Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4].[CH3:12][Si:13](Cl)([CH3:15])[CH3:14].C(N(CC)CC)C>C1COCC1.C(OCC)C>[CH3:12][Si:13]([CH3:15])([CH3:14])[O:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4]
Reactant: OCC(=S)Oc1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)OCC(=S)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of phenyl (hydroxy)thioacetate (0.237 g, 1.41 mmol) in THF (14.0 ml) was treated with trimethylsilyl chloride (0.643 ml, 5.07 mmol) and triethylamine (0.726 ml, 5.21 mmol) at room temperature. After stirring for 2 h at RT, the mixture was diluted with ethyl ether, washed with pH 7 phosphate buffer, dried (Na2SO4) and evaporated to give phenyl (trimethylsilyloxy)thioacetate (0.2315 g, 93%).
Reaction SMILES: [SH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]2[S:1][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:14][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1cc(C)c(S)c(C(=O)O)c1
Solvent: c1ccncc1
Product: Cc1cc(C)c2sc(-c3ccccn3)nc(=O)c2c1
Yield: 50.8 %

Procedure:
A mixture of 2-mercapto-3,5-dimethylbenzoic acid (1.6 g, 8.8 mmol), 2-cyanopyridine (1.0 g, 9.7 mmol) and pyridine (15 ml) was refluxed for 12 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (1.2 g, 52%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[C:27]([CH2:28][C:29]([O:31]C)=[O:30])=[CH:26][N:25]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:24]=2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[C:27]([CH2:28][C:29]([OH:31])=[O:30])=[CH:26][N:25]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:24]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of methyl [3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1-phenyl-1H-pyrazol-4-yl]acetate (587 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1-phenyl-1H-pyrazol-4-yl]acetic acid (502 mg, yield 88%), which was then recrystallized from ethanol-hexane. melting point: 164–165° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[CH:12][CH:11]=1.[C:24]([O:27][CH2:28][CH2:29]Br)(=[O:26])[CH3:25]>O>[CH2:28]([O:27][C:24]([CH2:25][O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[CH:14][CH:15]=1)=[O:26])[CH3:29]
Reactant: O=C(c1ccc(CO)cc1)c1cccnc1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1ccc(C(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg of 60% sodium hydride was gradually added to 10 ml of a DMF solution of 666 mg of 3-[4-(hydroxymethyl)phenylcarbonyl]pyridine under ice cooling. The reaction solution was stirred at room temperature for 1 hour, then 0.4 ml of 2-bromoethyl acetate was added and the mixture was stirred under the same reaction conditions for 3 hours. After the reaction was completed, the reactive product was diluted with water, extracted with ethyl acetate, and the resultant product was washed with brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to obtain the desired compound in an amount of 336 mg.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].OS(O)(=O)=O.N([O-])=O.[Na+]>CCO.O>[Br:8][C:7]1[CH:2]=[C:3]([OH:12])[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Nc1c(O)cc([N+](=O)[O-])cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(O)cc(Br)c1
Temperature: 50 °C
Yield: 82.2 %

Procedure:
To an ice-cold solution of 2-amino-3-bromo-5-nitro-phenol (6.50 g, 27.89 mmol) in EtOH (150.0 mL) was added concentrated H2SO4 (9.40 mL, 177.13 mmol) portion wise. The reaction mixture was then heated to 50° C. followed by portion wise addition of NaNO2 (6.19 g, 89.82 mmol). The resulting solution was refluxed at 80° C. for 2 h. The reaction mixture was then diluted with water and extracted with EtOAc (3×150.0 mL). The combined organics was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified over silica gel (100-200 M, 10% EtOAc-Hexane) to get the desired product (5.0 g, 82%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[S:19][C:10]3=[N:11][C:12]([O:17]C)=[C:13]([Cl:16])[C:14]([CH3:15])=[C:9]3[C:8]=2[NH2:20])=[O:6])[CH2:3][CH2:2]1.C[S-].[Na+]>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[S:19][C:10]3=[N:11][C:12]([OH:17])=[C:13]([Cl:16])[C:14]([CH3:15])=[C:9]3[C:8]=2[NH2:20])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(O)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
To a solution of 3-amino-5-chloro-6-methoxy-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (5.0 g, 16.04 mmol) in DMF (45 ml) is added solid 95% sodium thiomethoxide (1.30 g, 17.64 mmol). The reaction vessel is sealed and heated at 100° C. for 5 hours. The reaction is cooled to room temperature and quenched by the addition of water (75 ml). The mixture is acidified to pH2 by the addition of 5N HCl. Gradually, a thick, white precipitate is formed, which is stirred at 0° C. for 10 minutes, then collected by filtration. The solid is dried in the vacuum oven overnight at 60° C. to afford the title compound as a white solid (4.13 g, 86%). Mass (m/z): 298.0 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:27].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][P+:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][P+:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4].[Br-:27]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.1 %

