Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](C2C=C(C=CC=2)C#N)=[N:4][C:5](F)=[C:6]([F:9])[C:7]=1[CH3:8].[CH3:19][N:20]([CH3:29])[C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([OH:27])[CH:26]=1.[C:30](=[O:33])([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:9][C:6]1[C:5]([O:33][C:30]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:21]#[N:20])=[N:4][C:3]([O:27][C:25]2[CH:26]=[C:21]([N:20]([CH3:29])[CH3:19])[CH:22]=[CH:23][C:24]=2[CH3:28])=[C:2]([F:1])[C:7]=1[CH3:8]
Reactant: Cc1ccc(N(C)C)cc1O
Reactant: O=C([O-])[O-]
Reactant: Cc1c(F)c(F)nc(-c2cccc(C#N)c2)c1F
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(N(C)C)cc1Oc1nc(Oc2ccccc2C#N)c(F)c(C)c1F

Procedure:
In a manner similar to preparation 6, reaction of 3-(3,5,6-trifluoro-4-methylpyridin-2-yl)benzonitrile (1.1 g, 4.4 mmol), 5-dimethylamino-2-methylphenol (0.66 g, 4.4 mmol), and cesium carbonate (1.7 g, 5.2 mmol) in acetonitrile (10 mL) gave 3-[(3,5-difluoro-6-(5-dimethylamino-2-methylphenoxy)-4-methylpyridin-2-yl)oxy-benzonitrile; NMR (CDCl3) 7.3 (m,4), 7.0 (d,1), 6.5 (d,1), 6.3 (s,1), 2.8 (s,6), 2.4 (s,3), 2.0 (s,3) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.CO[C:19]1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=C[CH:24]=1>C1COCC1>[Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH:12]([CH2:19][CH3:24])[CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Solvent: C1CCOC1
Product: CCC(C)NC(=O)Nc1cc(C(N)=S)c(Br)cn1

Procedure:
The title compound was synthesized by a method analogous to the synthesis of Intermediate 42 starting with Intermediate 50 and Lawessons reagent in THF. MS (ESP): 332 (M+1) for C11H15BrN4OS
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)=[C:4]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[OH:19])[CH:3]=1.O1CCCC1.C([Mg]Cl)(C)C.C(O[B:41]1[O:45][C:44]([CH3:47])([CH3:46])[C:43]([CH3:49])([CH3:48])[O:42]1)(C)C>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]([C:4]2[CH:3]=[C:2]([B:41]3[O:45][C:44]([CH3:47])([CH3:46])[C:43]([CH3:49])([CH3:48])[O:42]3)[S:6][C:5]=2[C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)[OH:19])=[CH:21][CH:22]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: OC(c1ccc(Cl)cc1)c1cc(Br)sc1-c1ncn(C2CCCCO2)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(C(O)c3ccc(Cl)cc3)c(-c3ncn(C4CCCCO4)n3)s2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a mixture of {5-bromo-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}(4-chlorophenyl)methanol (5.19 g, 11.4 mmol) in tetrahydrofuran (146.9 mL, 1811 mmol) was added isopropylmagnesium chloride (1M in THF, 34.2 mL, 34.2 mmol) at −40° C. under argon. After addition, the reaction temperature was raised to rt for 15 min. The mixture was then cooled to −78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.149 mL, 39.94 mmol) was added. After the addition, the mixture was brought to rt. After 1 h, the mixture was heated at 75° C. overnight. The mixture was cooled to rt and quenched with saturated ammonium chloride solution. The mixture was stirred for 10 min then extracted with EtOAc. The organic layer was dried and evaporated in vacuum. The mixture was purified by chromatography to afford (4-chlorophenyl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)methanol as a thick oil (5.32 g, 65.0%). LCMS: (FA) ES+ 502.2, 504.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][OH:24])[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][O:24][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-methyl-N-(4-chlorophenyl)-benzenepropanamide (3.6 g) in CH2Cl2 (100 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (1.62 mL), and methanesulfonyl chloride (0.9 mL). After two hours the reaction mixture was washed with water (100 mL), brine (100 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (4.3 g).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23](C(O)=O)=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CNC[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:62][N:63]([CH3:66])[CH:64]=[O:65]>C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:64]([N:63]([CH3:66])[CH2:62][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:65])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCNC
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
To a mixture of 4-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}benzoic acid (1.06 g) synthesized above, ethyl 3-(methylamino)propanoate (438 mg), 1-hydroxybenzotriazole monohydrate (512 mg), triethylamine (930 μL) and N,N-dimethylformamide (20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (640 mg), and the mixture was stirred at room temperature for 1.5 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55% ethyl acetate/hexane) to give the title object compound (564 mg, 41%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[I-].[CH3:23][C:24]1([CH2:28][Zn+])[CH2:27][O:26][CH2:25]1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:23][C:24]4([CH3:28])[CH2:27][O:26][CH2:25]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: CC1(C[Zn+])COC1
Reactant: COC(=O)c1nc2n(c1I)C1CC(C1)c1ccc(Br)cc1-2
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1nc2n(c1CC1(C)COC1)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 90 °C
Reaction time: 0.02 h
Yield: 40.4 %

