Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([O:28]COC)=[CH:8][C:9]2[O:14][C:13]([CH3:16])([CH3:15])[C@@H:12]([OH:17])[C@H:11]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH:27]=1)=[O:4].B(Br)(Br)Br.CO.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([OH:28])=[CH:8][C:9]2[O:14][C:13]([CH3:16])([CH3:15])[C@@H:12]([OH:17])[C@H:11]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH:27]=1)=[O:4]
Reactant: COCOc1cc2c(cc1NC(=O)CCl)[C@@H](NCCc1ccccc1)[C@H](O)C(C)(C)O2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)Oc2cc(O)c(NC(=O)CCl)cc2[C@@H](NCCc2ccccc2)[C@@H]1O
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-N-{(±)-trans-3-hydroxy-7-methoxymethoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-6-yl}-acetamide (228 mg, 0.51 mmol) in methylene chloride (6 mL), boron tribromide (1 M solution in methylene chloride, 2.42 mL, 2.42 mmol) was added at 0° C., and the resulting mixture was stirred for 2 hours. Upon the completion of the reaction, methanol and saturated sodium hydrogencarbonate aqueous solution were added thereto, and the resulting solution was extracted with ethyl acetate, washed with saturated sodium hydrogencarbonate aqueous solution and then with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to obtain the aimed product (yield: 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[O:9][CH:10]=1)=[O:5])[CH3:2].[C:12]([CH:14]1[CH2:16][CH2:15]1)#[CH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:14]1([C:12]#[C:13][C:8]2[O:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1coc(Br)n1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1coc(C#CC2CC2)n1
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
A mixture of 2-bromo-oxazol-4-carboxylic ethyl ester (0.967 g, 4.40 mmol, Combi-Blocks), trans-dichlorobis(triphenylphosphine)palladium (II) (0.201 g, 0.286 mmol, Strem) and copper (I) iodide (0.165 g, 0.866 mmol, Aldrich) in toluene (15 ml) was purged with argon for 10 min. Ethynylcyclopropane (1.00 ml, 11.80 mmol) and triethylamine (1.70 ml, 12.22 mmol) were added. After 2.5 h, the reaction mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine. The solvent was removed under reduced pressure and the residue and was purified by silica gel flash chromatography, eluting with (EtOAc):hexanes (0:1→2:3) to give 452 mg (50%) of a light-orange oil. MS m/z=206 [M+H]+. Calculated for C11H11NO3: 205.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11][C:27]([C:24]3([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:26][CH2:25]3)=[O:28])[C:4]2=[N:3][CH:2]=1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1
Yield: 79 %

Procedure:
Combine (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (570 mg, 2.86 mmol), 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (commercially available, 633.19 mg, 3.15 mmol), 1-hydroxybenzotriazole (464 mg, 3.43 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (658 mg; 3.43 mmol) in tetrahydrofuran (10 mL). Add diisopropylethylamine (599 μL, 3.43 mmol) and stir the reaction for approximately 16 hours at ambient temperature under nitrogen. Dilute the reaction with ethyl acetate, wash with dilute sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (25% EtOAc/hexanes to 85% EtOAc/hexanes) to give the title compound (860 mg, 79%) as a white solid: MS (m/z): 383 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C>[CH3:7][O:6][C:4]([C:3]1([C:1]#[N:2])[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:5]
Reactant: BrCCCCBr
Reactant: COC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl cyanoacetate (Fluka; 25 g, 252.3 mmol) and potassium carbonate (83.7 g, 605.5 mmol) were stirred in DMF (250 mL). 1,4-Dibromobutane (Aldrich; 30.1 mL, 252.3 mmol) was slowly added. This caused and exotherm that continued after the addition was completed and a water bath was used to prevent the temperature exceeding 90° C. The mixture slowly cooled to ambient temperature and was stirred overnight and then heated at 75° C. for 3 hours.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.CCCCCC>[Cl:17][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)n1ccc(Cl)n1
Temperature: -78 °C

Procedure:
To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol) in dry tetrahydrofuran (1500 mL) at −78° C. was added dropwise a solution of 2.5 M n-butyl-lithium (472 mL, 1.18 mol) in hexane while maintaining the temperature below −65° C. Upon completion of the addition the reaction mixture was maintained at −78° C. for an additional 45 minutes, after which time a solution of hexachloroethane (279 g, 1.18 mol) in tetrahydrofuran (120 mL) was added dropwise. The reaction mixture was maintained for an hour at −78° C., warmed to −20° C. and then quenched with water (1 L). The reaction mixture was extracted with methylene chloride (4×500 mL); the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride as eluent to afford the title product compound as a yellow oil (160 g).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:15])([F:14])[C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>CCCCCC>[F:3][C:4]([F:15])([F:14])[C:5]1[CH:6]=[C:7]([CH:11]([Br:1])[CH3:12])[CH:8]=[CH:9][CH:10]=1
Reactant: BrBr