Procedure:
N-(tert-butoxycarbonyl)-N-methyl-β-alanine (Matrix Scientific, 368 mg, 1.81 mmol) was dissolved in N,N-dimethylformamide (3.7 mL) and treated with N,N-carbonyldiimidazole (308 mg, 1.90 mmol). The reaction mixture was stirred at room temperature for 30 minutes. (4-Aminobutyl)(triphenyl)phosphonium bromide (1.12 g, 2.72 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction was then diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.26 g, 100%, 86% pure) as a white foam. Sample was used crude in next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN1C(=O)CCC1.CCOC(C)=O>O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)n1cc(-c2nc(N3CCOCC3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 150 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), morpholine (113 mg), and NMP (1.0 ml) was heated at 150° C. with stirring for 1 day. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was recrystallized from MeOH-IPE and dried in vacuo to give 5-[5-amino-6-(4-morpholinyl)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (84 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1cccc(Br)c1
Product: C[C@@H](CCl)COc1cccc(Br)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23](=O)([O-:25])[NH2:24].C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:23](=[O:25])[NH2:24])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: NC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(N)=O)c3)c2cc1OC
Yield: 45 %

Procedure:
Using the procedure described in Example 113C, 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (104 mg, 0.35 mmol) and the carbamate from the previous step (124 mg, 0.45 mmol) were reacted in the presence of N,N-diisopropylethylamine (73 μl, 0.42 mmol) to give 143-cyclopentylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (75.22 mg, 45%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H) 7.57 (s, 2H), 7.56-7.39 (t, 2H) 7.29 (d, 1H), 6.98 (d, 1H), 5.95 (s, 1H), 4.00 (s, 6H), 3.04-3.01 (m, 1H), 1.99-1.93 (m, 2H), 1.69-1.61 (m, 6H)); LC-MS (ESI) m/z 476 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)c(Cl)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.5 %

Procedure:
3,4-Dichlorophenyl 4-methoxyphenyl ketone (235 mg) obtained in Example 120 was dissolved in dichloromethane (2 ml), a solution of 1.0 M boron tribromide in dichloromethane (7 ml) was added while cooled in ice, and the admixture was stirred at room temperature for two days. The reaction mixture was then poured into ice water and partitioned between water and chloroform. The chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 173 mg of the title compound (yield: 77%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:20][C:21]#[C:22][CH3:23])[CH:19]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:20][C:21]#[C:22][CH3:23])[CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CC#CCn1cnc(C(Cc2ccc(N)nc2)C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC#CCn1cnc(C(Cc2ccc(N)nc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
A solution of 25 mg (0.08 mmol) of the compound from example 32a in 2 ml of THF was mixed with 88 μl of 1N NaOH and stirred at RT for 4 h. Then, and again after stirring overnight, 40 μl of NaOH were added. After stirring for a further 24 h, the reaction mixture was neutralized with 2N HCl and freeze-dried. Preparative HPLC afforded 5 mg of the title compound as bistrifluoroacetate.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:17])[CH:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]=O>CO>[ClH:1].[CH2:19]([C@H:18]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH2:7][C@@H:5]([C:4]([O:3][CH3:2])=[O:17])[NH:6]1)[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)C(N)Cc1c[nH]c2ccccc12
Reactant: CCCCC=O
Agent: Cl
Solvent: CO
Product: CCCC[C@@H]1N[C@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Yield: 53 %

