Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[C:22]1([C:28]2[NH:29][C:30](=[O:33])[NH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:19][C:11]1([CH3:20])[O:10][C:9](=[O:21])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH:32]=[C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:29][C:30]3=[O:33])=[CH:3][CH:4]=2)[C@H:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Reactant: O=c1[nH]cc(-c2ccccc2)[nH]1
Product: CC1(C)OC(=O)N(c2ccc(-n3cc(-c4ccccc4)[nH]c3=O)cc2)[C@H]1c1ccccc1
Yield: 9 %

Procedure:
The title compound was prepared as described in General Scheme B using intermediate C in place of intermediate B and 4-phenyl-1H-imidazol-2(3H)-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.). Purification was performed using preparative LC/MS with 0.1% NH4OH in ACN and water as the mobile phase. The pure fractions were dried under reduced pressure to afford (4S)-5,5-dimethyl-3-(4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-4-phenyl-1,3-oxazolidin-2-one as a white solid (15 mg, 0.055 mmol, 9% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.01 (br. s., 1H), 7.71-7.65 (m, 2H), 7.62-7.50 (m, 4H), 7.41-7.34 (m, 4H), 7.34-7.20 (m, 4H), 5.49 (s, 1H), 1.65 (s, 3H), 0.92 (s, 3H). m/z (ESI) 426.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C2C(=CC=CC=2)NC=1)(=O)CCCCCC.Br[CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=1)=[O:53].BrCCCC([O-])=O>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=3)=[O:53])[CH:23]=2)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(COC(=O)CCCBr)cc1
Reactant: CCCCC(OC/C=C/C(=O)c1c[nH]c2ccccc12)c1ccc(CC(C)C)cc1
Agent: CCCCCCC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])CCCBr
Product: CCCCC(OC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
The procedure of Ex. 1 was repeated except that (E)-3-[4-[1-(4-isobutylphenyl)pentyloxy]-2-butenoyl]indole obtained in Step 4 of Pre. Ex. 19 was used in place of 3-heptanoylindole, and 4-methoxybenzyl 4-bromobutyrate obtained in Step 5 of Pre. Ex. 19 was used in place of 4-bromobutyrate to give 4-methoxybenzyl (E)-4-[3-[4-[1-(4-isobutylphenyl)pentyloxy]-2-butenoyl]1-indolyl]butyrate as an oil.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCN(CC)CC.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[F:36][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([CH:29]6[CH2:34][CH2:33][N:32]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:31][CH2:30]6)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C3CCNCC3)ccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C3CCN(S(C)(=O)=O)CC3)ccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-(piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (92) (15.6 mg, 0.032 mmol) and Et3N (0.013 mL, 0.095 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (0.0074 mL, 0.095 mmol) and stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (F49). MS (m/z) 571.1 (M+1)+.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.[N+:11]([CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:10][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[O:15])=[CH:5][CH:4]=1
Reactant: [C-]#[N+]CC(=O)N1CCN(C)CC1
Reactant: O=Cc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(C(=O)[C@@H]2N=CO[C@H]2c2ccncc2)CC1
Yield: 78 %

Procedure:
To a stirred and cooled (0° C.) solution of KOH (0.335 g, 5.98 mmol) in 7 mL MeOH were added successively pyridine-4-carbaldehyde (0.705 g, 6.58 mmol) and 2-isocyano-1-(4-methyl-piperazin-1-yl)-ethanone VIB 01128 (1.00 g, 6.58 mmol). The mixture was stirred at 0° C. until precipitation and concentrated. The mixture was partitioned between EtOAc (20 mL) and H2O (10 mL). The aqueous layer was extracted twice with EtOAc (60 mL). The EtOAc fractions were combined, washed twice with brine (2×10 mL), dried over MgSO4 and filtered. After evaporation and drying trans-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(4-methylpiperazin-1-yl)methanone VIB 01130 was obtained (1.282 g, 78% yield) as a yellow oil.
Reaction SMILES: C([C@@H]1[O:9][C:8](=[O:10])[C@@:7]([CH3:14])([CH:11]([CH3:13])[CH3:12])[O:6]1)(C)(C)C.[OH-].[K+].Cl>CO.O>[CH3:14][C@:7]([OH:6])([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=[O:9]
Reactant: CC(C)[C@@]1(C)O[C@H](C(C)(C)C)OC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)[C@](C)(O)C(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
To a magnetically stirred solution of (7) (94 g, 0.47 mol) in methanol (450 mL) and water (100 mL), in a 1-L, one-neck, round-bottom flask was added potassium hydroxide pellets (48 g, 0.85 mol, 1.8 equivalents). The reaction was then heated to reflux for 30 minutes. The mixture was cooled to room temperature and concentrated in vacuo to afford a milky suspension. This mixture was diluted with water (100 mL), cooled to 0° C., and acidified with concentrated hydrochloric acid (15 mL) to pH 6. Additional water (100 mL) was added, and the mixture extracted with ethyl acetate (3×400 mL). The combined organics were washed with water (1×600 mL), saturated aqueous chloride solution (1×600 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford a pale yellow oil which on drying in vacuo afforded 59 g (94% yield) of (8) as a crystalline solid. The 1H NMR of the product was consistent with the material previously prepared.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][N:8]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[N:7]=1)=[O:5])C.[OH-].[Na+].CO>CO.O>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1nn(CCN(C)C)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Yield: 63 %

