Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:18])([F:17])[C:13]([CH3:16])([OH:15])[CH3:14].[H-].[Na+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][C:13]([CH3:16])([CH3:14])[C:12]([F:18])([F:17])[F:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-fluoro-4-nitro-benzene (2.82 g) and 1,1,1-trifluoro-2-methyl-propan-2-ol (2.3 ml) in DMF (90 ml) under an argon atmosphere was added under ice cooling NaH (0.914 g, 55% suspension in oil) and the mixture was stirred for 3 h at RT. It was then partitioned between diethyl ether and water, the layers were separated, dried over Na2SO4 and the solvent was evaporated off to give 1-nitro-4-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzene as a brown oil (4.9 g) that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:18])[CH:17]=[C:13]3[NH:12][C:11](=O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:14]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:13]2[N:12]=1
Reactant: Cc1cc2[nH]c(=O)cc(-c3ccc(F)c(F)c3)n2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc2nc(Cl)cc(-c3ccc(F)c(F)c3)n2n1
Temperature: 25 °C

Procedure:
7-(3,4-Difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (821 mg) is dissolved in POCl3 (15 mL) and pyridine (0.2 mL) and stirred overnight while heating. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and the target compound (301 mg) is yielded by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 8.08 (m, 1H), 7.78 (m, 1H), 7.36 (q, J=8.7 Hz, 1H), 6.73 (s, 1H), 6.40 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][S:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:9][S:8][CH2:7][C:5]1[O:6][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=2)=[CH:3][C:4]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(Br)oc1CSC
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CSC
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A mixture of methyl 5-bromo-2-[(methylsulfanyl)methyl]furan-3-carboxylate (5.3 g), 4-(trifluoromethyl)phenylboronic acid (4.6 g), tetrakis(triphenylphosphine)palladium(0) (1.2 g), 2N aqueous sodium carbonate solution (24 mL) and 1,2-dimethoxyethane (50 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (5.0 g, 75%) as an oil.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([Br:12])[CH:14]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cccc(Br)c1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cccc(Br)c1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 3-bromobenzoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent. The compound was then dissolved in tetrahydrofuran, excess hydrogen chloride (1M solution in diethyl ether) was added, and the solution was evaporated and then recrystallised from methanol/diethyl ether to give the hydrochloride salt of the title compound as a colourless solid; MS (ES+) 309, 311 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([CH:26]4[CH2:28][CH2:27]4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[F:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N:21]([C:19]2[C:18]([CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:11]3[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH:20]=2)[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:39][C:38]=1[F:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12

Procedure:
A mixture of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (2.0 g, 4.77 mmol), (4-(benzyloxy)-3-fluorophenyl)boronic acid (1.762 g, 7.16 mmol), Cu(OAc)2(1.301 g, 7.16 mmol), triethylamine (3.33 mL, 23.87 mmol) and powdered 3 Å molecular sieves (2 g) in CH2Cl2 (60 mL) was stirred in a flask open to the air and equipped with a drying tube. After 12 hours the mixture was treated with additional (4-(benzyloxy)-3-fluorophenyl)boronic acid (1.762 g, 7.16 mmol) and Cu(OAc)2(1.301 g, 7.16 mmol) and stirred at room temperature for 4 d. The mixture was diluted with CH2Cl2, filtered through Celite and the dark brown filtrate was concentrated to dryness. The crude material was purified by flash chromatography on silica gel (0-4% EtOAc/CH2Cl2) to afford the desired compound which was further purified by flash chromatography on silica gel eluted (0-40% EtOAc/hexane) to give the desired compound as a light-tan solid (406 mg, 14%). LCMS (m/z, ES+)=619 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Cl)CCC.[CH3:14][O:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[N:23]([C:31]([C@H:33]1[CH2:38][CH2:37][C@H:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32])[CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:17].[I:40]I>C1COCC1>[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([I:40])=[CH:21][C:22]=1[N:23]([C:31]([C@H:33]1[CH2:34][CH2:35][C@H:36]([CH3:39])[CH2:37][CH2:38]1)=[O:32])[CH:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1)=[O:17]
Reactant: II
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Agent: CCCC[Mg]Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Reaction time: 24 h

