Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[H-].[Na+].[Br:14][C:15]1[C:16](Cl)=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1.OC1C=CC([N+]([O-])=O)=CN=1>C(OCC)C>[Br:14][C:15]1[C:16]([CH3:1])=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: O=[N+]([O-])c1ccc(O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ncc([N+](=O)[O-])cc1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of diethyl malonate (17.6 mL, 0.116 mol) in diethyl ether (250 mL) at ambient temperature was treated with sodium hydride (80% in mineral oil, 3.5 g, 0.116 mol), and the mixture was stirred for 1 hour. Then 3-bromo-2-chloro-5-nitropyridine (25 g, 105 mmol; prepared from 2-hydroxy-5-nitropyridine according to the procedure of V. Koch and S. Schnatterer, Synthesis 1990, 499-501) was added in portions over 5 minutes. After the mixture had stirred for 1 hour, the solvent was evaporated, and the residue was heated at 100° C. for 1 hour. After the mixture had cooled, 12 N H2SO4 was added, and the mixture was heated at reflux for about 16 hours. The mixture was allowed to cool to ambient temperature, then further cooled as it was treated with 50% NaOH to give an alkaline pH. The resulting solution was extracted with CHCl3 (3×), and the organic extracts were washed with H2O, dried (MgSO4) and evaporated to afford 17.1 g of the title compound as a red oil: 1H NMR (CDCl3, 300 MHz) δ2.81 (s, 3H), 8.61 (d, J=2 Hz, 1H), 9.26 (d, J=2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10](Cl)[C:9]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:9]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: Fc1ccc2c(c1)Sc1cc(Cl)ccc1CC2Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1OCCN1CCN1CCN(C2Cc3ccc(Cl)cc3Sc3cc(F)ccc32)CC1

Procedure:
17 G. of 3,10-dichloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin are treated with 45.5 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and stirred at 120°-130° C. (internal temperature) for 8 minutes. The mixture is treated with 2N sodium hydroxide and extracted with ether. The ether solution is washed to neutrality and shaken out with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and extracted with methylene chloride. The organic solution is washed with water and dried over magnesium sulfate. The residue is recrystallized from acetone, whereby there is obtained 3-{2-[4-(3-chloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone (melting point 168°-170° C.) which is converted into the dimethanesulfonate (melting point 191°-193° C.) by reaction with methansulfonic acid.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]([C@@H:7]([C@@H:9]([C@H:11]([CH3:13])[OH:12])[OH:10])[OH:8])=[O:6]>O>[O:3]=[CH:4][C@H:5]([C@@H:7]([C@@H:9]([C@H:11]([CH3:13])[OH:12])[OH:10])[OH:8])[OH:6]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)C(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Temperature: 37 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
Scaled up sequential synthesis of 1. Compound 6 (6.0 g, 50 mmol) was hydrolyzed in water (50 mL) with Dowex 50W-X8 resin (H+ form, 200-400 mesh, 6.0 g, pH 2.8) for 4 h at 60° C. After the resin was filtered off and washed with water, a solution of 2 (18.60 mL, 10.0 mmol, synthesized by Wong, C.-H. J. Org. Chem. 1994, 59, 7182) was added, the mixture adjusted to pH 6.8 with 6N NaOH (1.8 mL) and L-fuculose aldolase (24 mL, 305 units) was added. The mixture was readjusted to pH 6.8 with 6N NaOH (0.2 mL) and the solution was degassed with argon and protected from light. After 3 h at room temperature (DHAP analysis indicates 95% conversion) the mixture was adjusted to pH 4.7 with 6N HCl (1.8 mL), acid phosphatase (1.33 mL, 400 units) was added and the mixture heated at 37° C. for 18 h. The mixture was then cooled to room temperature and adjusted to pH 7.5 with 6N NaOH (2.6 mL). MnCl2 (1 ml, 0.11 M) and L-fucose isomerase (4 mL, 3280 units) were added. The mixture was stirred at room temperature for 9 h and adjusted to pH 7.0 with 6N HCl. Methanol (2 vol) was then added and the precipitate was filtered off through Celite and washed with MeOH (4×25 mL). MeOH was removed under reduced pressure (bath temp. <25° C.) and water (100 mL) was added on the aqueous residue and the mixture was continuously extracted with AcOEt for 48 h. The organic extract was discarded and the aqueous solution evaporated under reduced pressure (bath temp. <25° C.). The residue was treated with methanol (50 mL) and the white solid formed was filtered off, washed with more methanol (2×15 mL) and discarded. Charcoal was added to the filtrate and the mixture heated at 30° C. for 15 min. After filtration to remove charcoal, methanol was removed and toluene was added time to time to remove traces of water (bath temp. <25° C.). After removing the solvents, the residue was dissolved in hot absolute ethanol (12.5 mL), seeded with 1 and stored at 4° C. for 2 days. Compound 1 (543 mg, 3.3 mmol, 33.1%) was obtained as a white solid whose physical and spectroscopic data were in accordance with those from an authentic sample: m. p. 139-140° C.; [α]D=−76.6° (c=0.9, water).
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2].N1CCCCC1.[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45]([NH:47][CH2:48][C:49]3[CH:57]=[CH:56][C:52](C(O)=O)=[CH:51][CH:50]=3)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1>CN(C=O)C.C(N(CC)C(C)C)C>[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45]([NH:47][CH2:48][C:49]3[CH:50]=[CH:51][C:52]([C:1]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:2])=[CH:56][CH:57]=3)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCC1c2ccccc2-c2ccccc21
Agent: CCN(CC)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(O)CCNC(=O)c1ccc(CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To the above resin bound Fmoc β-alanine was added 500 μL of a 20% solution of piperidine in DMF. Upon shaking for 30 min, the resin was drained and washed with 1 mL DMF containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2×1 mL). Then 200 μmol 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benzoic acid (74.2 mg) dissolved in a mixture of 430 μL DMF and 70 μL diethylisopropylamine was added followed by 200 μmol bromo-tris-pyrrolidinophosphosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 μL DMF. The mixture was shaken for 4 hours at 25° C. followed by filtration and washing of the resin with 3×1 mL DMF.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[C:15]=1[C:24]([OH:26])=[O:25])(=[O:12])=[O:11])([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[C:15]=1[C:24]([OH:26])=[O:25])(=[O:12])=[O:11]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])ccc2c1CCCC2
Agent: [Ni]
Solvent: CO
Product: Nc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Reaction time: 5 h
Yield: 90.4 %