Reactant: CC(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(Br)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
bromine (32.5 g≡10.4 ml) was added over 15 minutes to a stirred mixture of (±)-1-(3-trifluoromethylphenyl)-ethanol [38 g, described by Overberger et al., Org. Synth. Coll. 3, 200 (1955)], triphenylphosphine (56 g) and dry dimethylformamide (200 ml) in an atmosphere of nitrogen. The temperature of the mixture was maintained at 40°-50° C. by ice-cooling. Further bromine was added dropwise to give a permanent orange colour and after stirring for 15 minutes the mixture was poured into a mixture of ice-water (1 liter) and hexane (500 ml). The mixture was filtered and the solid material was washed well with hexane. The hexane solutions were combined, washed with water (4×100 ml), dried over sodium sulphate and distilled to give (±)-1-(3-trifluoromethylphenyl)ethyl bromide, b.p. 98°-105° C./15 mmHg, as a clear mobile oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].C[Al+]C.Cl[C:18](=[O:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([C:18](=[O:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7][NH:8]2)([O-:3])=[O:2]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitroindole (2.00 g, 12.3 mmol) in CH2Cl2 (60 mL) at 0° C. was added dimethylaluminum chloride (1 M in hexanes, 14.8 mL, 14.8 mmol) and the mixture was stirred for 30 min. Ethyl 4-chloro-4-oxobutyrate (2.44 g, 14.8 mmol) was added dropwise and the resulting mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction mixture was carefully quenched with 10% aqueous citric acid (150 mL) and extracted with CH2Cl2 (3×150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was partially purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 65:35, and the resulting crude product was recrystallized from CH2Cl2:MeOH to give the title compound. MS: m/z=291 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13]>O1CCOCC1>[Cl:6][C:7]1[C:8]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: COCCN
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: COCCNc1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-methoxyethyl amine (4.11 mL, 43.9 mmol), TEA (6.11 mL, 43.9 mmol) and 5,6-dichloronicotinonitrile (Bionet GC-0755, 7.6 g, 43.9 mmol) was prepared in dioxane and stirred at RT for 24 hours. The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure. The residue taken up with EtOAc (100 mL) and washed with water (3×100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a white powder (6.9 g, 75%). LC/MS, M+(ESI): 212.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.42 (1H, d), 8.07 (1H, d), 7.48 (1H, t), 3.58 (2H, m), 3.47 (2H, m), 3.23 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=1)(=O)=O>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)OCCOc1ccc2c(c1)CCCC2
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3c(c2)CCCC3)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl methanesulfonate (1.08 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and extracted with dichloromethane. The organic layers were dried (Na2SO4), filtered and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 4:1) to provide, after crystallization from diethyl ether-hexane, 0.86 g of alpha-oxo-4-[[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy) ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 95°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=O)[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:26][O:27][NH2:28]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=[N:28][O:27][CH3:26])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON
Reactant: O=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of the 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 43, 159.9 mg, 0.41 mmol) and methoxyamine hydrochloride (52.3 mg, 0.62 mmol) in methanol (1.2 mL) and pyridine (1.2 mL) was heated under reflux for 3.5 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (75 mL), washed with a 1N aqueous hydrochloric acid solution (75 mL) and a saturated aqueous sodium chloride solution (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-methoxyimino-cyclopentyl)-N-thiazol-2-yl-propionamide (168.2 mg, 98%) as a white foam: mp 69-72° C. (foam to gel); (ES)+-HRMS m/e calcd for C18H19Cl2N3O2S (M+H)+ 412.0648. found 412.0652.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:10]([C@H:18]([CH3:22])[CH2:19][CH:20]=[O:21])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].O>C(OC(C)C)(C)C>[O:10]([C@H:18]([CH3:22])[CH2:19][CH:20]([C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)[OH:21])[Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: C[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Reactant: Clc1cnc(Cl)c(Br)c1
Solvent: O
Solvent: CC(C)OC(C)C
