[NH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
To a solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (397 mg, 1.0 mmol) in THF (10 mL) was added N,N′-di-t-butoxycarbonyl-pyrazole-1-carboxamidine (370 mg, 1.2 mmol) and potassium carbonate (207 mg, 1.5 mmol) and the mixture stirred at room temperature for 16 h. The reaction was diluted with aqueous NH4Cl (15 mL) and the mixture extracted with ethyl acetate (3×10 mL). The combined organic fractions were dried (Na2SO4), filtered, concentrated and purified by chromatography on silica gel (19:1 CH2Cl2/MeOH) to afford N′,N″-di-t-butoxycarbonyl-N-(4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzyl)-guanidine as a pale foam (426 mg, 67%). 1H NMR (CDCl3) δ 1.25 (s, 9H), 1.44 (s, 9H), 1.65 (m, 1H), 1.99 (m, 2H), 2.04 (m, 1H), 2.72–2.79 (m, 2H), 3.73 (s, 2H), 3.94 (d, 1H, J=16.1 Hz), 4.07 (m, 1H), 4.11 (d, 1H, J=12.1 Hz), 4.51 (d, 2H, J=6.2 Hz), 7.14 (m, 4H), 7.39 (m, 3H), 7.55 (m, 1H), 7.63 (m, 1H), 8.47 (m, 1H (NH)), 8.66 (d, 1H, J=4.8 Hz).
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:8])([CH3:5])[CH3:4].[OH-].[Na+]>Cl>[CH3:2][C:3]1([CH3:5])[CH2:4][S:8][C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6]1
Reactant: CC(C)(CO)NC(=S)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CSC(Nc2ccccc2)=N1
Temperature: 90 °C
Yield: 30.2 %

Procedure:
N-(1-hydroxy-2-methylpropan-2-yl)-N′-phenylthiourea (80.1 g, 0.36 mol) was dissolved in 2,400 mL of 35% HCl, and the resulting mixture was stirred while heating at 90° C. for 1.5 hours. After cooling, the mixture was neutralized with NaOH and extracted with diethyl ether. The extract was washed with saturated brine and then anhydrous sodium sulfate was added. The organic phase was distilled off under reduced pressure and the residue was washed three times with hexane. The crystals thus obtained were dried under reduced pressure at room temperature, and then recrystallized from methanol twice to give 22.4 g of the title compound (yield 18%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[S:10][CH:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=1[C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)(=O)C>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)csc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1csc(NC(=O)OC(C)(C)C)c1C(=O)O
Temperature: 80 °C
Yield: 79 %

Procedure:
A solution of ethyl 2-bis(t-butoxycarbonyl)amino-4-isopropylthiophene-3-carboxylate (22.5 g, 55 mmol) in methanol (425 ml) was stirred and a solution of potassium hydroxide (14.5 g, 259 ml) in water (145 ml) was added. The mixture was heated at 80° C. for 16 h, cooled to 0° C. and acidified (pH=5) with glacial acetic acid. The precipitate was filtered off and recrystallized from ethyl acetate/petroleum ether to afford 12.4 g (80%) of 2-t-butoxycarbonylamino-4-isopropylthiophene-3-carboxylic acid. M.p. 205°-206° C. 1H-NMR (CDCl3, δ): 1.25 (d, 6H) 1.55 (s, 9H), 3.6 (m, 1H) 6.45 (s, 1H), 7.25 (s, 1H), 10.2 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[S-:6].[Na+].[CH3:11][O:12][N:13]=[C:14]([C:20](=[O:23])[CH2:21]Br)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C.C(OCC)(=O)C>[CH3:11][O:12][N:13]=[C:14]([C:20](=[O:23])[CH2:21][S:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Reactant: COc1cccc([S-])c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(=NOC)C(=O)CSc1cccc(OC)c1
Temperature: 25 °C