Procedure:
A solution of Example 270 (1.4192 g, 3.77 mmol) in methanol (20 mL) was added to Raney-nickel (14.1 g). The vessel was pressurized to 60 psi with H2 and shaken for 5 hours. The reaction was then filtered and concentrated to yield the desired product (1.18 g, 90%). MS (ESI(+)) m/e 332 (M+H)+, 364 (M+NH4)+, 369 (M+Na)+; MS (ESI(−)) m/e 345 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.48 (d, 1H), 7.17 (t, 1H), 6.92 (d, 1H), 6.80 (d, 1H), 6.71 (d, 3H), 6.52 (t, 1H), 2.92 (m, 2H), 2.58 (m, 2H), 1.60 (m, 4H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.B(F)(F)F.[O:31]1CC[CH2:33][CH2:32]1>>[O:1]1[C:3]2([CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:2][O:31][CH2:32][CH2:33]1
Reactant: C1CCOC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: FB(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)COCCO4)c(F)c2)C(=O)O1
Yield: 44 %

Procedure:
A mixture of (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.275 mmol) ethylene glycol (0.330 mmol) and Catalytic amount of BF3.etharate in 10 ml tetrahydrofuran was stirred under reflux for 2 hours. The reaction mixture was evaporated to the dryness under vacuum. The residue obtained was purified on the silica gel column chromatography to provide title compound in 44% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.O.[C:21](O)(=[O:23])C>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:8])[C:3]=1[OH:9])[CH:21]=[O:23]
Reactant: Oc1c(F)cccc1F
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C

Procedure:
2,6-difluorophenol (1 eq) and hexamethylenetetramine (2 eq) were dissolved in a water/acetic acid mixture (10:90). The reaction mixture was refluxed for 18 hours then cooled to room temperature.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8].ClC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:35][C:36]1[S:37][C:38](Br)=[CH:39][CH:40]=1.[OH-].[NH4+].O>CN1CCCC1=O>[Br:35][C:36]1[S:37][C:38]([N:3]2[CH:4]=[CH:5][S:1]/[C:2]/2=[N:6]\[C:7]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:8])=[CH:39][CH:40]=1
Reactant: Brc1ccc(Br)s1
Reactant: O=C(Nc1nccs1)N1CCCC1
Agent: Clc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(/N=c1\sccn1-c1ccc(Br)s1)N1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial charged with a stir bar, N-1,3-thiazol-2-ylpyrrolidine-1-carboxamide (69 mg, 0.35 mmol, Example 32A) was added, followed by copper(I) trifluoromethanesulfonate benzene complex (35 mg, 0.07 mmol), 5-chloro-1,10-phenanthroline (30 mg, 0.14 mmol) and cesium carbonate (125 mg, 0.39 mmol). A loose cap with a septum was placed on the vial and then the vial was placed under vacuum in a vacuum oven for 30 minutes. The solid mixture was purged with nitrogen gas a couple of times. 2,5-Dibromothiophene (102 mg, 0.42 mmol) dissolved in 1-methyl-2-pyrrolidinone (1.0 mL) was added to the mixture. The vial was capped and placed on a heater/stirrer and heated to 120° C. overnight. Then 1 mL of a solution of concentrated ammonium hydroxide/water (1:2) was added. The reaction was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (C8, gradient 10-100% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: C[C:2](=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].Cl>CO>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]([CH3:7])=[CH:2][C:3]([OH:5])=[O:4])=[CH:13][CH:12]=1
Reactant: CC(C(=O)O)=C(C)c1ccc(OCCCCO)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=CC(=O)O)c1ccc(OCCCCO)cc1
Yield: 86.9 %