Procedure:
A solution of 1-(2-Dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester, D22 (610 mg, 2 mmol) in methanol/water (15 ml/10 ml) was treated with 2N sodium hydroxide (4 ml). After stirring at room temperature for 16 h the methanol was removed in vacuo and the residue treated with 2N HCl (4 ml). The water was removed in vacuo. Dichloromethane was added to the residue and the inorganic solid was removed by filtration. Removal of the solvent form the filtrate in vacuo afforded the title compound as a white solid (350 mg, 63%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:14][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[C:12]([CH3:13])[N:11]=1)(=[O:26])=[O:25]
Reactant: Cc1nc(N)ccc1COCC1CC1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1ccc(COCC2CC2)c(C)n1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-ylamine (0.06 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.089 g) as an amorphous light yellow solid (0.058 g). MS (ESI−): 413.1 ([M−H]−)
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=1[O:31][C:30]([CH3:33])=[CH:29][C:28]3=[O:34])[C:7]([C:16]([O:18]CCC#N)=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2].[OH-].[Na+].C(OCC)C>COCCOC.O>[CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=1[O:31][C:30]([CH3:33])=[CH:29][C:28]3=[O:34])[C:7]([C:16]([OH:18])=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2]
Reactant: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)OCCC#N)=C(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCOC
Solvent: O
Product: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
640 mg (1.39 mmol) of the compound from Example 40A are dissolved in 30 ml of 1,2-dimethyoxyethane/water (2:1 v/v), mixed with 2.76 ml (2.76 mmol) of 1 N sodium hydroxide solution and stirred at room temperature for 30 min. The reaction mixture is then mixed with 20 ml of diethyl ether. The aqueous phase is separated off, adjusted to a pH of 4-5 with 1 N hydrochloric acid and extracted three times with ethyl acetate. The organic phases are combined and dried with magnesium sulfate. The volatile components are removed in a rotary evaporator. Drying in vacuo results in 335 mg (56% of theory) of the title compound in a purity of 94% (LC-MS).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:17]([CH:6]([C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCCC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
(1)-(b) To 19.0 g of methyl 4-(4-chlorobenzoyl)butyrate was added 14.5 g of aniline, 0.6 g of p-toluenesulfonic acid monohydrate and 200 ml of toluene, and the mixture was refluxed with dehydration for 22.5 hours. The solvent was evaporated off under reduced pressure, and the residue was dissolved in 200 ml of methanol. A solution of 40 ml of an aqueous 20% sodium hydroxide solution and 3.0 g of sodium borohydride were added at 0° C., and the mixture was stirred at -3° to +5° C. for 1 hour. The reaction temperature was raised to room temperature, and then heated at 60° C. for 1 hour. After removal of solvent, the residue was diluted with 60 ml of water, adjusted to pH 6 to 7 with concentrated hydrochloric acid, extracted with ethyl acetate. The ethyl acetate extract was washed with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried, and treated with activated charcoal. After removal of charcoal and the solvent, the residue was recrystallized from isopropyl ether to give 18.5 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid as colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[Cl:11]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N)ccc1Cl

