Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)#[N:7].[C:14](O)([CH3:17])([CH3:16])[CH3:15].[OH-:19].[Na+]>O>[C:14]([NH:7][C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=[O:19])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1cnccn1
Reactant: [OH-]
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)NC(=O)c1cnccn1
Reaction time: 3 h

Procedure:
To 1030 g of an 80% aqueous solution of sulfuric acid (8.40 moles of sulfuric acid), 220.5 g (2.10 moles) of 2-cyanopyrazine was added dropwise keeping the internal temperature at 40° C. or less with stirring. In succession, 187 g (2.52 moles) of tert-butyl alcohol was added dropwise to the mixture, keeping the internal temperature at 9° to 15° C., over 3 hours. Further, the temperature was kept at the same temperature for 2.5 hours. After the reaction, the reaction liquid was added to 3500 g of water with stirring. Thus obtained mixture was neutralized with an aqueous solution of sodium hydroxide. Precipitated crystalline solid was separated by filtration, washed with water and then dried to obtain 338.7 g (1.89 moles) of N-tert-butyl-2-pyrazine-carboxamide. It had a melting point of 88° to 90° C. Further, from the water layer, from which the intended product had been separated by filtration, 7.17 g (0.04 mole) of the intended product was further obtained by extraction thereof with toluene.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH:13]([OH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:1]([O:26][CH:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
108.3 g (1.05 mol; 1.05 eq) of acetic anhydride are diluted in 370 ml of dichloromethane at 20° C. The solution obtained is cooled to 0±2° C. before introducing 2.8 ml of a 96% sulphuric acid solution in a time of about 10 minutes. After stirring for about 10 minutes, 184.2 g (1 mol, 1 eq) of benzhydrol are introduced in portions at 0° C.±2° C. in 60±15 minutes. The reaction medium is maintained in contact for 2 hours at this temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[NH:13][CH:12]=[N:11][C:10]=2[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]3[CH2:22][C@@H:21]3[C:23](O)=[O:24])=[CH:16][CH:15]=2)=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C[CH2:41][N:42](C(C)C)[CH:43](C)C.CNC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[NH:13][CH:12]=[N:11][C:10]=2[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]3[CH2:22][C@@H:21]3[C:23]([N:42]([CH3:43])[CH3:41])=[O:24])=[CH:16][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(O)[C@H]1C[C@@H]1c1ccc(-c2nc[nH]c2Sc2ccc(Cl)cn2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN(C)C(=O)[C@H]1C[C@@H]1c1ccc(-c2nc[nH]c2Sc2ccc(Cl)cn2)cc1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
(1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-1H-imidazol-4-yl}phenyl)cyclopropanecarboxylic acid (Step 3 product, 73 mg, 0.196 mmol), HOBT (60 mg, 0.393 mmol), and EDC (113 mg, 0.589 mmol) were dissolved in 3 mL of DMF, to which were added Hunig's base (0.206 mL, 1.178 mmol) and dimethyl amine (2 M THF solution, 0.294 mL, 0.589 mmol). The reaction was heated at 80° C. for 30-60 min. Upon cooling to rt, the reaction was diluted with EtOAc (80 mL), and the reaction mixture was washed with water (2-3 times) and brine, dried, and concentrated to dryness. The residue was purified by silica column (80-100% EtOAc in hexanes) to give 62 mg (79%) of the title compound. 1H NMR (500 MHz, (CD3OD): 8.38 (s, 1H), 7.97 (s, 1H), 7.65 (d, 2H), 7.59 (d, 1H), 7.18 (d, 2H), 6.82 (d, 1H), 3.16 (s, 3H), 2.97 (s, 3H), 2.38 (m, 1H), 2.19 (m, 1H), 1.54 (m, 1H), 1.27 (m, 1H). LCMS: m/z 399 (M+H)+. Human FAAH lysate assay: IC50=649.6 nM.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](C(O)=O)[CH:9]=1)([O-:3])=[O:2].C1(P([N:34]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.CN(C)C=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:34])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Oc2cccc([N+](=O)[O-])c2)ccn1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cc(Oc2cccc([N+](=O)[O-])c2)ccn1
Yield: 88.2 %