Procedure:
A solution of methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (75 mg, 0.16 mmol) in 1 mL DMA was sparged with nitrogen and treated with ((3-methyloxetan-3-yl)methyl)zinc(II) iodide (1.11 mL, 0.59 M, 0.65 mmol) reagent while nitrogen was sparging. After 1 min, solid Pd(PPh3)4 (ca. 10 mol %) was added and the mixture stirred at 90° C. overnight. The mixture was diluted with ammonium chloride and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. Purification by flash column chromatography (12 g isco, 10-100% EtOAc) gave 27 mg of methyl 10-bromo-3-((3-methyloxetan-3-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This product was taken up in 1 mL of DMF and treated with 0.2 mL formamide then 0.2 mL of 25% wt NaOMe in MeOH. After 1 hour at room temp, the mixture was diluted with ammonium chloride and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. This material was used in subsequent operations without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:21])([F:20])[C@H:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCCP(=O)=O.[CH2:28]([S:30]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[C:38]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)[C:37]([CH2:55][N:56]1[CH2:61][CH2:60][CH:59]([N:62]3[CH2:66][CH2:65][CH2:64][CH2:63]3)[CH2:58][CH2:57]1)=[C:36]2[C:67](O)=[O:68])(=[O:32])=[O:31])[CH3:29]>C(OCC)(=O)C.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:28]([S:30]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[C:38]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:53])([F:54])[F:52])[CH:46]=1)[C:37]([CH2:55][N:56]1[CH2:61][CH2:60][CH:59]([N:62]3[CH2:66][CH2:65][CH2:64][CH2:63]3)[CH2:58][CH2:57]1)=[C:36]2[C:67]([NH:19][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]([F:20])([F:21])[F:10])=[O:68])(=[O:31])=[O:32])[CH3:29]
Reactant: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)c1cc2c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c(CN3CCC(N4CCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reaction time: 15 h
Yield: 54 %

Procedure:
N,N-Diisopropylethylamine (0.087 mL, 0.495 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.045 g, 0.215 mmol), and propylphosphonic anhydride (0.126 mL of a 50% solution in ethyl acetate, 0.215 mmol) were added to a suspension of 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.165 mmol) in dichloromethane (2.54 mL). The mixture was stirred for 15 h, diluted with 10% Na2CO3 (2 mL) and methylene chloride (5 mL), and poured into a hydrophobic frit to separate the phases. The organic phase was absorbed onto florisil and purified via column chromatography (ISCO, 1-10% methanol/methylene chloride). The material was dissolved in methylene chloride, and the organic phase was washed with 10% Na2CO3 (2×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide as a light orange solid (0.068 g, 51% yield). MS (m/z) 763.2 (M+H+).
Reaction SMILES: [C:1]1(SC[Li])C=CC=CC=1.[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][CH3:31])[C:24]=2[O:32][CH2:33][O:34][CH3:35])[CH2:22][CH2:21]1>>[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:1])=[C:25]([O:30][CH3:31])[C:24]=2[O:32][CH2:33][O:34][CH3:35])[CH2:21][CH2:22]1
Reactant: [Li]CSc1ccccc1
Reactant: COCOc1ccccc1C1(c2ccc(O)c(OC)c2OCOC)CC1
Product: COCOc1ccccc1C1(c2ccc(OC)c(OC)c2OCOC)CC1