Procedure:
To a stirred solution of sodium 3-methoxythiophenoxide in 150 ml of ethanol (prepared by reacting 14 g of 3-methoxythiophenol with 5.94 g of sodium methoxide) were added dropwise over ten minutes 27.7 g of ethyl 2-methoxyimino-3-oxo-4-bromobutyrate. The reaction mixture was stirred at 25° C. for sixteen hours, and then the solvent was removed by evaporation under reduced pressure to give an oil. The oil was dissolved in ethyl acetate and washed several times with water. The organic layer was dried and the solvent was removed by evaporation to afford 16.28 g of ethyl 2-methoxyimino-3-oxo-4-(3-methoxyphenylthio)butyrate. NMR (CDCl3): δ1.32 (t, 3H); δ3.79 (s, 3H); δ4.05 (s, 3H), δ4.34 (q, 2H); δ6.7-7.3 (m, 4H).
Reaction SMILES: [OH:1][C@@:2]1(CC([O-])=O)[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:4](=[CH:5][CH:6]=[C:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:3]1.[OH-].[Na+]>C(O)C>[OH:1][C@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:4](=[CH:5][CH:6]=[C:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([OH:19])([CH3:17])[CH3:18])[CH2:3]1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@](O)(CC(=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h
Yield: 112.7 %

Procedure:
A solution of acetate 9a (75 mg) in ethanol (10 ml) containing 5% aqueous NaOH (1 ml) was set aside for 24 h and then the solvent was evaporated in vacuo. The residue was taken in ethyl acetate (30 ml) and washed consecutively with 5% HCl, water, and saturated aqueous NaHCO3. Evaporation of the solvent gave (20S) 3b,25-dihydroxycholesta-5,7-diene 9b (74 mg) which was used for the next step without purification; λmax 240, 249, 260 and 272 nm; high resolution mass spec. for C27H44O2 calcd.: 400.3341(M+); found: 400.3334(100%), 398.3162(M+ --H2O, 11%), 385.3101(M+ --CH3, 14%), 380.3086, 24%), 367.3013(M+ --CH3 --H2O, 67%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1[Cl:45])=[O:35])[CH2:17][O:18][C:19](=[O:32])[NH:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([F:31])=[CH:26][CH:25]=2)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N:22][C:21]([NH:20][C:19](=[O:32])[O:18][CH2:17][C@@H:16]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1[Cl:45])=[O:35])[CH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH2:8])=[CH:30]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCNC(=O)CNC(=O)OC(C)(C)C)COC(=O)Nc1cc2cc(F)ccc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCNC(=O)CN)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of (6-Fluoro-isoquinolin-3-yl)-carbamic acid (S)-5-(2-tert-butoxycarbonylamino-acetylamino)-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentyl ester (105 mg, 0.16 mmol) in DCM (10.0 mL) was added TFA (1.0 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated and re-dissolved DCM. The DCM layer was washed with K2CO3 (2 N), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel column using a mixture of DCM and MeOH to give (S)-5-(2-aminoacetamido)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (71 mg, 79%). LRMS (M+H+) m/z 563.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2ccccc2o1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1-c1nc2ccccc2o1
Temperature: 70 °C

Procedure:
A mixture of 8 g (0.033 mol) of 2-(2′-nitrophenyl)benzoxazole and 37.58 g (0.167 mol) of SnCl2.2H2O in 200 ml of ethanol was heated at 70° C. until the reaction was completely finished.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:34](=[O:35])[N:22]([CH2:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:25])[CH:7]=1)[CH2:23][CH3:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C=NCc1ccccc1
Product: CCN(Cc1cc(F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccccc1

Procedure:
[2′-(3-Benzyl-1-ethyl-ureidomethyl)-4′-fluoro-6-methoxy-biphenyl-3-yl]-acetic acid (Compound 1-187) was prepared by following the procedures of Example 24 and using (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=O>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=[C:4]([C:5](=[O:8])[CH2:6][CH3:7])[C:3](=[O:9])[C:2]([F:10])([F:11])[F:1]
Reactant: CCC(=O)CC(=O)C(F)(F)F
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Product: CCC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)C(F)(F)F

