Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:26])[NH:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:16]2)=[C:11]([O:27][CH3:28])[CH:10]=1>CS(C)=O.CCOCC>[CH3:28][O:27][C:11]1[CH:10]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:18]=[C:17]2[C:12]=1[C:13](=[O:26])[NH:14][C:15]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1)=[N:16]2
Reactant: COc1cc(F)cc2nc(-c3ccnc(C)c3)[nH]c(=O)c12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COCCOc1cc(OC)c2c(=O)[nH]c(-c3ccnc(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-ethanol (0.64 g, 8.40 mmol) in anhydrous DMSO (4 mL) was added sodium hydride (60% suspension in mineral oil, 0.12 g, 5.00 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of 7-fluoro-5-methoxy-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one (0.24 g, 0.84 mmol) in anhydrous DMSO (12 mL). The reaction mixture was stirred at 80° C. for 3 hours, then cooled to room temperature, and diluted with ether (500 mL). The solid was filtered and washed with ether. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 4% methanol in dichloromethane). The compound was further purified by preparative HPLC to give the title compound as a white solid. Yield: 60 mg (21%). MP 260-262° C. 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, J=5.07 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J=5.07 Hz, 1H), 6.80 (d, J=2.34 Hz, 1H), 6.61 (d, J=2.34 Hz, 1H), 4.25 (t, J=4.68 Hz, 2H), 3.86 (s, 3H), 3.71 (t, J=3.90 Hz, 2H), 3.33 (s, 3H), 2.57 (s, 3H). MS (ES) m/z: 342.07 (M+1) (100%).
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)CCC.[Na+].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][CH2:28][CH:29]=[O:30])=[CH:22][CH:21]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([S:26][CH2:27][CH2:28][CH:29]([OH:30])[CH2:2][C:3](=[O:4])[CH3:5])=[CH:24][CH:25]=1
Reactant: O=CCCSc1ccc(Br)cc1
Reactant: COC(=O)CC(C)=O
Agent: CCCC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(O)CCSc1ccc(Br)cc1
Reaction time: 3 h
Yield: 99.5 %

Procedure:
9.86 Grams of methyl acetoacetate were dissolved in 15 ml of water, and 12.67 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 1.10 g of sodium butyrate and 2.42 g of tetrabutylammonium bromide were added thereto and then an additional concentrated aqueous hydrochloric acid solution was added to the mixture so that the mixture was adjusted to pH 6.8. Further, 29.45 g of a toluene solution containing 31.2% of 3-(4-bromophenylthio)propanal were added thereto and was stirred at 45°-50° C. for 9 hours. The organic layer separated from the mixture was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Then the layer was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 14.54 g of crude 6-(4-bromophenylthio)-4-hydroxy-2-hexanone (purity: 81.8%, yield: 99.5%). A purified product was obtained by recrystallization from diisopropyl ether. The purified product had a melting point of 53.0-54.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[CH3:32][CH:33]([CH3:36])[CH2:34]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:32][CH:33]([CH3:36])[CH3:34])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Reactant: CC(C)CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Reaction time: 16 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.57 mmol), 2-methyl-propan-1-ol (0.078 mL; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 498.1 (M+); Rt: 2.03 min
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C.[I-].[K+]>[F:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: O=C(CCCCl)c1c[nH]c2ccc(F)cc12
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCCN1CCNCC1)c1c[nH]c2ccc(F)cc12
Temperature: 80 °C
Yield: 129.6 %

Procedure:
To a magnetically stirred solution of 4-chloro-1-(5-fluoro-1H-indol-3-yl)-butan-1-one (10.93 g, 45.6 mmol) in acetonitrile (100 ml), piperazine (20.33 g ml, 236 mmol) and a small amount of potassium iodide (0.1 g) were added, and the resulting mixture was heated at 80° C. for 48 hours. The formed solid material was removed by filtration and the residue was concentrated in vacuo to give 37 g crude yield. This crude product was further purified by column chromatography (gradient: ethylacetate/methanol/25% aqueous ammonia=90/5/5 to methanol) to give 17.1 g crude 1-(5-fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)-butan-1-one. Then this crude 1-(5-fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)-butan-1 -one (10.71 g, 0.389 mol) was dissolved in dichloromethane (500 ml) and Boc2O (25.53 g, 0.117 mol) was added. The resulting mixture was stirred for 4 hours at room temperature. The mixture was successively washed with 5% aqueous NaHCO3 and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Subsequent column chromatography (gradient: dichloro-methane/methanol=99/1 to dichloro-methane/methanol=90/10 (v/v)) gave pure 4-[4-(5-fluoro-1H-indol-3-yl)-4-oxobutyl]-piperazine-1-carboxylic acid tert-butyl ester (3.85 g, 37% yield). 1H-NMR (400 MHz, DMSO-d6) δ 1.38 (s, 9H), 1.80 (quintet, J=7, 2H), 2.25-2.35 (m, 6H), 2.84 (t, J=7, 2H), 3.22-3.32 (m, 4H), 7.06 (dt, J˜9 and 3, 1H), 7.47 (dd, J˜9 and 5, 1H), 7.85 (dd, J˜9 and 3, 1H), 8.38 (s, 1H), 12.01 (brs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-].COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=1
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1ccccc1F
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2ccccc2F)n1

