Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][N:21]([CH3:43])[CH2:22][C:23]([C:25]1[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]([O:33]CC2C=CC=CC=2)=[O:32])=[CH:27][CH:26]=1)=[O:24].CC#N.O>CO.[Pd]>[N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1][C:2]=1[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][N:21]([CH3:43])[CH2:22][C:23]([C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:41][CH:42]=1)=[O:24]
Reactant: CN(CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1)Cc1nc2ccccc2n1Cc1nc2ccccc2[nH]1
Agent: [Pd]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CN(CC(=O)c1ccc(OCC(=O)O)cc1)Cc1nc2ccccc2n1Cc1nc2ccccc2[nH]1
Reaction time: 1 h

Procedure:
A mixture of benzyl 4-[2-[[[1-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetate (0.08 g, 0.18 mmol) and 5% Pd/C (0.11 g) in MeOH (15 mL) was shaken on a Parr apparatus under H2 (41 psi) for 1 h. The mixture was filtered through a bed of celite®, and the filter pad was washed with glacial AcOH and MeOH. The filtrate was concentrated to give the crude product (0.07 g). Preparative HPLC (Hamilton PRP-1® column, step gradient, 10-30% CH3CN/H2O containing 0.1% TFA) afforded the title compound: MS (ES) m/e 484.2 [M+H]+. Anal. Calcd for C27H25N504 .3 C2HF3O2 : C, 48.01; H, 3.42 N, 8.48. Found: C, 48.40; H, 3.72; N, 8.77.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH:19]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:20]1[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:19]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:20]2[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C1CCCCN1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCCCN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl pipecolinate hydrochloride (Aldrich), the title compound was prepared as a solid (mp=114-118° C.). The reaction was monitored by tlc (Rf=0.71 in 10% MeOH/DCM) and the product was purified by acid/base washes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:53].CCCCCC>C1COCC1>[Br:53][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Br)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methyl-4-hydroxypyrrolidine (910 mg, 2.0 mmol) and Ph3P (628 mg, 2.4 mmol) in THF (20 ml) was added CBr4 (993 mg, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hr. n-Hexane (40 ml) was added thereto. The resulting solid was filtered off, and dried in vacuo. The residue was purified by column chromatography on silica gel with n-hexane to n-hexane-EtOAc (3:2, v/v) as eluent to give cis-4-bromo-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methylpyrrolidine (1.0 g, quant.) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.06 (s, 9H), 1.31 and 1.45 (each s, 9H), 2.63 (m, 2H), 3.49 (m, 1H), 3.89–4.14 (m, 5H), 7.35–7.42 (m, 6H), 7.64–7.66 (, 4Hm).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=2)=[C:10]([C:19]([OH:21])=O)[S:11][C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:32]([N:34]([CH2:37]C)[CH2:35]C)C.Cl.[CH3:40][NH:41][O:42][CH3:43]>ClCCl.CN(C=O)C>[CH3:32][N:34]([CH:37]=[N:29][S:28]([C:25]1[CH:24]=[CH:23][C:22]([C:9]2[C:8]([CH3:7])=[C:12]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:11][C:10]=2[C:19]([N:41]([O:42][CH3:43])[CH3:40])=[O:21])=[CH:27][CH:26]=1)(=[O:30])=[O:31])[CH3:35]
Reactant: CCN(CC)CC
Reactant: Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.2 %