Procedure:
The title compound was prepared by a similar method to that of Preparation 9 using 1,1,1-trifluorohexane-2,4-dione and 3,5-dichlorobenzaldehyde. The crude product was purified by flash chromatography on silica gel eluting with a solvent gradient of pentane gradually changing to pentane:ethyl acetate (5:1, by volume). The product was further purified by flash chromatography eluting with dichloromethane:pentane (1:10, by volume) to afford a mixture of the title compounds (500 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:5](Br)[CH:6](Br)[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9](=[O:12])[C:10]=2[CH:11]=1.C1CCN2C(=NCCC2)CC1.[CH3:30][OH:31]>>[Br:1][C:2]1[S:3][C:4]2[C:5]([O:31][CH3:30])=[CH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9](=[O:12])[C:10]=2[CH:11]=1
Reactant: O=C1c2ccccc2C(Br)C(Br)c2sc(Br)cc21
Reactant: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2ccccc2c(=O)c2cc(Br)sc12

Procedure:
A methanol (1100 mL) solution of the compound obtained in Example 13 (90.2 g, 200 mmol) was refluxed while heating overnight. After allowing the mixture to cool in the air, DBU (63.4 g, 417 mmol) was further added thereto, and the mixture was refluxed while heating for another overnight. The reaction mixture was allowed to cool in the air, and the precipitated crystals were separated by filtration and dried, to give the captioned compound in an amount of 55.7 g, 173 mmol (2 steps, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([C:25]1[CH:26]=[C:27]([C:37](=[O:40])[CH2:38]Br)[CH:28]=[C:29]([C:32]([CH3:36])([CH3:35])[CH2:33][CH3:34])[C:30]=1[OH:31])([CH3:24])[CH2:22][CH3:23].Cl>C(OCC)(=O)C>[CH3:24][C:21]([C:25]1[CH:26]=[C:27]([C:37](=[O:40])[CH2:38][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:10][CH3:11])[CH:28]=[C:29]([C:32]([CH3:36])([CH3:35])[CH2:33][CH3:34])[C:30]=1[OH:31])([CH3:20])[CH2:22][CH3:23]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)CC)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1cc(C(=O)COc2ccc(C=O)cc2OC)cc(C(C)(C)CC)c1O
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of 1.55 g (10 mmol) of 4-hydroxy-3-methoxy-benzaldehyde, 0.30 g (2.0 mmol) of sodium iodide and 3.05 g (22 mmol) of potassium carbonate in 100 ml of ethyl acetate is stirred for 30 minutes. Then 3.56 g (10 mmol) of 1-[3,5-bis(1,1-dimethyl-propyl)-4-hydroxy-phenyl]-2-bromo-ethanone is added and stirring at room temperature is continued for 16 hours. Then the mixture is acidified with 2N HCl and extracted with ethyl acetate. The combined extracts are washed with water, dried and evaporated. Crystallization of the crude product from hexane yields 2.95 g (69%) of compound 107, m.p. 106-107° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.C(N(CC)C(C)C)(C)C.[C:36](O)(=[O:38])[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH-].[Na+]>CN(C=O)C>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:38])[CH3:37])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) in DMF (3 ml) was added N,N-diisopropylethylamine (113 mg, 150 μl, 0.88 mmol), acetic acid (22.6 mg, 21.5 μl, 376 μmol) and TBTU (121 mg, 376 μmol). The mixture was allowed to stir at room temperature for 16 h, poured into ice/water (5 ml) and 1N NaOH (5 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4) and evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) and trituration from dichloromethane (1 ml) and heptane (5 ml) for 30 min. The precipitate was collected by filtration, washed with heptane and dried to yield the title compound as a white solid (39 mg, 42%), MS (ISP) m/z=369.3 [(M+H)+], mp 162° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:31])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([O:29]C)=[O:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Li+]>CO.O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:31])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNc3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNc3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-42 (70 mg) was dissolved in methanol (5 ml) and a lithium hydroxide solution (45 mg) in water (5 ml) was added thereto. The same manner to Example 2-12 was conducted to give the titled compound as a colorless solid. Yield: 14 mg (21%); mp 247° C., MS APCI-ve 413 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([C:13]#[N:14])=[CH:5]2.[CH3:15][O-:16].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:16][CH3:15])[C:6]([C:13]#[N:14])=[CH:5]2
Reactant: C[O-]
Reactant: N#Cc1cc2cc(Br)ccc2nc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc2ccc(Br)cc2cc1C#N