Procedure:
To a slurry of 5-amino-2-chloro-benzoic acid (20.0 g, 0.12 mol) in methanol (150 mL) was added concentrated sulfuric acid (25 mL). The resulting reaction was heated at reflux for 4 hours, cooled, and concentrated in vacuo. The residual was taken up in water and neutralized with Na2CO3. The aqueous was extracted with CH2Cl2 (3×). The organics were dried over sodium sulfate and concentrated in vacuo to yield the above named compound (14.0 g).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:45]/[O:46][C:47]([C:50]([O:52]C(C)(C)C)=[O:51])([CH3:49])[CH3:48])/[C:15]([NH:17][C@@H:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:22]([CH2:25]Cl)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1)=O)(C)(C)C.[I-].[Na+].C(OC([NH:66][CH2:67][C:68]1[CH:69]=[N:70][N:71]([CH2:93][CH3:94])[C:72]=1[NH:73]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)(C)C.C(OCC)(=O)C>CN(C)C=O.O>[NH2:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:45]/[O:46][C:47]([C:50]([OH:52])=[O:51])([CH3:48])[CH3:49])/[C:15]([NH:17][C@@H:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:70]4[N:71]([CH2:93][CH3:94])[C:72]([NH2:73])=[C:68]([CH2:67][NH2:66])[CH:69]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CCn1ncc(CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)ns1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(N)c(CN)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 47 h
Yield: 21.1 %

Procedure:
To a suspension of a mixture of benzhydryl 7β-[(Z)-2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (1 g) and sodium iodide (199 mg) in N,N-dimethylformamide (3 ml) was added 4-tert-butoxycarbonylaminomethyl-1-ethyl-5-tritylaminopyrazole (1.17 g), and the mixture was stirred at room temperature for 47 hours. The reaction mixture was added to a mixture of ethyl acetate (30 ml) and water (20 ml). The organic layer was separated, washed with brine (15 ml), and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated to about 5 ml under reduced pressure. The concentrate was poured into diisopropyl ether (150 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the resulting solid in methylene chloride (4.5 ml) were added anisole (1.5 ml) and trifluoroacetic acid (3 ml). The resulting solution was stirred at room temperature for 3 hours and poured into diisopropyl ether. The resulting precipitate was collected by filtration and dried in vacuo. The obtained powder was dissolved in a phosphate buffer (pH 7) and adjusted to about pH 6 with saturated aqueous sodium hydrogencarbonate solution. The solution containing the objective compound was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated in vacuo. The concentrate was adjusted to about pH 2 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 20% aqueous 2-propanol. The eluate was evaporated in vacuo and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-amino-4-aminomethyl-2-ethyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (155 mg) as an amorphous solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2ccc(F)cc2)C1
Solvent: C1CCOC1
Product: Fc1ccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)cc1
Yield: 84.3 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(4-fluorophenyl)piperidin-1-yl]methanone (20 mg, 0.058 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 16 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:23][CH2:24][O:25][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[CH2:26][CH3:27])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 73.9 %