Procedure:
Oxalyl chloride (0.19 g, 0.13 ml, 1.49 mmol) was added dropwise at 0° C. to a solution of 4-methyl-5-morpholino-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 24e, 0.19 g, 0.497 mmol) in a mixture of dichloromethane (15 ml) and DMF (0.073 g, 0.08 ml, 0.99 m mol). The resulting mixture was allowed to warm to room temperature and stirred for 1.5 hr, under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and used directly for further reaction. The residue so obtained was dissolved in dry dichloromethane (15 ml) and to this was added triethylamine (0.251 g, 0.35 ml, 2.48 mmol) followed by the addition of N,O-dimethylhydroxylamine hydrochloride (0.098 g, 0.99 mmol) under stirring at 0° C. The reaction mixture was stirred at room temperature for 2 hr. The progress of reaction was monitored by TLC. The reaction mixture was washed with water (2×10 ml) and the resulting organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude product. The crude product was further purified by column chromatography over silica gel (100-200 mesh) using 1% methanol in dichloromethane as an eluent to obtain the title compound (0.127 g, 53%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:14])=[O:13].B(F)(F)F.[C:19](=O)(O)[O-].[Na+]>>[CH3:19][O:13][C:12]([C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:9]=2[CH:10]=[CH:11][C:2]=1[OH:1])=[O:14]
Reactant: O=C(O)c1c(O)ccc2ncccc12
Reactant: O=C([O-])O
Agent: FB(F)F
Agent: [Na+]
Product: COC(=O)c1c(O)ccc2ncccc12

Procedure:
6-Hydroxy-5-quinolinecarboxylic acid [as reported by Da Re, P. et al. in Ann. Chem. (Rome) 1970, 60(3), 215-24 (C. A. 73, 25338m)] is reacted with methanolic boron trifluoride solution for several hours. The resulting mixture is added to an aqueous solution of sodium bicarbonate to give finally a basic solution. The solution is extracted with chloroform. The chloroformm extract is dried over anhydrous sodium sulfate and concentrated and the residue is crystallized from a suitable solvent.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([NH:17][CH3:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([NH:17][CH3:18])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: OCc1ccsc1
Reactant: CNc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution of 3-thiophenemethanol (1.42 g, 0.0113×1.1 mol) in 20 ml of dry tetrahydrofuran, sodium hydride (1.35 g (ca.60% in mineral oil), 0.0113×3.0 mol) was added. After the bubbling ceased, a solution of 2,6-dichloro-4-methylaminopyridine (2.0 g, 0.0113 mol) in 30 ml of dry tetrahydrofuran was added dropwise at room temperature.
Reaction SMILES: [NH2:1][OH:2].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>>[OH:2][NH:1][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NO
Reactant: CCOC(=O)/C=C\C(=O)OCC
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 1 h

Procedure:
Hydroxylamine free base (50% aqueous solution, 2.0 g, 30.3 mmol) was dropwise added to diethyl maleate (4.41 g, 25.6 mmol) and stirred for 60 minutes at 40°-45° C. to give diethyl N-hydroxyaspartate. Toluene (5.02 g) and p-toluenesulfonic acid (0.05 g, 0.26 mmol) were added to the reaction mixture and refluxed for 4.5 hours. The reaction mixture was analyzed by GLC, which showed that the reaction proceeded to give 89% diethyl 2-aminomaleate (80% yield based on the external standard).
Reaction SMILES: O1CCCC1.[CH2:6]([O:8][C:9](=[O:42])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH:22]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[C:23](=[N:26][C:27]([O:29]CC)=O)SC)[C:15]=1[F:41])[CH3:7].[N:43]1[CH:48]=[CH:47][CH:46]=[N:45][C:44]=1[NH:49][NH2:50].N12CCCN=C1CCCCC2>CO>[CH2:6]([O:8][C:9](=[O:42])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH:22]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]#[N:40])=[CH:37][CH:38]=2)[C:23]2[NH:26][C:27](=[O:29])[N:49]([C:44]3[N:45]=[CH:46][CH:47]=[CH:48][N:43]=3)[N:50]=2)[C:15]=1[F:41])[CH3:7]
Reactant: CCOC(=O)N=C(SC)C(Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCOC(=O)OCC)c1F
Reactant: NNc1ncccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)OCCOc1cc(OC)cc(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1F
Reaction time: 1 h