Procedure:
A mixture of DL-tryptophan methyl ester hydrochloride (30.49 g), n-valeraldehyde (12.4 g) and methanol (400 ml) is refluxed for 48 hours and then concentrated to about 1/5 volume. After cooling, the precipitates are separated by filtration and recrystallized from methanol to give methyl (1RS,3RS)-cis-1-butyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochloride (20.5 g, 53%), m.p. 218° C. (decomp.) The hydrochloride thus obtained is treated with aqueous ammonia and recrystallized from diisopropyl ether-isopropanol to give the corresponding free base, m.p. 85°-87° C.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].[C:8]1([CH2:14][SH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1.ClCCl>[CH2:14]([S:15][CH2:4][C:5]([OH:7])=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: SCc1ccccc1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CSCc1ccccc1
Temperature: 100 °C
Yield: 55.2 %

Procedure:
1N aqueous sodium hydroxide solution (500 cc), cooled to a temperature of approximately 5° C., is added in the course of 1 hour to bromoacetic acid (70 g). The mixture obtained is added to a solution of phenylmethanethiol (50 g) and 1N aqueous sodium hydroxide solution (500 cc) in tetrahydrofuran (500 cc), and then heated to approximately 100° C. for 90 minutes. The mixture is cooled to a temperature in the region of 5° C. There are added 12N aqueous hydrochloric acid solution (100 cc) and then dichloromethane (3,000 cc) in the course of 30 minutes. The organic phase is separated off after settling has taken place, and the aqueous phase is extracted with dichloromethane (2×200 cc). The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallized in boiling cyclohexane (50 cc). (Benzylthio)acetic acid (40.5 g), m.p. 58°-60° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:13][CH3:14].Cl[C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][N:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][N:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(B(O)O)cc(OC)c1Cl
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2cc(OC)c(Cl)c(OC)c2)c1

Procedure:
4-Chloro-3,5-dimethoxyphenylboronic acid (7.45 g) and ethyl 2-chloroisonicotinate (6.39 g) were condensedn in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(O)cc1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(=NCCc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
A solution of N,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (22.4 g, 77.3 mmol) is dissolved in 130 mL of THF and added dropwise under nitrogen to 10.6 g (77.3 mmol) of tyramine in 100 mL of THF at 0° C. Reaction reaches completion overnight according to TLC. The solvent is removed in vacuo. Purification on a silica gel column, eluted successively with 5% EtOAc/Hexane, 15% EtOAc/Hexane, and 35% EtOAc/Hexane, provides the title compound as a white solid, m.p. 132°-133° C. (dec.) (21.0 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[C:29]2[C:28](=[O:30])[N:26]([CH3:27])[C:25](=[O:31])[N:24]([CH3:32])[C:23]=2[N:22]=[CH:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][CH2:19][N:20]3[C:29]4[C:28](=[O:30])[N:26]([CH3:27])[C:25](=[O:31])[N:24]([CH3:32])[C:23]=4[N:22]=[CH:21]3)[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: Cn1c(=O)c2c(ncn2CCCCl)n(C)c1=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Product: Cn1c(=O)c2c(ncn2CCCN2CCC(C(=O)c3ccc(F)cc3)CC2)n(C)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
10.2 g 4-(p-fluorobenzoyl)-piperidine and 16.5 g 7-(chloropropyl)-theophylline are carefully mixed in the solid state and heated to 100° C. in a round flask in an oil bath. The mixture at first results in a clear melt, subsequently begins to crystallize and then changes into a solid mass. It is allowed to cool after 10 minutes, dissolved in ethyl acetate and 2n hydrochloric acid is added, whereby a dark oil separates in the organic phase, crystallizing on standing overnight. By recrystallizaing with 100 ml carbon tetrachloride, an intially oily then crystallizing substance is obtained, 7.4 g of the product with an mp of 114° to 119° C. (yield: 43.5%)
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:17][O:18][C:19](=[O:21])[N:20]=3)=[C:12]([Cl:22])[CH:11]=2)=[C:5]([CH3:7])[N:6]=1.[S:23]1[C:27](B(O)O)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[S:23]1[C:27]([C:2]2[S:3][C:4]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[NH:17][O:18][C:19](=[O:21])[N:20]=4)=[C:12]([Cl:22])[CH:11]=3)=[C:5]([CH3:7])[N:6]=2)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1nc(Br)sc1COc1ccc(-c2nc(=O)o[nH]2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cc3ccccc3s2)sc1COc1ccc(-c2nc(=O)o[nH]2)c(Cl)c1
Temperature: 40 °C
Yield: 46.1 %