Procedure:
When an initial charge of 3.3 moles of phenylthiomethyl lithium per mole of olefin was employed, the product was 1-(2-methoxymethoxyphenyl)-1-(4-hydroxy-3-methoxy-2-methoxymethoxyphenyl)cyclopropane, an oil obtained in 33 percent yield and identified by proton NMR spectroscopy.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:15])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)#N.[OH-:16].[K+].C[OH:19]>O>[CH3:15][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1)[C:1]([OH:19])=[O:16]
Reactant: Cc1cc(C#N)cc(-c2ccccc2)c1
Reactant: [OH-]
Reactant: CO
Agent: [K+]
Solvent: O
Product: Cc1cc(C(=O)O)cc(-c2ccccc2)c1
Yield: 65 %

Procedure:
A solution of 3-cyano-5-phenyltoluene (5.06 g; 26 mmol) and potassium hydroxide (2.94 g; 52 mmol) in methanol (40 ml) and water (60 ml) was refluxed for 24 hours. After evaporation of the methanol and filtration of the unsoluble material, the mixture was acidified to pH 2 with 6N HCl. The resulting precipitate was filtered, washed with water and dried to give 3-methyl-5-phenylbenzoic acid. Yield=65%.
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][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2OCCCO2)=[CH:18][CH:17]=1.[O:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].N1CCCCC1>C(O)(=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][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH:25]=[C:35]2[O:31][C:32](=[O:37])[NH:33][C:34]2=[O:36])=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC2OCCCO2)cc1
Reactant: O=C1COC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC=C2OC(=O)NC2=O)cc1
Yield: 25.9 %

Procedure:
A mixture of 2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-1,3-dioxane (2.0 g), 2,4-oxazolidinedione (0.99 g), piperidine (0.21 g) and acetic acid (50 ml) was heated for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure, to which was added ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium hydrogencarbonate, 2N HCl and water, successively, which was then dried (MgSO4), followed by concentration. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-ethyl acetate (5:1), 5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butylidene]-2,4-oxazolidinedione (0.55 g, 26%) was obtained. Recrystallization from ethyl ether-methanol gave colorless needles, m.p.152-153° C.
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][Br:19])=[CH:13][C:12]=1[C:21]#[N:22])=[O:9])C1C=CC=CC=1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][C:8](=[O:9])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][Br:19])=[CH:13][C:12]=1[C:21]#[N:22])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: N#Cc1cc(C(=O)CBr)ccc1NC(=O)Oc1ccccc1
Product: CC(C)(C)NC(=O)Nc1ccc(C(=O)CBr)cc1C#N