Procedure:
To a stirred solution of diisopropyl amine (0.3 mL, 2.14 mmol) in THF (10 mL) was added n-BuMgCl (2.0 M in ether, 1.0 mL, 2.0 mmol), stirred for 24 h. To the resultant solution was added drop wise a solution of 3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (0.189 g, 0.5 mmol) in THF (2.0 mL), stirred for 1 h at room temperature. It was then added a solution of Iodine (1.28 g, 5.0 mmol) in THF (2.0 mL), stirred for 1 h. Reaction mixture was then quenched with 10% aq Na2S2O3 solution, extracted with EtOAc, washed with brine, dried, and concentrated. Purification of the residue on small plug of silica gel bond elute using DCM/CHCl3/MeOH/Et3N (200:90:16:1) as eluent gave 5-iodo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (0.250 g, quantitative). NMR 1H (CDCl3, 400 MHz): 7.05 (s, 1H), 4.68-4.55 (m, 1H), 3.83 (s, 3H), 2.95-2.8 (m, 2H), 2.26 (s, 3H), 2.2-1.1 (m, 14H), 0.819 (d, J=6.3, 3H), 0.75-0.6 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([C:9]#[C:10][Si](C)(C)C)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]>CO.O>[O:1]=[C:2]([C:9]#[CH:10])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: C[Si](C)(C)C#CC(=O)CCCC(=O)O
Solvent: O
Solvent: CO
Product: C#CC(=O)CCCC(=O)O
Temperature: 45 °C
Reaction time: 18 h

Procedure:
The known 5-oxo-7-(trimethylsilyl)hept-6-ynoic acid (1.15 g, 2; prepared using the procedure described in J. Org. Chem., Vol. 62, No. 4, 1997, pp. 982-991) was dissolved in methanol (40 ml) and a solution of Borax (Na2B4O7×10H2O, 2.7 g) in water (6 ml) was added. The resulting reaction mixture was stirred for 18 h at 45° C. under argon. The reaction mixture was then quenched by the addition of 1 M HCl (20 ml) and methanol removed in vacuo. The remaining aqueous solution was then extracted with ethyl acetate (4×35 ml). After washing the pooled organic extracts with brine (2×40 ml), drying with MgSO4 and then filtering, volatiles were removed in vacuo. The crude orange oil remaining was purified by flash chromatography (5% ethyl acetate→10%→15% ethyl acetate/hexane) yielding a pale yellow oil product, 5-oxohept-6-ynoic acid (328 mg, J), which crystallized under storage. 1H NMR (400 MHz, CDCl3): δ1.75 (m, 2H), 2.22 (t, 2H), 2.63 (t, 2H), 4.8 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.C(O)C.[Pd]>[N:11]1[CH:12]=[CH:13][N:14]=[CH:15][C:10]=1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cccc(-c2cnccn2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc(-c2cnccn2)c1
Yield: 96.4 %

Procedure:
A suspension of 2-(3-nitrophenyl)pyrazine (500 mg) in tetrahydrofuran (5 ml) and ethanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 200 mg) under hydrogen atmosphere for 6 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from dichloromethanediisopropyl ether to give 3-(pyrazin-2-yl)aniline (410 mg, 96.5%).
Reaction SMILES: CON(C)[C:4](=[O:21])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[CH3:23][Li]>O1CCCC1.Cl.CO>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4](=[O:21])[CH3:23])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1ccc(C=CC(=O)N(C)OC)cc1OC1CCCC1
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(/C=C/C(C)=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of N-methoxy-N-methyl-3-(3-cyclopentyloxy-4-methoxyphenyl)prop-2-enamide (1.986 g, 6.50 mmol) in dry tetrahydrofuran (15 ml) at -78° C. was added methyl lithium (1.4M solution in hexanes, 10.20 ml, 14.3 mmol) dropwise over 3 minutes. The resulting solution was stirred for 1 hour at 0° C., after which time the reaction mixture was diluted with 5% HCl in methanol (20 ml) at 0° C., and partitioned between brine (35 ml) and an equal volume of methylene chloride and diethyl ether (100 ml). The organics were dried (Na2SO4) and concentrated in vacuo to give a light yellow oil. The oil was purified by flash chromatography (SiO2 ; ethyl acetate/hexane (35:65)) to afford the title compound as a colorless oil (1.642 g).
Reaction SMILES: C(OC([NH:11][C@:12]1([C:22]([OH:24])=[O:23])[C@@H:17]2[CH2:18][C@@:14]3([C:19]([OH:21])=[O:20])[C@@H:15]([CH2:16]2)[C@@H:13]13)=O)C1C=CC=CC=1.[H][H]>C(O)C.O.[Pd]>[NH2:11][C@:12]1([C:22]([OH:24])=[O:23])[C@@H:17]2[CH2:18][C@@:14]3([C:19]([OH:21])=[O:20])[C@@H:15]([CH2:16]2)[C@@H:13]13
Reactant: [H][H]
Reactant: O=C(N[C@]1(C(=O)O)[C@H]2C[C@H]3[C@@H]1[C@@]3(C(=O)O)C2)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: N[C@]1(C(=O)O)[C@H]2C[C@H]3[C@@H]1[C@@]3(C(=O)O)C2
Yield: 27.7 %