Procedure:
After the atmosphere in the reaction vessel had been replaced with nitrogen, the tetrahydrofuran solution containing Carbonic acid 2-(3-{1-(4-cyanophenylamino)-2-[ethoxycarbonylimino]-2-methylsulfanylethyl]-2-fluoro-5-methoxyphenoxy)ethyl ester ethyl ester obtained in Example 64 was added, rinsing in with tetrahydrofuran (1250 mL) and stirred. Thereafter, pyrimidin-2-yl-hydrazine (275 g, 2.497 mol) was added portionwise at a bath temperature of 15° C., rinsing in with tetrahydrofuran (1000 mL), and the mixture was stirred at a bath temperature of 22° C. for 14 hours. Pyrimidin-2-yl-hydrazine (8.2 g, 0.074 mol) was additionally added, rinsing in with tetrahydrofuran (30 mL), and stirring was continued for one hour. Thereafter, the bath temperature was set at 15° C., 1,8-diazabicyclo[5.4.0]undec-7-ene (304 g, 1.999 mol) was added dropwise to the mixture, rinsing in with tetrahydrofuran (50 mL), and then the bath temperature was set at 22° C. and the mixture was stirred for 2.5 hours. Thereafter, the bath temperature was set at 15° C., and ethyl acetate (7504 mL) and 1 N hydrochloric acid (7504 mL) were added to the reaction solution. Then, the bath temperature was set at 22° C., the organic layer was collected, and the aqueous layer was further extracted with ethyl acetate (3752 mL). All the organic layers were combined, the organic layer was washed with 10% aqueous sodium chloride solution (7504 g) twice, and concentrated under reduced pressure. The residue obtained was subjected to azeotropic distillation three times with methanol (1250 mL of methanol was used, each time). To the residue obtained, tetrahydrofuran (375 mL) and methanol (475 mL) were added to obtain the suspension of the captioned compound.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl[CH2:39][C:40]1[NH:44][C:43]2[CH:45]=[C:46]([CH3:50])[C:47]([CH3:49])=[CH:48][C:42]=2[N:41]=1>C(#N)C>[CH3:50][C:46]1[C:47]([CH3:49])=[CH:48][C:42]2[NH:41][C:40]([CH2:39][N:11]([CH:9]3[C:10]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7][CH2:8]3)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])=[N:44][C:43]=2[CH:45]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: Cc1cc2nc(CCl)[nH]c2cc1C
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc2nc(CN(CCCCN3C(=O)c4ccccc4C3=O)C3CCCc4cccnc43)[nH]c2cc1C
Temperature: 60 °C
Yield: 28 %

Procedure:
To a stirred solution of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (154 mg, 0.441 mmol), diisopropylethylamine (0.15 mL, 0.861 mmol) and potassium iodide (15 mg, 0.090 mmol) in acetonitrile (2.5 mL) was added 2-chloromethyl-5,6-dimethyl-1H-benzimidazole (prepared according to the procedures described in Bridger et al. U.S. patent application U.S. Ser. No. 09/535,314) (77 mg, 0.426 mmol) and the mixture heated at 60° C. for 18 hours. The mixture was then concentrated and the residue diluted with CH2Cl2 (30 mL). The solution was washed with saturated aqueous NaHCO3 (1×20 mL) and brine (2×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give a crude brown foam. The foam was purified by flash chromatography (1.75 cm ID, 12 g silica, 50:1:1 CH2Cl2: MeOH: NH4OH) to give pure 2-{4-[(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (60 mg, 28%). 1H NMR (CDCl3) δ 1.34-1.51 (m, 2H), 1.53-1.73 (m, 3H), 1.81-2.06 (m, 2H), 2.12-2.22 (m, 1H), 2.34 (s, 6H), 2.55-2.89 (m, 4H), 3.51 (t, 2H, J=7.3 Hz), 3.93-4.08 (m, 3H), 7.1 (dd, 1H, J=7.5, 4.8 Hz), 7.31-7.39 (m, 3H), 7.63-7.67 (m, 2H), 7.72-7.77 (m, 2H), 8.58 (d, 1H, J=4.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[CH3:9].[ClH:10].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:15]([Cl:10])(=[O:17])=[O:16])=[CH:4][C:3]=1[CH3:9]
Reactant: Cl
Reactant: O=S=O
Reactant: Cc1cc(N)cnc1Cl
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)Cl)cnc1Cl
Yield: 62 %

