Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:19])[F:20])[CH:12]=2)[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2cccc(OC(F)(F)F)c2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Yield: 95.6 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-5-methyl-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylate (6.0 g, 19.91 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (5.47 g, 19.04 mmol, 96%) was obtained.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=[O:41])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:45]=[CH:44][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(=O)OC)cc3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(OC)c1)OCC
Yield: 93.1 %

Procedure:
To a mixture of methyl 4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (0.34 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and tetrahydrofuran and methanol were evaporated under reduced pressure. The precipitated crystals were collected by filtration to give 4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (0.31 g, yield 94%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 194-195° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17](Br)=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:26]4[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(-c3ccc(OC)cc3)cc21
Temperature: 80 °C
Yield: 62.5 %

Procedure:
To a stirred solution of 9-bromo-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (0.20 g, 0.60 mmol), (o-tolyl)3P (0.19 g, 0.6 mmol) and 4-methoxyphenylboronic acid (0.23 g, 1.5 mmol) in DME/EtOH (1:1, 12 mL) was added 2.1 mL of 1M Na2CO3 solution and Pd(OAc)2 (27 mg) at ambient temperature. The reaction mixture was heated at 80° C. under N2 for 1 hour and monitored by LC-MS. The solution was diluted with DCM (20 mL), and washed with brine. The aqueous phase was extracted with DCM (20 mL) twice. The combined organic phase was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (0.136 g) as a light yellow solid; 1H-NMR (CDCl3): δ 10.41 (1H, s), 7.73 (1H, d), 7.50 (3H, m), 7.29 (1H, d), 7.21 (1H, d), 6.90 (2H, m), 5.23 (1H, s), 4.20 (2H, dd), 3.76 (3H, s), 3.55 (2H, m), 3.12 (2H, m), 1.26 (3H, t); MS (ESI): 363 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2([OH:19])[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[C:5]([CH2:20][CH:21]=[CH2:22])[CH:4]=1)=O.[ClH:23].[O:24]([NH2:26])[CH3:25]>C(O)C>[ClH:23].[CH3:25][O:24][N:26]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2([OH:19])[CH:16]3[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]3)[CH2:12]2)=[C:5]([CH2:20][CH:21]=[CH2:22])[CH:4]=1
Reactant: C=CCc1cc(C=O)ccc1C#CC1(O)CN2CCC1CC2
Reactant: CON
Agent: Cl
Solvent: CCO
Product: C=CCc1cc(C=NOC)ccc1C#CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-[2-(4-formyl-2-allylphenyl)ethynyl]quinuclidin-3-ol (1.0 g) and methoxylamine hydrochloride were dissolved in ethanol (35 ml) and the mixture stirred at 25° C. for 12 hours. The ethanol was evaporated and the residue crystallised from ethyl acetate to give 3-[2-(4-methoxyiminomethyl-2-allylphenyl)ethynyl]quinuclidin-3-ol hydrochloride as a solid, m.p. 143° C.; microanalysis, found: C, 64.7; H, 7.0; N, 8.0% C20H24N2O2HCl. 0.5H2O requires C, 64.9; H, 7.0; N, 7.6% NMR ([CD3 ]2SO/CD3COOD): 1.5-2.3 (5H, m), 3.2 (4H, t), 3.4 (1H, d), 3.6 (1H, dd), 3.9 (3H, s), 5.1 (2H, m), 6.0 (1H, m), 7.5 (3H, m) and 8.2 (1H, s), m/z 325 (M+H).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:50]/[O:51][CH:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)/[C:27]([NH:29][C@@H:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH2:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NC1SC=C(/C(=N/OC)/C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(NC(C)C)N=NN=4)CS[C@H]23)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:50]/[O:51][CH:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)/[C:27]([NH:29][C@@H:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH2:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC3CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: Nc1nc(/C(=N/OC2CCCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nnnn4N)CS[C@H]23)cs1
Yield: 33.4 %