Procedure:
A mixture of 3-nitrophenol (3.65 g, 26.2 mmol), potassium tert-butoxide (3.23 g, 28.8 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 min. After stirring, methyl 4-chloropyridine-2-carboxylate (3.00 g, 17.5 mmol) and potassium carbonate (10.9 g, 78.6 mmol) were added, and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (20 mL) and 8N aqueous sodium hydroxide solution (3 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (345 mg, 8.0%) as a white solid. A mixture of 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (339 mg, 1.24 mmol) thus-obtained, diphenylphosphoryl azide (333 μL, 1.55 mmol), triethylamine (215 μL, 1.55 mmol), N,N-dimethylformamide (5 mL) and water (5 mL) was stirred at 100° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (253 mg, 8.8%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=1[CH2:58][OH:59]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=2[CH2:58][OH:59])=[CH:11][C:10]1=[O:17]
Reactant: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Reactant: OCc1ccc(F)cc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2CO)cc(=O)n1-c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(2,6-Difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (step 1) (3.0 g, 12.65 mmol) was dissolved in N,N-dimethylformamide and cooled to 0° C. Triphenylphosphine (3.98 g, 15.18 mmol) and diethyl azodicarboxylate (2.39 ml, 15.18 mmol) were added and stirred for 10 minutes. 1,2-Bis(hydroxymethyl)-4-fluorobenzene (2.57 g, 16.44 mmol) was added and stirred at 0° C. for 1 hour, then allowed to warm to room temperature and stirred overnight. LC-MS showed only 1 product, not a mixture of regioisomers, as expected. The reaction was added to water and extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. A Biotage silica column was done using 60% ethyl acetate/hexanes as an eluent. Desired product, with a substantial impurity was obtained. Another Biotage silica column was ran using 30% ethyl acetate/hexanes to obtain pure product. The resulting oil was triturated with diethyl ether to obtain a white solid (720 mg, 15%). 1H NMR (300 MHz, CDCl3) δ 7.51-7.39 (m, 2H), 7.26 (dd, J=9.62, 2.51 Hz, 1H), 7.13-7.01 (m, 3H), 6.03 (d, J=2.42 Hz, 1H), 5.96 (d, J=2.41 Hz, 1H), 5.06 (s, 2H), 4.73 (s, 2H), 2.81 (br s, 1H), 2.02 (s, 3H); LC/MS, tr=2.37 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 376 (M+H). ES-HR/MS m/z 376.1181 (M+H calcd for C20H16F3NO3 requires 376.1155). Identity of the positional isomer was determined from hmbc, 2-D NMR experiments using H to C2- and 3-bond coupling.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.N1C=CC=CC=1>ClCCl>[CH2:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1)[CH:5]=[CH2:6]
Reactant: Nc1ccc(CO)cc1
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1ccc(CO)cc1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
Alloc-Cl (537 g) in dichloromethane (5 ml) was added dropwise to a solution of (4-amino-phenyl)-methanol (500 mg) and pyridine (5 ml) in dichloromethane (5 ml). After stirring for 2 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The title compound (243 mg) was obtained by recrystallization from dichloromethane. The mother liquor was chromatographed on silica gel in heptane/ethyl acetate=1/1 (v/v) as eluent which yielded another 245 mg of the title compound. Yield: 488 mg.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]1([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])[CH:13]=[CH:12][N:11]=[CH:10]1>CCOCC.O1CCCC1>[OH:16][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCc2cc(C(=O)Cn3ccnc3)ccc2N1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCc2cc(C(O)(Cn3ccnc3)c3ccccc3)ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 ml of 3M phenylmagnesium bromide in ether was added to a suspension of 1.0 g of 6-(imidazol-1-yl acetyl)-3,4-dihydrocarbostyril in 25 ml of tetrahydrofuran at 0° C., the mixture stirred for 30 minutes at 0° C., then at 25° C. for 18 hours. The reaction was quenched with 10 ml of water and extracted with 10% methanol in methylene chloride. The organic extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a gum which was chromatographed on silica gel, eluting with 5% methanol in methylene chloride, to give 6-[1-hydroxy-1-phenyl-2-(imidazol-1-yl)ethyl]-3,4-dihydrocarbostyril as a foam. 1H NMR (CDCl3) δ2.56 (d, 1H, J=8.1 Hz), 2.58 (d, 1H, J=8.1 Hz), 2.78 (s, 1H), 2.88 (t, 2H, J=8.1 Hz), 4.65 (s, 2H), 6.57 (s, 1H), 6.74 (d, 1H, J=8.82 Hz), 6.77 (s, 1H), 7.14 (m, 2H), 7.25 (s, 1H), 7.30-7.40 (m, 5H), 8.62 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[OH-:26].[Na+].Cl.[NH2:29]O.Cl>CO>[OH:26][NH:29][C:21](=[O:22])[CH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reactant: [OH-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1)NO
Reaction time: 8 h