Procedure:
To a solution of 1.1 g (3.3 mmole) of (+/−)-(1R*,2R*,3R*,4S*,6S*)-3-benzyloxycarbonylamino-tricyclo[2.2.1.02,6]heptane-1,3-dicarboxylic acid in 100 mL of 1:1 ethanol/water was added 0.25 g of 10% palladium on carbon. The mixture was treated with 60 psi of hydrogen on a Parr apparatus for 24 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuum to give 0.18 g of the title compound as a gray solid sesquihydrate. Extraction of the catalyst and celite with boiling water, filtration of the extracts through a millipore filter and concentration in vacuum led to the isolation of an additional 0.32 g of white solid. This was recrystallized from water to give 0.21 g of the title compound as a white crystalline one-quarter hydrate, m.p.>250° C.
Reaction SMILES: [C:1](C1C=CC=CC=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC(C)=CC=1.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[OH:29])=[CH:26][CH:25]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(Br)cc1
Product: Cc1ccc(C(O)c2ccc(Br)cc2)cc1

Procedure:
The procedure below details the synthesis of a benzophenone dimer comprising a metal carboxylate and linked by a diamine terminated bridging moiety via the scheme set forth in FIG. 1. As shown in FIG. 1, synthesis of the benzophenone crosslinker (8) starts with a reaction between a Grignard reagent derived from commercially available 4-bromotoluene (1) and 4-bromobenzaldehyde (2), yielding (4′-bromophenyl)-4-methylphenyl methanol (3). Alcohol (3) was then oxidized with potassium permanganate (KMnO4) to provide 4-bromophenyl-p-toylmethanone (4), followed by oxidation of the methyl group with CrO3 to yield 4-(p-bromobenzoyl) benzoic acid (5). Esterification of acid (5) provided 4-(p-bromobenzoyl) benzoate (6). The bifunctional coupling between pentane diamine (NH2(CH2)5NH2)and methyl 4-(p-bromobenzoyl) benzoate (6) to yield the benzophenone dimer (7) was achieved using 1,1-bis(diphenyphosphino)ferrocene (DPPF) as the catalyst. The benzophenone dimer (7) was then hydrolyzed to provide the dipotassium salt (8). Details of each step are set forth below.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2[C:20](=O)[CH2:21][CH2:22][CH:17]2[CH2:16]1>O.C(O)C>[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2/[C:20](=[N:2]/[OH:3])/[CH2:21][CH2:22][CH:17]2[CH2:16]1
Reactant: NO
Reactant: O=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C1\CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (3.47 g, 50.0 mmol) and sodium acetate (4.27 g, 52.0 mmol) were dissolved in 15 mL of water and added to a solution of 2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one (11.33 g, 40 mmol) from Step C in ethanol (80 mL). The reaction was brought to reflux for 5 minutes and allowed to cool to 70° C. After 1 hour, the reaction mixture was cooled, and the solvent was removed in vacuo to give (E)-2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one oxime which was used without additional purification in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.O[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@:21]1([CH3:27])[CH2:25][O:24][C:23](=[O:26])[NH:22]1)[CH:15]=[CH:14]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CC(=O)OCC>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([O:8][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C@:21]2([CH3:27])[CH2:25][O:24][C:23](=[O:26])[NH:22]2)[CH:15]=[CH:14]3)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4,4-Dimethylcyclohexanol (63.2 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (100 mg, 0.0004 mol), triphenylphosphine (129 mg, 0.000493 mol), and tetrahydrofuran (4 mL, 0.05 mol), diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred at room temperature overnight. The mixture was diluted with EA and washed with 5% citric acid and brine then dried with magnesium sulfate and concentrated. The crude was taken up into DCM and subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].O>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Yield: 91.9 %

Procedure:
Under a dry argon atmosphere, a borane-tetrahydrofuran complex (39.7 g, 0.463 mole) as a 1 M solution in tetrahydrofuran was added slowly to a stirred solution of 2,6-dimethyl-3-nitrobenzoic acid (60.2 g, 0.308 mole) in 350 ml of anhydrous tetrahydrofuran. The reaction mixture was heated at 60° for approximately 18 hours. Water (20 ml) was slowly added to the reaction mixture, and the resultant mixture was concentrated under reduced pressure to give a residue. The residue was washed with three 100 ml portions of methylene chloride, then three 100 ml portions of a 2 N aqueous sodium hydroxide. The washes were combined and the organic phase separated. The aqueous phase was washed with four 250 ml portions of methylene chloride, and the organic phases were combined, dried with anhydrous magnesium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give 2,6-dimethyl-3-nitrobenzene-1-methanol (51.3 g, mp 86.5°-88.5°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[C:26]([Cl:36])[C:23]=1[CH:24]=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]4[N:19]=[C:24]([C:23]5[C:22]([Cl:21])=[CH:29][C:28]([N:30]6[CH2:31][CH2:32][O:33][CH2:34][CH2:35]6)=[CH:27][C:26]=5[Cl:36])[NH:20][C:15]=4[CH:14]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Solvent: CS(C)=O
Product: Clc1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cc(N6CCOCC6)cc5Cl)[nH]c4c3)o2)cc1
Reaction time: 18 h