Product: C[C@H](CC(O)c1cc(Cl)cnc1Cl)O[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a cooled (-70° C.) solution of n-butylithium (129.3 mL of 1.18 M hexanes solution, 0.153 mol) in isopropyl ether was added a solution of 3-bromo-2,5-dichloropyridine (36.45 g, 0.161 mol) in isopropyl ether (225 mL) over a period of 30 minutes. The resulting white suspension was then treated with a solution of 3(R)-t-butyldimethylsiloxybutyraldehyde (34.14 g, 0.169 mol) in isopropyl ether (106 mL) and allowed to stir for an additional 30 minutes at -70° C. followed by warming to room temperature. After the addition of 480 mL of water, the biphasic mixture was separated and the organic layer was extracted with isopropyl ether (2×200 mL). The combined organic layers were washed once with water, heated with decolorizing carbon [G-60 DARCO (trademark)] filtered through diatomateous earth [Celite (trademark)] and condensed on a rotary evaporator. The resulting hazy yellow liquid was heated at 80° C. under high vacuum overnight to yield the desired product (mixture of diastereomers) as an amber oil (40.52 g, 72%): Rf 0.36 (25% Et2O in hexanes); 1H NMR (60 MHz, CDCl3) δ 0.1 (s, 6H), 0.82 (s, 9H), 1.18 (m, 3H), 1.72 (m, 2H), 4.16 (m, 1H), 4.42 (m, 1H), 5.10 (m, 1H), 7.92 (d, 1H, J=2.6 Hz), 8.13 (d, 1H, J=2.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[Cl:13]S(O)(=O)=O.II.S(Cl)(Cl)=O>O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[Cl:1][C:2]1[C:10]([Cl:13])=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Agent: II
Agent: O=C(Cl)c1cc(F)c(F)cc1Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1Cl
Temperature: 0 °C
Yield: 71 %

Procedure:
211 g (1 mol) of 2-chloro-4,5-difluorobenzoyl chloride are introduced into 500 g of chlorosulfonic acid, and 3 g of iodine are added. The mixture is chlorinated (10 l/h) for 1.7 h at 40° C. and then diluted with water (500 g), with stirring, the temperature being allowed to rise to 80° C. In this procedure, the acid chlorides initially present in the solvent are hydrolyzed in 2 h to the carboxylic acids, which are isolated by filtration after cooling to 0° C. After drying, the mixture is reacted with thionyl chloride (2 mol) at 80° C. and excess thionyl chloride is then distilled off. The mixture is then distilled, as indicated in Example 1, to give 46.4 g (0.22 mol, 22%) of 2-chloro-4,5-difluorobenzoyl chloride and 174.9 g (0.71 mol, 71%) of 2,3-dichloro-4,5-difluorobenzoyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][S:16]([O:19]C3C=CC=CC=3)(=[O:18])=O)[CH:12]=2)[NH:7][CH:6]=1.[CH3:27][NH2:28]>N1C=CC=CC=1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][S:16]([NH:28][CH3:27])(=[O:18])=[O:19])[CH:12]=2)[NH:7][CH:6]=1
Reactant: CN
Reactant: CN(C)CCc1c[nH]c2ccc(CCS(=O)(=O)Oc3ccccc3)cc12
Solvent: c1ccncc1
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(CCN(C)C)c2c1

Procedure:
The product of stage (v) (70 mg) in a saturated solution of methylamine in pyridine (4 ml) was heated at 100° in a "reactival" for 1.5 h. The mixture was concentrated and the residue oil purified by column chromatography (B) to give the title compound as an oil (7 mg), which was shown by n.m.r. and t.l.c. (B, Rf 0.3) to be identical with the product of Example 10 method (I).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@H:18]2[CH2:22][C@@H:21]([OH:23])[CH2:20][NH:19]2)=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:19]2[CH2:20][C@H:21]([OH:23])[CH2:22][C@@H:18]2[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][C:3]3=[O:2])=[CH:14][CH:13]=2)=[O:17])=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
7.3 12.64 g (36.98 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride are suspended in 1200 ml of dichloromethane, and 5.4 ml of triethylamine are added with cooling in an ice bath. The solution of 5.96 g (38.83 mmol) of 4-chlorophenyl isocyanate in 100 ml of dichlormethane is subsequently added dropwise to the mixture at 2° C. over the course of 1.5 hours, and the reaction solution is then left to stir for a further 30 minutes with ice cooling. The dichloromethane solution is then washed successively with 100 ml of 1N hydrochloric acid and 100 ml of water and dried over sodium sulfate. After the drying agent has been filtered off and the methylene chloride solution has been evaporated to ⅓ of the original volume in a rotary evaporator, the precipitated product is filtered off, washed with 50 ml of petroleum ether and dried in a desiccator, giving 14.6 g (86%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide (“A8”) as a white powder, ESI 459; m.p. 216°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:25].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22][O:23][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC1CN(c2ccccc2C)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred, 0° C. solution of 1-t-butyloxycarbonyl-2-(2-hydroxyethyl)-4-(2-methylphenyl)piperazine from Step 1 above (0.38 g; 1.2 mmol) and iodomethane (0.20 mL; 3.4 mmol) in dry THF (20 mL) was added NaH (60 mg of a 60% suspension in mineral oil; 1.5 mmol). The reaction was stirred at 0° C. for 15 min and then at ambient temperature for 18 h. The reaction was quenched by adding several drops of MeOH and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The organic phase was separated and washed with water and brine. The s organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc:hexanes as eluant. The title compound was obtained as a gum (1H-NMR: consistent with structure; TLC: silica gel, 1:3 EtOAc:hexanes: single component, Rf =0.62; FABMS: M+ H @ m/e=335; HPLC: >99%, retention time 11.7 min).