Procedure:
A scintillation vial was charged with the product from Example 28 (38 mg, 0.1 mmol), sodium hydroxide (40 mg, 0.1 mmol), hydroxylamine hydrochloride (33 mg, 0.1 mmol), and 4 mL of methanol. The reaction vial was placed in a shaker at room temperature overnight. After this time, the mixture was acidified with 10% HCl, concentrated, and purified on a RP-HPLC to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.10 (m, 2H), 1.48 (m, 2H), 1.67-1.85 (m, 5H), 1.88 (d, J=6.75 Hz, 2H), 2.47 (m, 1H), 7.12 (s, 1H), 7.34 (d, J=8.28 Hz, 2H), 7.72 (d, J=8.24 Hz, 2H), 8.63 (br s, 1H), 10.34 (s, 1H), 13.96 (br s, 1H): MS (ESI) m/z 366.1 [M−H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[NH:22][NH:23][CH3:24].[CH2:25](Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:22][N:23]([CH3:24])[CH3:25])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: ClCCl
Reactant: CNNC
Solvent: CCO
Product: CN(C)N=C(CCC(=O)O)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A stirred suspension of 4-(4′-chloro-biphenyl-4-yl)-4-oxo-butyric acid (0.578 g, 0.00200 mol) in a solution of dimethylhydrazine (0.46 mL, 0.0061 mol) in absolute ethanol (6 mL) was refluxed under nitrogen for 2.4 hours and allowed to cool. The volatiles were rotary evaporated, and the residue dissolved (CH2Cl2) and purified by column chromatography on silica gel, eluting with dichloromethane-methanol (24:1) to give 0.33 g of 4-(4′-chloro-biphenyl-4-yl)-4-(dimethylhydrazono)-butyric acid as a yellow solid; mp 158-160° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][C@@H:20]([CH:23]([CH3:25])[CH3:24])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[O:28]1CCC(C2C3=NC=CC=C3CN2C([O-])=O)[CH2:29]1>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][CH:20]([CH:23]4[CH2:24][CH2:29][O:28][CH2:25]4)[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:26][CH:27]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Reactant: O=C([O-])N1Cc2cccnc2C1C1CCOC1
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CNC3C2CCOC2)cc1

Procedure:
Procedure same as that for (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide, using tert-butyl34(4-(ethylsulfonyl)benzyl)carbamoyl)-7-(tetrahydrofuran-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as a starting material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]=[CH2:25])[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]3[O:35][CH2:25]3)[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 72 h

Procedure:
To a solution of methyl 2-[(4′-bromo[1,1′-biphenyl]-4-yl)-sulfonylamino]-pent-4-eneoate 13c (10.2 g, 24.1mmol) in CH2Cl2 (150 mL), NaHCO3 (11.0 g, 50 mmol) and water (140 mL) at 0° C., is slowly added m-chloroperbenzoic acid (57-86%) (19.4 g, ˜80 mmol). The reaction is stirred for 72 hours. The mixture is diluted with aqueous NaHCO3 and this mixture is extracted with ethyl acetate (3×250 mL). The combined ethyl acetate layer is washed with brine, dried over MgSO4, filtered and concentrated to an oil. Purification of this compound is accomplished by column chromatography with 40% ethyl acetate in hexanes as the eluent to give the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH:23]=[O:24].O>C1COCC1.CCOC(C)=O>[CH2:10]([O:9][CH:8]([O:12][CH2:13][CH3:14])[C:5]1[CH:6]=[CH:7][C:2]([CH:23]([OH:24])[CH2:22][C:21]([CH3:26])([CH3:25])[CH3:20])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCOC(OCC)c1ccc(Br)cc1
Reactant: CC(C)(C)CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(OCC)c1ccc(C(O)CC(C)(C)C)cc1
Temperature: -78 °C
Yield: 57.5 %