Procedure:
Under ice-cooling, thionyl chloride (0.6 mL) was added dropwise over 30 min to water (3.4 mL). The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, under ice-cooling, 6-chloro-5-methylpyridine-3-amine (278 mg) was added to concentrated hydrochloric acid (6 mL) and the mixture was stirred. An aqueous solution (2 mL) of sodium nitrite (148 mg) was added dropwise while keeping the inside temperature at not higher than 5° C., and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 5° C. to the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (5 mg). Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration and washed with water to give the title compound as a pale-yellow solid (yield 271 mg, 62%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(=O)(O)O.[NH2:12][C:13]([NH2:15])=[NH:14]>O>[O-:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[NH2:14][C:13]([NH2:15])=[NH2+:12]
Reactant: O=C(O)C(F)(F)F
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Product: NC(N)=[NH2+]
Product: O=C([O-])C(F)(F)F
Temperature: 90 °C

Procedure:
Trifluoroacetic acid (50.0 ml, 74.0 g, 649 mmol) was added to 500 ml of distilled water in a 4-liter beaker with stirring. Guanidine carbonate (58.5 g, 324.5 mmol) was added at room temperature in portions with stirring as to avoid bubbling over the sides of the beaker due to the evolution of carbon dioxide. The reaction was stirred at room temperature for 2 hours. The water was removed in vacuo with heating to approximately 90° C. for 4 hours. The product was recovered as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[N:13][OH:14]
Reactant: COc1cccc(F)c1C=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(F)c1C=NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with 2-fluoro-6-methoxylbenzaldehyde (Compound A, 2.43 g, 15.8 mmol) and hydroxylamine hydrochloride (“NH2OH. HCl”, 1.21 g, 17.3 mmol) in ethanol (60 mL) and H2O (120 mL) was added aq. NaOH (50% w/w 3.2 mL). The reaction mixture was stirred at room temperature for 1 hour. At the conclusion of this period, the reaction was neutralized with concentrated HCl to pH 7 and then extracted with methylene chloride (“CH2Cl2”, 3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide 2-fluoro-6-methoxybenzaldehyde oxime, Compound B, as a white solid (2.45 g, 92%). m/z (ES+) 169 (M+H).
Reaction SMILES: Cl.Cl.N=[C:4]1[CH:10]([OH:11])[CH2:9][CH2:8][CH2:7][CH:6]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[NH:5]1.C(C1CCCCC(=O)N1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=C.C[Si]([O:40]O[Si](C)(C)C)(C)C>>[OH:11][CH:10]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:4]1=[O:40]
Reactant: N=C1NC(CN2CCOCC2)CCCC1O
Reactant: C=CC1CCCCC(=O)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)OO[Si](C)(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1C(=O)C(O)CCCC1CN1CCOCC1