Procedure:
In a 300 ml three neck distillation flask, the compound prepared above in (6b) (20.4 g, 77.2 mmol) and methanol (50 ml) were placed. To the flask, aqueous solution (30 ml) of potassium hydroxide (8.66 g, 154 mmol) was dropwise added. After the mixture was refluxed for 2 hours, dilute hydrochloric acid was added to precipitate crystalline product. The product was collected by filtration, and recrystallized from acetonitrile to obtain the titled compounds (16.8 g, yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc(F)cc2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg (0.067 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 3 mg (0.08 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 12 mg (0.08 mmol) of 4-fluorobenzyl chloride was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: C([Mg]Br)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[O:12]=[C:13]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[OH:12][C:13]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]1
Reactant: COC(=O)C1CC(=O)C1
Reactant: COc1ccc(C[Mg]Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)C1CC(O)(c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Anisylmagnesium bromide (15.6 mL of 0.5 M solution in THF, 7.80 mmol) was added dropwise over 1 h to a stirred solution of methyl 3-oxocyclobutanecarboxylate (1.00 g, 7.80 mmol) in dry Et2O (71.0 mL) at −78° C. under N2. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Satd aq. Na2SO4 was added and the mixture was stirred until a clear solution resulted. This mixture was extracted with Et2O (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 20% EtOAc in hexanes over 2088 mL, gradient to 40% EtOAc in hexanes over 2448 mL) to afford methyl 3-hydroxy-3-(4-methoxyphenyl)cyclobutanecarboxylate. Rf=0.18 (20% EtOAc/hexanes). LCMS calc.=259.10. found=259.01 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 3.75 (s, 3H); 3.44-3.37 (m, 2H); 3.32-3.18 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:33])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:36]1([CH2:42][C:43]([NH2:45])=[O:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:33])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:39]3[CH2:40][CH2:41][N:36]([CH2:42][C:43]([NH2:45])=[O:44])[CH2:37][CH2:38]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1ccccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C32H36N5O3Cl2 [(M+H)+] 608.2190, observed 608.2190.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CC[CH:32]([N:35]=[C:36]=NC2CCCCC2)CC1.O1CCCC1.CNC>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([N:35]([CH3:36])[CH3:32])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 88.4 %

Procedure:
In 80 ml of dry THF were dissolved 4.9 g (20 m mol) of N-benzyloxycarbonyl-L-proline (29) and 3.5 g (26 m mole) of HOBT and then 4.53 g (22 m mol) of DCC was slowly added to the solution at 0° C. After stirring the mixture for 30 minutes at the same temperature, 10 ml of solution of 2M dimethylamine tetrahydrofuran was added. The resulting mixture was allowed to stand for 12 hours at room temperature. THF was distilled off from the reaction mixture under reduced pressure, the residue thus formed was dissolved in 200 ml of ethyl acetate, and the solution was washed, in succesion, with 75 ml of an aqueous solution of 0.5N hydrochloric acid, 75 ml of a saturated aqueous sodium hydrogencarbonate solution, and 50 ml of water. After drying the organic layer with anhydrous magnesium sulfate, ethyl acetate was distilled off and the residue thus formed was purified by silica gel column chromatography (400 ml of Wako gel C-200, ethyl acetate) to provide 4.8 g of (S)-1-benzyloxycarbonyl-N,N-dimethyl-2-pyrrolidinecarboxamide (88) having a melting point of 66°-67° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][N:20](C=O)[CH2:19][C:18]=3[CH:26]=2)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>CO.Cl>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][NH:20][CH2:19][C:18]=3[CH:26]=2)=[O:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CN(C=O)CCO3)CC1
Agent: Cl
Solvent: CO
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CNCCO3)CC1
Yield: 96.8 %