Procedure:
The starting compound, 4'-(3-tert. butyl-ureido)-2-bromo-3'-cyano-acetophenone was prepared by reacting 4'-phenoxycarbonylamino-2-bromo-3'-cyanoacetophenone with tert. butylamine at room temperature.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[O:5][C:6]2[C:16]([N:17]=1)=[CH:15][C:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=1[CH:7]=2)[CH3:3].[Cl:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[N:27]([CH3:28])[C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[CH3:34])=[N:25][N:24]=1>>[ClH:18].[CH3:3][CH:2]([C:4]1[O:5][C:6]2[C:16]([N:17]=1)=[CH:15][C:9]1[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][CH2:21][S:22][C:23]3[N:27]([CH3:28])[C:26]([C:29]4[O:33][CH:32]=[N:31][C:30]=4[CH3:34])=[N:25][N:24]=3)[CH2:13][CH2:14][C:8]=1[CH:7]=2)[CH3:1]
Reactant: Cc1ncoc1-c1nnc(SCCCCl)n1C
Reactant: CC(C)c1nc2cc3c(cc2o1)CCNCC3
Product: Cc1ncoc1-c1nnc(SCCCN2CCc3cc4nc(C(C)C)oc4cc3CC2)n1C
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.21 mmol) and 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole and was obtained as a colourless slightly hygroscopic solid (78 μmol).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([C:27]1[S:31][CH:30]=[C:29]([C:32]([OH:34])=O)[CH:28]=1)[CH3:26].[O:35]1[C:40]2([CH2:45][CH2:44][N:43]([CH2:46][C:47]3[CH:48]=[C:49]([CH2:53][CH2:54][OH:55])[CH:50]=[CH:51][CH:52]=3)[CH2:42][CH2:41]2)[CH2:39][NH:38][CH2:37][CH2:36]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([C:27]1[S:31][CH:30]=[C:29]([C:32]([N:38]2[CH2:39][C:40]3([CH2:41][CH2:42][N:43]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][CH2:54][OH:55])[CH:48]=4)[CH2:44][CH2:45]3)[O:35][CH2:36][CH2:37]2)=[O:34])[CH:28]=1)[CH3:26]
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Reactant: CCc1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
HATU (0.209 g) was added to a stirred solution of 5-ethylthiophene-3-carboxylic acid (0.086 g), 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.160 g), and triethylamine (0.3 mL) in DMF (2 mL). After 1 h, the reaction mixture was diluted with ethyl acetate (25 mL) and washed with brine (2×25 mL). The ethyl acetate layer was evaporated in vacuo. Purification by silica gel chromatography eluting with 10:1, ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 0.18 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=1)=[O:6].[OH-:20].[K+].Cl>C(O)C>[CH:4]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:15])=[O:20])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CON(C)C(=O)Cc1ccc(C(=O)CCCCl)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1ccc(C(=O)C2CC2)cc1
Reaction time: 18 h
Yield: 9.5 %

Procedure:
Add purified [4-(4-chloro-1-oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide (9.4 g, 330 mmol) to a solution of potassium hydroxide (22.0 g) in ethanol (160 mL). Stir 18 hours. Pour the solution into dilute hydrochloric acid (30 mL of concentrated hydrochloric acid in 500 mL of water). Extract the solution with three 500-mL portions of ethyl acetate. Dry the combined organic phases over anhydrous magnesium sulfate and concentrate to give the title compound (6.4 g, 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][C:17](O)=[O:18])=[O:14])=[CH:11][C:10]=1[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:33][CH2:32][C@@H:31]2[CH2:34][C@H:28]1[C:29](=[O:42])[N:30]2C(OC(C)(C)C)=O.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CCOC(C)=O.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][C:17](=[O:18])[NH:26][C@H:27]2[CH2:33][CH2:32][C@@H:31]3[CH2:34][C@H:28]2[C:29](=[O:42])[NH:30]3)=[O:14])=[CH:11][C:10]=1[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N
Reactant: CC(C)(C)c1cc(C(=O)NCC(=O)O)ccc1OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)c1cc(C(=O)NCC(=O)N[C@H]2CC[C@@H]3C[C@H]2C(=O)N3)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.6 %

Procedure:
To a solution of 2-(4-(benzyloxy)-3-tert-butylbenzamido)acetic acid (418 mg, 1.22 mmol) in anhyd DMF (8 mL) was added (1R,2S,5R)-tert-butyl 2-amino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (287 mg, 1.11 mmol), BOP reagent (738 mg, 1.67 mmol), and N-methylmorpholine (366 μL, 3.34 mmol). The mixture was stirred at room temperature for 12 h under nitrogen atmosphere and then diluted with EtOAc (250 mL). The organic layer was washed with water (100 mL), 0.1 N HCl (100 mL), satd NaHCO3 (100 mL), and brine (50 mL), dried (Na2SO4), and concentrated in vacuo. 4-(benzyloxy)-3-tert-butyl-N-(2-oxo-2-((1R,2S,5R)-7-oxo-6-aza-bicyclo[3.2.1]octan-2-ylamino)ethyl)benzamide (713 mg, quant.) was isolated as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.81-6.93 (m, 8H), 6.69 (s, 1H), 5.15 (s. 1H); 5.16 (s, 1H), 4.13-4.06 (m, 4H), 3.20-2.80 (m, 2H), 2.40-1.30 (m, 6H), 1.52 (s, 9H), 1.42 (s, 9H); MS found: (M+H)+=564.
Reaction SMILES: C(OC([N:6]1[CH2:13][CH:12]2[CH2:14][CH:8]([CH2:9][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:11]2)[CH2:7]1)=O)C.[ClH:21]>>[ClH:21].[ClH:21].[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:10]2[CH2:11][CH:12]3[CH2:14][CH:8]([CH2:7][NH:6][CH2:13]3)[CH:9]=2)[CH:16]=1
Reactant: CCOC(=O)N1CC2C=C(c3cccnc3)CC(C2)C1
Agent: Cl
Product: C1=C(c2cccnc2)CC2CNCC1C2