Procedure:
Following the general method described in example 2b, 2-[2-(2-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a brown crystalline material. MS: m/e=224 (M+).
Reaction SMILES: [ClH:1].[ClH:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C.O>[ClH:17].[Cl:1][C:8]1[CH:9]=[C:10]([Cl:2])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCNCC2)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 530 mg (2.0 mmol) of 1-(3-Methoxyphenyl)piperazine dihydrochloride in 7 mL of acetic acid and 4 mL of water at 0° C. was added 700 mg (4.4 mmol) of N-chlorosuccinimide. The reaction was taken out of the ice/water bath after 2 hours, and allowed to stir overnight. After 12 hours, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ether and water. The phases were separated, the aqueous was basified with 1M NaOH, and was extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, the solution was acidified with 5M HCl in isopropanol and was diluted with ethyl acetate to effect crystallization. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.38 (s, 1H), 6.72 (s, 1H), 3.78 (s, 3H), 3.32 (m, 4H), 3.19 (m, 4H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-4-fluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=1.1 Hz, 1 H), 7.78 (d, J=8.7 Hz, 1 H), 7.53 (dd, J=8.5, 1.5 Hz, 1 H), 7.10-6.98 (m, 2 H), 6.84-6.76 (m, 2 H), 4.63 (t, J=5.0 Hz, 2 H), 4.22 (t, J=5.0 Hz, 2 H), 2.49 (s, 3 H); MS (ES) m/z 329 (M+1).
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]([CH2:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][C:11](O)=[O:12])=[O:7].ClC(OCC)=O.C([N:26](CC)CC)C>>[C:11]([CH2:10][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][C:6]([O:5][CH3:4])=[O:7])(=[O:12])[NH2:26]
Reactant: COC(=O)C[C@H](CC(=O)O)CC(C)C
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: COC(=O)C[C@@H](CC(N)=O)CC(C)C
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
A round-bottomed flask is equipped with magnetic stirrer and charged with methylene dichloride (100 ml), (S)-3-((Methoxycarbonyl)methyl)-5-methylhexanoic acid (20 g) and with triethylamine (0.77 g) and cooled to 0-5° C. followed by addition of ethyl chloroformate (9 g). The mixture was stirred for 1-2 h at a temperature of 20° C. to 25° C., followed by quenching with 25% aqueous ammonia (100 ml). The resulted slurry is filtered and washed with water and dried to obtain a solid of (R)-methyl 3-(carbamoylmethyl)-5-methylhexanoate.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[C:9](=[O:20])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[C:4]([OH:6])=[O:5].[OH-].[Na+].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.Cl>O>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH:3]([CH2:7][C:8]2[C:9](=[O:20])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)[C:4]([OH:6])=[O:5])=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc2[nH]c(=O)c(CC(N)C(=O)O)cc2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2[nH]c(=O)c(CC(NC(=O)c3ccc(Cl)cc3)C(=O)O)cc2c1