Procedure:
A solution of the 3-(1-acetyl-4-piperidinyl)-1-(4-formyl 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1-propanone (6.77 g) in methanol (100 ml) and concentrated hydrochloric acid (100 ml) were heated together at 80-85° C. for 2 hours. The methanol was then distilled off and the residual aqueous solution was made basic with saturated aqueous solution of potassium carbonate and extracted with ethyl acetate-tetrahydrofuran (2:1). The extract was washed with saturated NaCl/H2O and dried over MgSO4, and the solvent was distilled off under reduced pressure to provide 3-(1-acetyl-4-piperidinyl)-1-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1-propanone (6.04 g) as light-yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:30])=[C:5]([C@@H:10]2[S:15](=[O:17])(=[O:16])[CH2:14][C@@H:13]3[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N+:12]3([O-])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CO>[C:1]([C:3]1[C:4]([CH3:30])=[C:5]([C@@H:10]2[S:15](=[O:16])(=[O:17])[CH2:14][C@@H:13]3[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1c([C@H]2C[N+]3([O-])CCN(C(=O)OC(C)(C)C)C[C@H]3CS2(=O)=O)ccc(F)c1C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CS2(=O)=O)ccc(F)c1C#N
Temperature: 80 °C

Procedure:
The above compound from step A (23 mg, 0.052 mmol) was combined with TRIPHENYLPHOSPHINE (24.71 mg, 0.094 mmol) in DMF (0.4 M) and warmed to 80° C. for 20 minutes. LC-Ms showed the completion of the reaction. The reaction mixture was diluted with methanol and purified with mass-directed reverse phase HPLC eluting with 10% acetonitrile/water with 0.1% TFA to 100% acetonitrile with 0.1% TFA to yield the title compound: 1H-NMR (500 MHz, CD3OD): δ ppm 9.05 (m, 1H), 7.24 (m, 1H), 4.63 (bs, 1H), 4.03 (m, 2H), 3.32-3.45 (m, 2H), 3.05 (m, 3H), 2.92 (m, 1H), 2.75 (m, 2H), 2.63 (S, 3H), 2.25 (m, 1H), 1.48 (s, 9H); LC-MS: M+1=424.
Reaction SMILES: C=O.[OH:3][CH:4]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1)[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1.[BH4-].[Na+].Cl.[C:32](=O)([O-])O.[Na+]>CO>[OH:3][CH:4]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:22][CH:23]=1)[CH2:5][CH2:6][CH2:7][N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)[CH3:32]
Reactant: O=C([O-])O
Reactant: Cc1cccc(CCNCCCC(O)c2ccc(NS(C)(=O)=O)cc2)n1
Agent: C=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: Cc1cccc(CCN(C)CCCC(O)c2ccc(NS(C)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
5.19 ml of formalin was added to a solution of 2.12 g (free compound: 6.12 mmol) of N-[4-[1-hydroxy-4-[2-(6-methyl-2-pyridyl)ethylamino]butyl]phenyl]methanesulfonamide obtained in Example 3-(4) in 20 ml of methanol. The mixture was refluxed for 30 min. The mixture was cooled at 0° C. and 0.81 g of sodium borohydride was added in small portions thereto. The mixture was stirred at 0° C. for 20 min. 36 ml of 1N hydrochloric acid was added thereto to acidify it. The solution thus obtained was poured into 100 ml of a saturated sodium hydrogencarbonate solution. After extraction with dichloromethane, the organic layer was concentrated to give 2.16 g (yield: 94%) of the intended compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:6][CH2:7][N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9]1)[CH2:4][OH:5].C1([O:26][C:27](=O)[NH:28][C:29]2[S:30][C:31]([CH2:34][CH3:35])=[N:32][N:33]=2)C=CC=CC=1.C(N(CC)CC)C>CS(C)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:10]2[CH2:11][N:8]([CH2:7][CH2:6][C@H:3]([NH:2][C:27]([NH:28][C:29]3[S:30][C:31]([CH2:34][CH3:35])=[N:32][N:33]=3)=[O:26])[CH2:4][OH:5])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Reactant: CCc1nnc(NC(=O)Oc2ccccc2)s1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1

Procedure:
A solution of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride (1.04 g, 2.82 mmol), (5-Ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester (0.70 g, 2.82 mmol) and triethylamine (1.6 ml, 11.28 mmol) in DMSO (70 ml) is stirred at ambient temperature for 18 hour, then partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organic phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by recrystallisation from hot ethylacetate to afford 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea. [M+H] 426.18.