Procedure:
A solution of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-cyclopentyloxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.27 g, 2.8 mmol) in 80% formic acid (11 ml) was stirred at room temperature for 50 minutes and then treated in a manner similar to that described in Example 6, (d) to give pale brown powder of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-cyclopentyloxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (0.53 g, 33%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([O:10][CH3:11])[CH:3]=1.ClCCl.[CH2:15](N(CC)CC)[CH3:16]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.CCO>[CH:15]([C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([O:10][CH3:11])[CH:3]=1)=[CH2:16]
Reactant: CCN(CC)CC
Reactant: COc1cc(Cl)ncc1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1cc(OC)c(C#N)cn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A 20 mL microwave tube was charged with 6-chloro-4-methoxypyridine-3-carbonitrile (200.0 mg, 1.2 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (97.0 mg, 0.12 mmol), potassium vinyl trifluoroborate (318.0 mg, 2.37 mmol), and triethylamine (0.33 mL, 2.37 mmol), and EtOH (6 mL). The microwave tube was evacuated and filled with nitrogen (two times) and heated to 140° C. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The extracts were concentrated and chromatographed over a column of SiO2 (0-30% EtOAc/hexanes as eluent). Evaporation of the solvent yielded the title compound. 1H NMR (500 MHz, DMSO-d6), δ 8.65 (s, 1H), 6.89 (s, 1H), 6.83 (dd, J=10.7 Hz, 1H), 6.42 (d, J=7.3 Hz, 1H), 5.70 (d, J=10.6 Hz, 1H) 4.05 (s, 3H);
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:31]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:38][CH2:37][CH2:36][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NCCN4CCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 2 mL of dioxane and 32.3 mg of 2-pyrrolidin-1-ylethanamine. After chromatography on a column of silica, eluting with a mixture of dichloromethane/methanol/28% aqueous ammonia (95/4/1 by volume), 42.4 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]-methyl}pyridin-2-yl)-3-(2-pyrrolidin-1-ylethyl)urea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:20][C@H:19]2[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[N:13]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O.NC1C=CC(Br)=CC=1NC([C@@H]1C[C@H]2[C@H](CCCC2)N1C(OC(C)(C)C)=O)=O>C(O)(=O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:10]([C@@H:12]3[CH2:20][C@H:19]4[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)[N:13]3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:1][C:2]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)Nc2ccc(Br)cc2N)C[C@@H]2CCCC[C@@H]21
Agent: CC(C)(C)OC(=O)N1[C@H](C(=O)Nc2cc(Br)ccc2N)C[C@@H]2CCCC[C@@H]21
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@H](c2nc3ccc(Br)cc3[nH]2)C[C@@H]2CCCC[C@@H]21
Temperature: 65 °C

Procedure:
An isomeric mixture (14) of (2S,3aS,7aS)-tert-butyl 2-((2-amino-4-bromophenyl)carbamoyl)octahydro-1H-indole-1-carboxylate and (2S,3aS,7aS)-tert-butyl 2-((2-amino-5-bromophenyl)carbamoyl)octahydro-1H-indole-1-carboxylate (160 g, 0.36 mol) was dissolved in acetic acid (480 mL) and the reaction mixture was stirred at 65° C. until the starting materials were consumed (as judged by LC-MS analysis). The reaction was cooled to rt and the solvent was removed under vacuum. The remaining residue was dissolved in ethyl acetate (500 mL) and aq ammonia (100 mL) was added carefully. Additional water (100 mL) was added and the organic layer was separated and collected. The aq phase was extracted with ethyl acetate (2×300 mL). The combined organic phase was washed with water (200 mL), followed by brine (200 mL), and dried over MgSO4. The solution was concentrated and the remaining residue was purified by silica gel column chromatography (hexanes/ethyl acetate) to afford (2S,3aS,7aS)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)octahydro-1H-indole-1-carboxylate (15) (140 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[S:33](Cl)(=[O:35])=[O:34]>O1CCCC1>[S:1]1[CH:5]=[C:4]([N:6]([S:33]([C:26]2[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=2[F:24])(=[O:35])=[O:34])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of tert-butyl 1,3-thiazol-4-ylcarbamate (Preparation 3, 28.94 g, 145 mmol) in anhydrous tetrahydrofuran (600 mL) at −70° C., under an atmosphere of nitrogen was added lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran, 145 mL, 145 mmol) drop-wise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour before cooling to −70° C. once again. A solution of 2, 4,5-trifluoro benzenesulfonyl chloride (40 g, 173 mmol) in tetrahydrofuran (80 mL) was added drop-wise and then the reaction mixture was slowly warmed to ambient temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution before concentrating in vacuo. The crude residue was purified by silica gel column chromatography (0% to 15% ethyl acetate in hexanes gradient elution) to afford the title compound as white solid (37 g, 64%).
Reaction SMILES: C([O:3][C:4]1[C:12]2(O)[CH:8]([C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][O:11]2)[CH2:7][CH2:6][CH:5]=1)C>CCO.Cl>[O:3]=[C:4]1[C:12]2[O:11][N:10]=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=2[CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)C1=NOC2(O)C(OCC)=CCCC12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1noc2c1CCCC2=O
Yield: 49.8 %