Procedure:
A mixture of 3-[4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-phenyl]-2H-[1,2,4]oxadiazol-5-one (300 mg, 0.7 mmol), Benzo[b]thiophene-2-boronic acid (142 mg, 0.8 mmol) and cesium carbonate (730 mg, 2.2 mol) in dimethylformamide (5 mL) and water (1 mL) is degassed using a stream of argon for 15 min. Tetrakis-triphenylphosphine-palladium (0) (34 mg, 0.03 mmol) is added and the mixture is warmed to 40° C. for 4 hours. The solvent is removed under reduced pressure and the residue is taken up in water (10 mL) and ethylacetate (30 mL). The phases are separated and the water phase is additionally extracted two-times with ethylacetate. The combined organic phases are dried over MgSO4 and the solvent is removed under reduced pressure. The crude product is purified using reverse phase HPLC to obtain 147 mg 3-[4-(2-Benzo[b]thiophen-2-yl-4-methyl-thiazol-5-ylmethoxy)-2-chloro-phenyl]-2H-[1,2,4]oxadiazol-5-one as an amorphous lyophilisate.
Reaction SMILES: [Br:1][CH:2]1[C:7]([CH3:8])=[C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]2[S:3]1=[O:29].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl.[W]>[Br:1][CH:2]1[C:7]([CH2:8][Br:30])=[C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]2[S:3]1=[O:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1Br
Agent: [W]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 26.2 %

Procedure:
The reference 2-bromo-3-bromomethyl compound in the above HPLC analysis was prepared as follows: To a solution of 4.6 g (9.5 mmoles) of t-butyl 2-bromo-7-phenylacetamido-3-methyl-3-cephem-4-carboxylate 1-oxide in 350 ml of methylene chloride cooled in ice and irradiated with a 150 W tungsten lamp were added in portions over a period of 105 minutes 3.05 g (17.1 mmoles) of N-bromosuccinimide. After the addition was completed, the irradiation was continued for another hour and the orange-colored solution was concentrated to dryness by evaporation at low temperature. The residue was chromatographed on silica gel (elution with methylene chloride/acetone; first 72:1, then 49:1, v/v) to obtain 1.4 g (26%) of t-butyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:5][S:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[CH2:9]([C:8]1[NH:1][C:2]2[C:6](=[CH:5][S:4][CH:3]=2)[N:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(=O)Nc1cscc1N
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
1 g of the product of Step A was dissolved at ambient temperature with stirring in 3 ml of phosphorous oxychloride and then the solution was heated at reflux for one hour. The solution was evaporated to dryness and 100 ml of a saturated aqueous solution of sodium bicarbonate were added. The mixture was stirred for 20 minutes at ambient temperature followed by extraction with methylene chloride. The extracts were washed with sodium bicarbonate solution and the organic phase was dried, filtered and evaporated. The oil was dissolved in 600 ml of ethyl ether at reflux, followd by filtration and evaporation to dryness to obtain 570 mg of product which was crystallized from 2 ml of isopropyl ether to obtain 500 mg of the expected product melting at 118° C.