Procedure:
hexahydro-2-imino-7-[(4-morpholinyl)methyl]-1H-azepin-3-ol, dihydrochloride ##STR220## 215 A) The product of Example 214, part A, 1,1-dimethylethyl 2-ethenylhexahydro-7-oxo-1H-azepine-1-carboxylate, is treated with an organo lithium base at low temperature to generate the enolate which is subsequently reacted with bis(trimethylsilyl)peroxide by the methods of F. A. Davis et al Tettrahodron Lett. 1988, 29, 4269 and L. Camici et al Tettrahodron Lett. 1988, 29, 4197 to yield 1,1-dimethylethyl hexahydro-3-hydroxy-7-[(4-morpholinyl)methyl]-2-oxo-1H-azepine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:38])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH2:33][C:34](=[NH:37])[NH:35]O)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:39](N1C=CN=C1)(N1C=CN=C1)=[S:40].O.C(OCC)(=[O:54])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:38])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH2:33][CH:34]5[NH:37][C:39](=[O:54])[S:40][NH:35]5)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCOC(C)=O
Reactant: N=C(COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2)NO
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(COc2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)NS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of Example 407 (700 mg) in THF (20 ml) was added thiocarbonyldiimidazole (280 mg) and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. The organic layer was extracted, and the solvent was distilled off under reduced pressure. To the residue were added THF (50 ml) and boron trifluoride diethyl etherate (0.8 ml), and the mixture was stirred at room temperature for 1 hour. Chloroform, 2-propanol and water were added to the reaction mixture. The organic layer was extracted, and the solvent was distilled off under reduced pressure. The residue was reslurried with acetone to the titled compound (180 mg).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[C:15]([C:17](=[N:28]OS(C1C=CC(C)=CC=1)(=O)=O)[C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[C:23]#[N:24])#[N:16]>C(O)C>[NH2:16][C:15]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([C:23]#[N:24])[CH:25]=2)=[N:28][S:1][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: COc1ccc(C(C#N)=NOS(=O)(=O)c2ccc(C)cc2)cc1C#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1snc(-c2ccc(OC)c(C#N)c2)c1N
Reaction time: 5 h

Procedure:
Ethyl sulfanylacetate and triethylamine were dissolved in an ethanol solution of 5-[cyano({[(4-methylphenyl)sulfonyl]oxy}imino)methyl]-2-methoxybenzonitrile, followed by stirring for 5 hours under ice-cooling to obtain ethyl 4-amino-3-(3-cyano-4-methoxyphenyl)isothiazole-5-carboxylate. AP: 378.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O.ClCCl>O1CCCC1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[O:9])[CH2:3][CH2:2]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=C(Nc1ccc(F)cc1)NC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(F)cc1)NC1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of N-(piperidin-4-yl)-N′-(4-fluorophenyl)urea (0.3 g) in tetrahydrofuran (4 ml) were added in turn N,N-dimethylaminopyridine (0.23 g) and 4-fluorobenzenesulfonyl chloride (0.25 g) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was taken up into a mixture of water and dichloromethane. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give N-(1-(4-fluorophenylsulfonyl)-piperidin-4-yl)-N′-(4-fluorophenyl)urea (0.468 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][CH:13]([OH:16])[CH2:12][S:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][CH:13]([O:16][C:17](=[O:19])[CH3:18])[CH2:12][S:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC1CSC(COCc2ccccc2)CO1
Solvent: c1ccncc1
Product: CC(=O)OC1CSC(COCc2ccccc2)CO1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
5-Benzyloxymethyl-1,4-oxathian-2-ol (3.46 g) was dissolved in pyridine (37 ml), and the solution was cooled to 5° C. Acetic anhydride (3.27 ml) was added dropwise thereto, and the solution was stirred at the same temperature for 4 hours to complete the reaction. After removing the solvent by evaporation under reduced pressure, the residue was azeotroped with toluene to completely remove pyridine to obtain pale brown syrup. The syrup was purified on a silica gel column (eluent: n-hexane/ethyl acetate=3/1) to provide the desired product (2.94 g) as colorless syrup.
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[Br:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[Br:18][CH2:19][CH2:20][C:21]([N:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][CH2:10]1)=[O:22]
Reactant: O=C(Cl)CCBr
Reactant: c1ccc(C2CNCO2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCBr)N1COC(c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Four and five tenths (4.5) grams of 5-phenyl oxazolidine contained in 44.7 g. of benzene solution was mixed with 3.1 g. of triethylamine and stirred in a room temperature water bath, while 5.2 g. of 3-bromopropionyl chloride was added dropwise. After standing for about 30 minutes, the solution was washed with water, separated, dried over magnesium sulfate and the solvent stripped under vacuum. There was obtained a yield of 6 g. of an oil, the title compound, ND30 =1.5591.