Procedure:
To 7.0 g (15.6 mmol) 2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol in 20 ml DMF were added 1.9 g (28.0 mmol, 1.8 eq) imidazole, followed by 3.3 g (21.8 mmol, 1.4 eq) tert-butyldimethylchlorosilane in 20 ml DMF at 0° C. The solution was stirred at 50° C. for 6 h, and at RT for 48 h. Additional 235 mg (1.5 mmol, 0.1 eq) tert-butyldimethylchlorosilane were added and the solution was stirred at 50° C. for 2 h. The solution was poured on an aqueous solution of NaHCO3. The inorganic layer was extracted with ether, and the combined organic phases were washed with brine and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 95:5 gave 6.5 g (74%) {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amine as brown oil, MS: 563 (MH+, 1Br).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.CO.C1COCC1.CO.[N+:37]([C:40]1[NH:41][CH:42]=[C:43]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][C:48](=[O:52])[CH2:47]2)[N:44]=1)([O-])=O>[Ni].C(Cl)Cl.CO>[O:52]=[C:48]1[NH:49][CH2:50][CH2:51][N:46]([CH2:45][C:43]2[N:44]=[C:40]([NH:37][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:5])[NH:41][CH:42]=2)[CH2:47]1
Reactant: O=C1CN(Cc2c[nH]c([N+](=O)[O-])n2)CCN1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN4CCNC(=O)C4)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazin-2-one (Step 142.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 524.1 [M+H]+; tR=3.10 min (System 1); TLC: Rf=0.23 (DCM/MeOH, 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH:14]3[CH2:16][CH2:15]3)[CH2:12][O:11]C(=O)[NH:9]2)[CH:7]=1.O.[OH-].[Li+]>C(O)C.O>[NH2:9][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:17])([CH:14]1[CH2:16][CH2:15]1)[CH2:12][OH:11]
Reactant: O=C1NC(c2cc(Br)ccc2F)(C2CC2)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(CO)(c1cc(Br)ccc1F)C1CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of the crude (RS)-4-(5-bromo-2-fluoro-phenyl)-4-cyclopropyl-oxazolidin-2-one (4.802 g) in ethanol (25 ml) and water (125 ml) was treated with lithium hydroxide monohydrate (6.7 g, 160 mmol) and the reaction mixture was stirred at 100° C. overnight. For the workup, the reaction mixture was extracted with dichloromethane, the combined organic layers were washed with water, then dried over sodium sulfate and evaporated. The crude product was purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate as the eluent. (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-2-cyclopropyl-ethanol was obtained as a yellow oil (2.27 g, 52% of theory). Mass (calculated) C11H13BrFNO [274.132]; (found) [M+H]+=274, [M+2-H]+=276.
Reaction SMILES: FC(F)(OC1C=CC(C2OC([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)=NN=2)=CC=1)C(F)(F)F.Cl>CO.[OH-].[Na+]>[C:23]([OH:25])(=[O:24])[C:22]1[CH:27]=[CH:28][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(OC(F)(F)C(F)(F)F)cc3)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To methyl 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoate (1.07 g, 2.58 mmol) was added MeOH (26 mL) (starting material remained partially insoluble). A solution of 2 N NaOH (5.2 mL, 10.33 mmol) was added, and the reaction was stirred at room temperature for 18 h. Stirring had become hindered overnight due to the formation of solid. LC/MS showed 25% conversion to product. The reaction mixture was diluted with MeOH and additional 2 N NaOH (20 mL) was added and the reaction was heated to 45° C. for 24 h. The reaction was cooled and neutralized with 2 N HCl (20 mL). Some of the MeOH was concentrated off in vacuo, causing the product to precipitate. The white precipitate was vacuum filtered and dried in a vacuum oven at 45° C. to provide 44544-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoic acid as a white solid (760 mg, 90% purity, 66%): mp 301-307° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 8.34-8.26 (m, 4H), 8.18 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −85.25, −86.89; ESIMS m/z 401 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[N:11][CH:10]=[N:9]2)[N:5]=[C:4]([CH3:24])[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1)#[CH:26]>C(#N)C.C(N(CC)CC)C.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>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH2:13][C:12]1[N:8]([C:6]2[CH:7]=[C:2]([C:26]#[C:25][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[N:3]=[C:4]([CH3:24])[N:5]=2)[N:9]=[CH:10][N:11]=1
Reactant: COc1ccc(Cc2ncnn2-c2cc(Cl)nc(C)n2)cc1OC
Reactant: C#Cc1ccc(C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2ncnn2-c2cc(C#Cc3ccc(C)cn3)nc(C)n2)cc1OC
Temperature: 50 °C

Procedure:
A slurry of 4-chloro-6-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (1-3, 100 mg, 0.289 mmol, 1.0 eq), 2-ethynyl-5-methylpyridine (67.8 mg, 0.578 mmol, 2.0 eq), bis(triphenylphosphine)palladium(II) dichloride (10.15 mg, 0.014 mmol. 0.050 eq.) and copper(I) iodide (2.203 mg, 0.012 mmol 0.040 eq.) in a mixture of acetonitrile (1 ml) and triethylamine (1 mL) was heated at 50° C. for 16 h. The solvents were removed by roto-evaporation and the resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford 4-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methyl-6-((5-methylpyridin-2-yl)ethynyl)pyrimidine (1-4). 1H NMR (500 MHz, CDCl3) δ 8.78 (s, 1H), 7.94 (m, 2H), 7.69 (m, 2H), 6.86 (m, 2H), 6.79 (d, 1H, J=8.2 Hz), 4.79 (s, 2H), 3.84 (s, 6H), 2.82 (s, 3H), 2.54 (s, 3H). HRMS m/z (M+H) 429.2029 found, 429.2034 required.