Procedure:
7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene-3-carboxylic acid ethyl ester (90 mg, 0.03 mmol) was dissolved in concentrated 12 N HCl (10 ml) and refluxed overnight. The reaction was then concentrated by rotary evaporation, and the residue was converted to a free base with saturated sodium bicarbonate (˜20 ml). The mixture was treated with saturated with sodium chloride (˜3 g) and extracted with chloroform (3×10 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by column chromatography, using methanol/chloroform (10% methanol with 1% ammonium hydroxide) as eluent, to yield 26.2 mg of the free base. Concentrated HCl (5 drops) was added to a solution of the free base in ethanol (10 ml). The excess HCl and residual water were removed by repeated azeotropic rotary evaporation with ethanol. The crude salt was dissolved in hot isopropanol (5 ml) and diluted with diethyl ether (1 ml). The solution turned cloudy and was allowed to slowly cool for 1 h. White crystals formed on the sides. The supernatant was decanted, and the solid was washed with a 20% ether/isopropanol solution and dried on a hi-vacuum pump. This gave 7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene dihydrochloride as a white powder (14 mg, 16%, m.p. 219-221° C.).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[C:16]=1[NH2:17].NC(N)=S>CC(C)=O>[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[C:16]=1[NH:17][C:11]([NH2:12])=[S:10]
Reactant: Nc1c(Br)cccc1Br
Reactant: N#C[S-]
Agent: NC(N)=S
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: NC(=S)Nc1c(Br)cccc1Br
Reaction time: 0.17 h

Procedure:
A solution of 4.6 ml. of benzoyl chloride in 10 ml. of acetone was added over a period of 5 minutes to a solution of 3.32 g. of ammonium thiocyanate in 60 ml. of dry acetone at reflux. The resulting solution was refluxed for 10 minutes and a solution of 10.0 g. of 2,6-dibromoaniline in 40 ml. of acetone was added over a period of 10 minutes. After 15 minutes at reflux, the reaction mixture was poured onto 300 ml. of water and filtered. The resulting solid was suspended in 30 ml. of 10% sodium hydroxide and boiled for 10 minutes. The clear solution was acidified, neutralized to pH 8 with ammonia and filtered, giving 12.0 g. (97%) of 1-(2,6-dibromophenyl(thiourea, m.p. 186°-189°. Recrystallization from aqueous methanol gave the analytical sample, m.p. 192°-193°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:23](=[O:28])[CH2:24][CH2:25][C:26]#[CH:27])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1>C(N(CC)CC)C.[Cu]I.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>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([C:23](=[O:28])[CH2:24][CH2:25][C:26]#[C:27][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:14]=1
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 54.5 %

Procedure:
To a solution of CuI (7.7 mg, 0.041 mmol) in triethylamine (2.28 mL) were added 2-bromopyridine (129 mg, 0.82 mmol) and (PPh3)2PdCl2 (28.7 mg, 0.041 mmol). The reaction mixture was cooled to 0° C. and tert-butyl 4-chlorophenyl(pent-4-ynoyl)carbamate (250 mg, 0.82 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated under reflux for 3 h. at 70° C. Triethylamine was evaporated, water was added and the aqueous phase was extracted twice with DCM. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 70/30 as eluent) to afford 172 mg (Yield: 55%) of tert-butyl 4-chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate as a yellow oil.