Procedure:
1.5 Grams of 2-amino-3-(6-methoxy-2-quinolon-3-yl)propionic acid hydrochloride was dissolved in a solution containing 0.8 g of sodium hydroxide in 25 ml of water, then under ice-cooled condition, 1 g of p-chlorobenzoyl chloride was added dropwise with stirring. The reaction was carried out by adding 1N-sodium hydroxide aqueous solution and p-chlorobenzoyl chloride properly, until the starting material os disappeared from the reaction mixture by checking a sample of the reaction mixture through a thin-layer-chromatograph. After completion of the reaction, the reaction mixture was acidified with hydrochloric acid, the crystals precipitated were collected by filtration. The crystals were washed with ether, then recrystallized from methanol-water to obtain 0.7 g of 2-(4-chlorobenzoylamino)-3-(6-methoxy-2-quinolon-3-yl)propionic acid in the from of yellowish powdery product.
Reaction SMILES: C[O:2][C:3]1[C:4]([O:14]C)=[CH:5][C:6]2[S:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]=2[CH:13]=1.CO>ClCCl>[OH:2][C:3]1[C:4]([OH:14])=[CH:5][C:6]2[S:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]=2[CH:13]=1
Reactant: COc1cc2sn(C)c(=O)c2cc1OC
Solvent: ClCCl
Solvent: CO
Product: Cn1sc2cc(O)c(O)cc2c1=O
Temperature: -10 °C

Procedure:
To a suspension of 5,6-dimethoxy-2-methylbenzo[d]isothiazol-3-one (0.35 g) in dichloromethane (30 ml) boron tribromide (3.1 ml, 1 M solution in dichloromethane) was added at −40° C. The mixture was allowed to warm to −10° C. Next day methanol (30 ml) was added and the mixture was evaporated to dryness. To the residue sodium sulfite solution (9 ml, 5% in water) and brine (9 ml) were added. After stirring at 0° C. the precipitate was filtered.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH2:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[OH:19][C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][N:13]([CH2:12][CH:10]1[CH2:11][NH:8][CH2:9]1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28]
Reactant: CC(C)(O)CCN(Cc1ccc(Cl)cc1Cl)CC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)(O)CCN(Cc1ccc(Cl)cc1Cl)CC1CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
3-{[(2,4-dichlorobenzyl)-(3-hydroxy-3-methyl-butyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (88 mg, 0.2 mmol) is added to a stirred solution of dichloromethane (1.0 mL) and anisole (1.5 mL). Trifluoroacetic acid (0.6 mL) is added and the reaction is stirred for 2 h at room temperature. The reaction is concentrated to half volume and loaded onto a SCX-2 (10 g) column and washed with methanol (40 mL). The product is then eluted with 2M ammonia in methanol (25 mL) and concentrated to yield (57 mg, 87%) of N-(3-hydroxy-3-methylbutyl)-N-{[2,4-dichlorophenyl]-methyl}-azetidine-3-yl-methylamine. 1H NMR (400 MHz, CD3OD) δH: 7.49-7.47 (2H, m), 7.36-7.33 (1H, m), 3.80-3.70 (2H, m), 3.65 (2H, s), 3.49-3.40 (2H, m), 3.16-3.06 (1H, m), 2.79-2.77 (2H, m), 2.67 (2H, t, J=7.3 Hz), 1.69 (2H, t, J=7.3 Hz), 1.1 (6H, s). Mass spectrum (ion spray): m/z=331.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[CH:18]1[C:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[O:23][C:22]=2[CH:21]=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Br:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:2]([C:28]4[CH:29]=[CH:30][C:24]5[O:23][C:22]6[CH:21]=[CH:20][CH:19]=[CH:18][C:26]=6[C:25]=5[CH:27]=4)=[CH:3][C:4]=3[C:5]2([CH3:16])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: OB(O)c1ccc2oc3ccccc3c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccc4oc5ccccc5c4c3)cc21
Reaction time: 12 h
Yield: 48 %