Procedure:
To a 50 ml rbf was added 0.2250 g (0.785 mmol) 4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]benzene-1,2-diamine, 0.2041 g (0.785 mmol) of 2,6-Dichloro-4-morpholin-4-yl-benzaldehyde, and 5 mL of DMSO. To this dark brown solution was added 0.0190 g (0.118 mmol) of FeCl3. It was allowed to stir open to air for 18 h. The crude was then extracted with EtOAc, and the combined extracts were washed with water, brine and dried with Na2SO4. The volatiles were removed in vacuo and the concentrate was purified on silica gel (ACN/DCM, 1:9 to 10:0) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (d, J=5.05 Hz, 4 H) 3.71-3.77 (m, 4 H) 7.17 (s, 2 H) 7.70-7.75 (m, 2 H) 7.90 (d, J=8.72 Hz, 1 H) 7.99-8.07 (m, 1 H) 8.19 (d, J=8.21 Hz, 2 H) 8.27 (br. s., 1 H) 8.47 (s, 1 H) 13.17 (d, J=8.97 Hz, 1H. MS (m/z) 528.0 M (+1), tR=1.41, Meth 10
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH:6]([C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=O)[CH2:5]1)(=[O:3])[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[NH:22][N:23]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)C(C(=O)c2cccc(C#N)c2)C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCc2[nH]nc(-c3cccc(C#N)c3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a mixture of 3-(1-Acetyl-4-oxo-piperidine-3-carbonyl)-benzonitrile (2a) (8 g, 29.6 mmol) in ethanol (26 ml) at 10° C. hydrazine hydrate (4.44 g, 88.8 mmol) was added slowly within 5 min. The mixture was stirred 3 h and allowed to warm to room temperature overnight. The mixture was concentrated to ¼ of its volume until a precipitate formed. The suspension was stirred for 2 h, cooled down and filtrated. The solid was washed with a small amount of ethanol. A second portion of product precipitated overnight from the filtrate and was pooled with the first portion of solid to give 4.02 g of 3-(5-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile (3a) as a solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:37]([O:39][CH3:40])=[O:38])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([S:33][CH2:34][CH3:35])=[CH:29][C:28]3=[O:36])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:37]([O:39][CH3:40])=[O:38])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([S:33]([CH2:34][CH3:35])=[O:6])=[CH:29][C:28]3=[O:36])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc(=O)c2cc(C(=O)OC)cc(C(C)Nc3cc(F)cc(F)c3)c2o1
Solvent: ClCCl
Product: CCS(=O)c1cc(=O)c2cc(C(=O)OC)cc(C(C)Nc3cc(F)cc(F)c3)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
3-chlorobenzoperoxoic acid (326 mg, 1.13 mmol) was added in one portion to a stirred suspension of methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (475 mg, 1.13 mmol) in DCM (5 mL) cooled with an water/ice bath. The resulting mixture was stirred at RT for 1 h. The suspension was cooled to −15° C. and filtered, the solid was washed with cold DCM (5 mL). The filtrate was then washed with an aq. sol. of sodium thiosulfate pentahydrate in water (10 mL), and with a mixture of a sat. sol. of NaHCO3 and water (1:1, 15 mL). The organic layer was decanted, dried over MgSO4 and evaporated to afford the crude product methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-(ethylsulfinyl)-4-oxo-4H-chromene-6-carboxylate (500 mg, 100%) as a reddish foam. Mass Spectrum: M+H+ 436.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1(C)C=CC=CC=1>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(-c2ccccc2)ccc1F

Procedure:
5-Bromo-2-fluorobenzonitrile (53) (500 mg, 2.54 mmol) was coupled to phenylboronic acid (335 mg, 2.75 mmol) with Cs2CO3 (1.63 g, 5.00 mmol) in toluene (4 mL) in a microwave at 140° C. for 30 minutes. Water was added and the organics extracted several times with EtOAc, dried (MgSO4), filtered and the solvent concentrated in vacuo. The crude product was purified by Flash Master Jones Chromatography using a 25 g silica cartridge and eluting with 10% EtOAc in heptane to yield the title compound. Yield: 375 mg, 76%; LC-MS tr 1.63 min; HPLC Purity: 97%; MS (ES+) m/z not detectable (M+H)