Reaction SMILES: [S:1]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:12](O)[CH:13]=[CH2:14].O.[C:17]1(C)[CH:22]=CC=C[CH:18]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[S:1]([CH2:7][CH2:8][C:9]([O:11][CH2:22][CH:17]=[CH2:18])=[O:10])[CH2:2][CH2:3][C:4]([O:6][CH2:12][CH:13]=[CH2:14])=[O:5]
Reactant: O=C(O)CCSCCC(=O)O
Reactant: Cc1ccccc1
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C=CCOC(=O)CCSCCC(=O)OCC=C

Procedure:
A mixture of 3,3′-thiodipropionic acid (17.82 g, 10 mmol), allyl alcohol (20.4 mL, 30 mmol) and p-toluenesulfonic acid (0.750 g) in 100 mL of toluene was refluxed for 8 h in a Dean-Stark apparatus to azeotropically remove water. The reaction mixture was quenched with saturated solution of sodium bicarbonate and the toluene layer was separated and washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and gave approximately 20 g of crude 3,3′-thiodipropionic acid, diallyl ester. This material was sufficiently pure by NMR and was used in the subsequent reaction.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C@@H]12N(C3C=NC4C(=CC=CC=4)N=3)C[C@@H]1CCNC2.[CH3:36][O:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[C:39]=1[C:40](Cl)=[O:41].C1(C2C=CC=CC=2)C(C(Cl)=O)=CC=CC=1>>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[N:8]1[CH:1]2[CH:6]([CH2:5][CH2:4][N:3]([C:40]([C:39]3[C:43]([O:47][CH3:48])=[CH:44][CH:45]=[CH:46][C:38]=3[O:37][CH3:36])=[O:41])[CH2:2]2)[CH2:7]1
Reactant: c1ccc2oc(N3CC4CCNCC43)nc2c1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Agent: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Product: COc1cccc(OC)c1C(=O)N1CCC2CN(c3nc4ccccc4o3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Example 5, substituting 2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-benzooxazole (Intermediate 7) for (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline and 2,6-dimethoxy benzoyl chloride for biphenyl-2-carbonyl chloride. MS (ESI) mass calcd. for C22H23N3O4, 393.44; m/z found 394.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.54-7.27 (m, 2H), 7.25-7.06 (m, 3H), 6.57-6.01 (m, 2H), 5.12-4.00 (m, 5H), 3.98-3.33 (m, 7H), 3.20-2.94 (m, 2H), 2.24-1.72 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]([NH2:20])=[S:19].C(O)C>CN(C)C=O>[C:1]1([C:7]2[N:17]=[C:18]([SH:19])[NH:20][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: NC(N)=S
Solvent: CN(C)C=O
Solvent: CCO
Product: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1

Procedure:
21.2 g (0.10 mol) of benzoin were dissolved in DMF (dimethylformamide) with 10.8 g (0.15 mol) of thiourea with warming and the mixture was heated under reflux for 15 hours. After cooling, the DMF was stripped off and the residue was treated with ethanol. The precipitate resulting in the course of this was filtered off with suction, washed with cold ethanol, dried and reused without further purification. The yield was 18.4 g.