Procedure:
2,7-dibromo-9,9-dimethyl-9H-fluorene (5.0 g, 14.201 mmol), dibenzo[b,d]furan-2-ylboronic acid (1.50 g, 7.10 mmol), Pd(pph3)4 (820 mg, 0.71 mmol), K2CO3 (1.96 g, 14.201 mmol) were put in a 250 mL two-neck flask and dissolved in toluene/H2O. The solution was refluxed and stirred for 12 hours. After completion of the reaction, the solution was distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of hexane and methylenechloride (8:1). The solution was distilled under reduced pressure and was re-crystallized in a solution of methylene chloride and petroleum ether such that the white solid compound was obtained, (1.50 g, yield: 48%).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)=[CH:8][CH:7]=1)(=O)=O.[OH-].[K+].Cl>C1COCC1>[O:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2ncco2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1ccc(-c2ncco2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 4-(oxazol-2-yl)phenyl methanesulfonate (11.2 g, 46.81 mmol) in THF (200 mL), a freshly prepared aqueous solution of KOH (40 wt. %, 13.2 mL, 93.6 mmol, 2 equiv.) was added. The reaction mixture was stirred at 80° C. for 4 hours and at ambient temperature overnight. Another 2 equiv. of aqueous solution of KOH (40 wt. %, 13.2 mL, 93.6 mmol) was then added and the reaction mixture was continuously stirred at 80° C. for 3 hours. After cooling, the reaction mixture was cautiously brought to pH 5 with 1 M aqueous HCl. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flashmaster chromatography on 50 g of silica gel using a gradient of 100% CH2Cl2→90% CH2Cl2+10% methanol gave 4.25 g (56% th.; 38% pract.) of 4-(oxazol-2-yl)phenol; 1H NMR (CD3OD) δ 7.86 (d, 1H), 7.84 (d, 2H), 7.20 (d, 1H), 6.88 (d, 2H) ppm.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([O:17]COC)=[CH:16][C:10]=2[C:9]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])[CH2:2][CH2:3][CH3:4].O.CCCCCC>Cl.C(O)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=2[C:9]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1sc2ccc(OCOC)cc2c1OC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCCCOC(=O)c1sc2ccc(O)cc2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
A few drops of concentrated HCl were added to 5.92 g (15 mmol) VI in 150 ml acetic acid, followed by stirring for 10 h at room temperature. 500 ml water were then added to the reaction solution, followed by repeated extraction with Et2O. The combined organic phases were dried over Na2SO4 and freed from the solvent. Recrystallization from diethylether:n-hexane=4:1 produced 4.21 g (12 mmol, 80%) VII.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:23]=[C:14]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:1]34[CH2:6][CH:5]3[CH2:4][N:3]([CH2:30][C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)[CH2:2]4)=[CH:12][CH:11]=2)[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15]1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(Cc3cccnc3)C4)cc2)C(=O)O1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a stirred solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (210 mg, 0.6 mmol), in dichloroethane (25 mL), were added 3-pyridinecarboxaldehyde (0.06 mL, 0.6 mmol), triethyl amine (0.17 mL, 1.2 mmol) and sodium triacetoxyborohydride (254 mg, 1.2 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was quenched by adding saturated aq. NaHCO3 solution (20 mL) and product was extracted with DCM (3×25 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.5:9.5 MeOH:CHCl3) to provide the title compound (98 mg, 40%) as off white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([CH3:18])[N:3]=1.[S-2:19].[Na+].[Na+]>CN(C=O)C>[CH3:18][C:4]1[C:5]([C:16]#[N:17])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:7]([C:8]#[N:9])=[C:2]([SH:19])[N:3]=1
Reactant: Cc1nc(Cl)c(C#N)c(C2CCCCO2)c1C#N
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(S)c(C#N)c(C2CCCCO2)c1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
471 mg (1.35 mmol) of the compound from Example 40A are initially charged in 4 ml of dry DMF, and 126 mg (1.62 mmol) of sodium sulfide are added. The reaction mixture is stirred at RT for 12 h. The solvent is then removed on a rotary evaporator and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 200:1→5:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=[CH2:26])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:40]>C(Cl)Cl.C(=O)(O)[O-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]3[O:40][CH2:26]3)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(OCc1ccccc1)C(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(OCc1ccccc1)C1CO1
Reaction time: 2 h

Procedure:
The methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-3-phenylmethoxy-4-pentenoate 63d (1.23 g, 2.48 mmol) is dissolved in methylene chloride (9 mL) and sodium bicarbonate (252 mg), in water (4 mL), then the reaction is cooled to 0° C. 3-Chloroperoxybenzoic acid is added slowly and the reaction is stirred for two hours. The substrate is still present so additional 3-chloroperoxybenzoic acid is added (1 g) along with 175 mg sodium bicarbonate and the reaction is stirred overnight. The mixture is diluted with aqueous sodium bicarbonate solution and methylene chloride and the layers are separated. The aqueous layer is washed with ethyl acetate (3 times) and the organic layers are combined and dried under reduced pressure. The resulting material is redissolved in ethyl acetate and washed with dilute sodium bicarbonate solution and then with brine, dried over magnesium sulfate and concentrated in vacuo to a light brown oil (2 g). The crude material is adsorbed onto silica gel and purified over a silica column eluting with hexane:ethyl acetate (8:2) followed with hexane:ethyl acetate (1:1). Product fractions are combined and dried to give the desired product.