Procedure:
To a solution of ethyl 7-ethoxy-7a-hydroxy-3a,4,5,7a-tetrahydro-1,2-benzisoxazole-3-carboxylate 3.18 g (12.48 mmol) in 30 mL of EtOH, 3 mL of HCl 36% was added. The mixture was stirred at reflux for 48 hours. After cooling the solvent was removed under reduced pressure and the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/Hexane 3/7) to afford 1.3 g (50% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:6]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:6]=1)(=[O:27])=[O:26]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1

Procedure:
The title compound was prepared from 2-amino-4-(-3-nitrophenyl)thiazole and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (27.3 mg) with purity >90%. MS (pos) m/z 444.0, 446.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH2:24]([N:31]([CH2:33][CH2:34]Cl)[CH3:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:34][CH2:33][N:31]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:32])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2O)cc1
Yield: 114.3 %

Procedure:
A mixture of 9 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 7.7 g of 2-(N-benzyl-N-methylamino)ethyl chloride hydrochloride, 9.62 g of potassium carbonate and 600 ml of acetone is treated in the same manner as described in Example 4-(1). 14.8 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: CO[C:3](=[O:17])[CH:4]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[C:5]([O:7]C)=O.[NH2:18][C:19]1[NH:23][N:22]=[CH:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25].C(N(CCCC)CCCC)CCC>CO>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[C:4]1[C:3]([OH:17])=[N:18][C:19]2[N:23]([N:22]=[CH:21][C:20]=2[C:24]([O:26][CH3:27])=[O:25])[C:5]=1[OH:7]
Reactant: COC(=O)c1cn[nH]c1N
Reactant: COC(=O)C(C(=O)OC)c1c(F)cccc1Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: COC(=O)c1cnn2c(O)c(-c3c(F)cccc3Cl)c(O)nc12
Yield: 139.1 %

Procedure:
At room temperature, 15 g (57.5 mmol) of dimethyl(2-chloro-6-fluorophenyl)malonate were mixed with 9.4 g (57.5 mmol) of methyl 5-amino-1H-pyrazole-4-carboxylate and 15 ml (63.3 mmol) of tri-n-butylamine. The mixture was then stirred at 185° C. for 8 hours, during which time methanol was distilled off. After cooling, excess tri-n-butylamine was carefully decanted off. Concentration under reduced pressure gave 27 g of methyl 6-(2-chloro-6-fluorophenyl)-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (logPs=0.55; content according to HPLC: 83%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CC1C=CC(S(O)(=O)=O)=CC=1.C(N1CCOCC1)C.CN(C=O)C.[NH:41]([C:99]([O:101][CH2:102][C:103]1[CH:108]=[CH:107][CH:106]=[CH:105][CH:104]=1)=[O:100])[CH2:42][CH2:43][C:44]([NH:46][C@H:47]([C:58]([NH:60][CH2:61][C:62]([NH:64][C@H:65]([C:73]([NH:75][C@H:76]([C:84]([NH:86][C@H:87]([C:96](O)=[O:97])[CH2:88][C:89]1[CH:94]=[CH:93][C:92]([OH:95])=[CH:91][CH:90]=1)=[O:85])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)=[O:74])[CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:63])=[O:59])[CH2:48][CH2:49][CH2:50][NH:51][C:52](=[NH:57])[NH:53][N+:54]([O-:56])=[O:55])=[O:45].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:41]([C:99]([O:101][CH2:102][C:103]1[CH:104]=[CH:105][CH:106]=[CH:107][CH:108]=1)=[O:100])[CH2:42][CH2:43][C:44]([NH:46][C@H:47]([C:58]([NH:60][CH2:61][C:62]([NH:64][C@H:65]([C:73]([NH:75][C@H:76]([C:84]([NH:86][C@H:87]([C:96]([NH:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:97])[CH2:88][C:89]1[CH:90]=[CH:91][C:92]([OH:95])=[CH:93][CH:94]=1)=[O:85])[CH2:77][C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1)=[O:74])[CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:63])=[O:59])[CH2:48][CH2:49][CH2:50][NH:51][C:52](=[NH:57])[NH:53][N+:54]([O-:56])=[O:55])=[O:45]
Reactant: N=C(NCCC[C@H](NC(=O)CCNC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)N[N+](=O)[O-]
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
In 5 ml. of DMF was dissolved 275 mg. of H-Leu-OBzl-p-toluenesulfonate and the solution was neutralized with 0.9 ml. of 10 % N-ethylmorpholine-DMF. Under cooling at -10° C, 670 mg. of Z-β-Ala-Arg(NO2)-Gly-Phe-Phe-Tyr-OH, 251 mg. of HONB and 289 mg. of DCC were added. The mixture was stirred for 12 hours and the formed DC-urea was filtered off. The DMF was distilled off under reduced pressure and 30 ml. of water was added to the residue. The resulting precipitate was collected by filtration, washed with hot methanol and dried. Yield 703 mg. (87.9 %) melting point: 178- 181° C; α!D23 -15.0°(c=1.02 %, DMF)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.[C:16](OC(C)=C)(=[O:18])[CH3:17]>C(OCC)(=O)C>[C:16]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([NH2:1])[C:3]([C:12]([F:15])([F:13])[F:14])=[CH:4][CH:5]=2)[CH2:10]1)(=[O:18])[CH3:17]
Reactant: Nc1c(C(F)(F)F)ccc2c1CNCC2
Reactant: C=C(C)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2ccc(C(F)(F)F)c(N)c2C1