Procedure:
A solution of 6-bromo-2-chloro-3-cyano-quinoline (1.2 g) in methanol (30 cm3) was heated under reflux for 16 hours with sodium methoxide [made from sodium (0.116 g) and methanol (20 cm3)]. The mixture was cooled to 0° and the solid filtered to afford 6-bromo-3-cyano-2-methoxyquinoline, m.p. 172°-174°, (0.60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]>C(=O)(O)[O-].[Na+].C(OCC)C.C(Cl)Cl>[OH:12][C:13]1[CH:22]=[C:21]([O:23][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chlorobenzenesulfonyl chloride (2.49 g, 0.018 mol) was added dropwise to a rapidly stirred mixture of methyl 3,5-dihydroxybenzoate in saturated sodium bicarbonate (20 mL) and diethyl ether (20 mL) and allowed to stir at ambient temperature. After 2 days, 1.25 g of 2-chlorobenzenesulfonyl chloride was added and stirred for an additional 1 day. The reaction mixture was diluted with methylene chloride and separated. The aqueous layer was extracted with methylene chloride. The combined methylene chloride extracts were washed with brine and water, dried, and evaporated to an oil. The oil was triturated with hexanes (4 times) before placing the residual oil on a silica gel column and eluted first with methylene chloride, then 10% ethyl acetate/methylene chloride. The appropriate fractions were evaporated to give 1.35 g of solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[CH3:22][O:23][CH2:24][C:25](OC)=[O:26].O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:25](=[O:26])[CH2:24][O:23][CH3:22])=[CH:9][N:10]=1
Reactant: c1csc(C2OCCO2)n1
Reactant: COCC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COCC(=O)c1cnc(C2OCCO2)s1
Temperature: -70 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (2.20 g) in tetrahydrofuran (50 mL) was slowly added a 1.6M n-butyllithium hexane solution (9.6 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 1 hr, and methyl methoxyacetate (2.91 g) was added. The reaction mixture was warmed to room temperature, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (2.00 g, yield 62%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 65-66° C.
Reaction SMILES: [C:1](=[O:3])=O.Cl.[CH2:5]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl.C(OCC)C>[N-:15]=[C:1]=[O:3].[CH2:5]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C=O
Agent: C[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: [N-]=C=O

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (20 mL) solution containing alanine benzyl ester hydrochloride salt (0.003 mol, 0.65 g) and triethylamine (0.013 mol, 1.3 g) at -10° C. (ice and salt bath) for 30 min at a pressure of psig. The reaction mixture was transferred via cannula all at once under carbon dioxide to the precooled solution of phosphorus oxychloride (0.003 mol, 0.5 g) in 20 mL dichloromethane. After stirring for 20 min at -10° C. diethylether (40 mL) was added to the reaction mixture. A white ppt formed and was filtered off. The filtrate was concentrated in vacuo and the residue was extracted with 3×20 mL diethylether. The ether layers were concentrated and the residue was distilled under vacuum (ca. 0.1-0.3 torr) collecting product, alanine benzyl ester isocyanate, at 95°-96° C. (0.19 g, 30.9%) of 99% purity as judged by GC. IR (neat) 2241, 1744 cm-1. 1H NMR (CDCl3) δ 7.36 (s, 5H), 5.22 (s, 2H), 4.10 (q, 1H, J=14.3), 1.49 (d, 3H, J=7.1) ppm.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:19][C:20]1[CH:56]=[CH:55][CH:54]=[CH:53][C:21]=1[CH2:22][NH:23][C:24]([C@@H:26]1[C:30]([CH3:32])([CH3:31])[S:29][CH2:28][N:27]1[C:33](=[O:52])[C@@H:34]([OH:51])[C@@H:35]([NH:43][C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:56]=[CH:55][CH:54]=[CH:53][C:21]=1[CH2:22][NH:23][C:24]([C@@H:26]1[C:30]([CH3:32])([CH3:31])[S:29][CH2:28][N:27]1[C:33](=[O:52])[C@@H:34]([OH:51])[C@@H:35]([NH:43][C:44](=[O:50])[C@@H:45]([NH:46][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[CH:47]([CH3:49])[CH3:48])[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:25]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: CCOCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Ethoxyacetic acid (28 μl), HOBt (41 mg), and HDC.HCl (63 mg) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in DMF (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was recrystallized from ethyl acetate/n-hexane to obtain the title compound (153 mg).