Procedure:
8-Amino-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, prepared as in Example 17, is treated with one molar equivalent of isopropenyl acetate in refluxing ethyl acetate by the procedure of Example 15 to give 2-acetyl-8-amino-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:13]([CH:22]=O)=[CH:12]1)(=[O:10])=[O:9].CO.[CH3:26][NH2:27].[BH4-].[Na+].[ClH:30].C(=O)([O-])O.[Na+]>CO>[ClH:30].[CH3:26][NH:27][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])(=[O:10])=[O:9])[CH:12]=1
Reactant: CN
Reactant: Cc1ccccc1S(=O)(=O)n1cc(C=O)cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2C)c1
Reaction time: 0.25 h
Yield: 76 %

Procedure:
1-[(2-Methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (390 mg) was dissolved in methanol (10 mL), 40% methylamine methanol solution (280 mg) was added at room temperature and the mixture was stirred for 15 min. To the reaction mixture was added sodium borohydride (70 mg) at room temperature and the mixture was stirred for 10 min. Thereto was added 1 mol/l hydrochloric acid (10 mL), and the mixture was stirred for 5 min. The mixture was alkalized with a saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=50:50→0:100), and the obtained oil was dissolved in ethyl acetate (5 mL). 4 mol/l Hydrochloric acid-ethyl acetate (1 mL) was added and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 342 mg, 76%).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([O:7]C2CCCCO2)[CH2:5][CH:4]([CH:14]=[CH:15][CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].Cl>C(O)C>[OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([CH:14]=[CH:15][CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCCCCC(O)C=CC1CC(OC2CCCCO2)C(O)C1CCCCCCC(=O)O
Agent: Cl
Solvent: CCO
Product: CCCCCC(O)C=CC1CC(O)C(O)C1CCCCCCC(=O)O
Reaction time: 8 h

Procedure:
A mixture of 7-[2-hydroxy-5-(3-hydroxyoct-1-enyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid [0.34 g.; prepared as described above in Example 2(h)], ethanol (10 ml.), N aqueous hydrochloric acid (10 ml.) and a cation exchange resin [Dowex resin AG50W-X 8H+ (1.0 g.)] was stirred at 60°-62°C. for 8 hours. The mixture was filtered and the solid was washed with ethanol. The combined filtrate and washings were concentrated in vacuo to remove most of the ethanol, and the residue was extracted twice with diethyl ether. The combined ethereal extracts were extracted with 2N aqueous sodium carbonate solution, and the aqueous extract was acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting aqueous mixture was extracted with diethyl ether and the ethereal extract was dried over magnesium sulphate and evaporated to dryness. The residue (0.13 g.) was subjected to preparative thin-layer chromatography on silica gel, using a mixture of ethyl acetate, cyclohexane and formic acid (40:40:1 by volume) as the eluent, to give 7-[2,3-dihydroxy-5-(3-hydroxyoct-1-enyl)cyclopentyl]-heptanoic acid (0.01 g.),νmax 1700 cm-1, 980 cm-1. Elemental analysis: found: C, 67.8; H, 10.4%; C20H36O5 requires C, 67.4; H, 10.2%.