Procedure:
Dissolve 1-bromo-4-(diethoxymethyl)-benzene (6.1 g, 23.55 mmol) in anhydrous THF (150 mL) and cool the solution to −78° C. Add n-butyllithium (11.3 mL, 28.26 mmol, 2.5M solution in hexane) and stir the mixture for 30 min. Add 3,3-dimethylbutyraldehyde (4.7 mL, 35.33 mmol) and stir the mixture for 1 h. Add water and EtOAc. Warm the solution to room temperature and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts with Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (93:7) to give the desired intermediate as a colorless oil (3.8 g, 58%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O.Cl.C1COCC1>O1CCOCC1>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Oc3ccc(Cl)cc3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(Oc2cccc(CN3CCNCC3)c2)cc1
Reaction time: 3 h
Yield: 211.7 %

Procedure:
A solution of 4-[3-(4-chloro-phenoxy)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (29.6 g, 73.5 mmol) in 4:1 dioxane:H2O (100 mL) was treated with 4 M HCl in dioxane (60 mL). After 3 h, THF (200 mL) was added and the resulting white precipitate was filtered and dried under vacuum to give 1-[3-(4-chloro-phenoxy)-benzyl]-piperazine hydrochloride (26.4 g, 95%). MS (ESI+): calcd for C17H19ClN2O m/z 302.12. found 303.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]CCCCC.C([Li])CCC.IC.[Cl-:33].[Na+].O>O1CCCC1>[ClH:33].[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC
Reactant: C1=C(c2ccccc2)CCN(Cc2ccccc2)C1
Reactant: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Product: Cl
Temperature: -55 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
1-Benzyl-4-phenyl-1,2,3,6-tetrahydropyridine (160 mg, 0.64 mmol) was dissolved in anhydrous tetrahydrofuran (2 ml) to which was subsequently added dropwise n-butyl lithium hexane solution (0.64 mmol) at −10 to −20° C. in an atmosphere of argon, followed by 15 minutes of stirring. After cooling the reaction solution to −50 to −60° C., iodomethane (0.13 ml, 2.1 mmol) was added dropwise thereto and then the solution was stirred for 2 hours while gradually increasing the temperature to −20° C. After adding saturated brine to the reaction solution, the reaction product was extracted with ethyl acetate, and the resulting extract was washed with water and saturated brine and dried with anhydrous sodium sulfate. Then the solvent was evaporated under a reduced pressure. The thus obtained residue was dissolved in methanol (2 ml), and the solution was mixed with palladium-carbon (40 mg) and stirred at room temperature for 38 hours in an atmosphere of hydrogen. The reaction solution was filtered, the resulting mother liquor was mixed with hydrochloric acid-saturated methanol and then the solvent was evaporated under a reduced pressure to obtain crystals which were then washed with a small amount of ethyl acetate to obtain 83 mg of the title compound (0.28 mmol, 43% in yield).
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[CH3:11][C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][CH:27]=1)[O:15][CH2:16][C:17]1[CH:18]=[CH:19][NH:20][C:21]=1[C:22]([O-:24])=[O:23].[CH2:28](N(CC)CC)[CH3:29]>C(Cl)Cl>[CH3:19][N:20]1[C:21]([C:22]([O:24][CH2:28][CH3:29])=[O:23])=[C:17]([CH2:16][O:15][C:14]2[CH:25]=[CH:26][CH:27]=[C:12]([CH3:11])[CH:13]=2)[CH:18]=[C:6]1[CH:5]=[O:9]
Reactant: Cc1cccc(OCc2cc[nH]c2C(=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(COc2cccc(C)c2)cc(C=O)n1C
Reaction time: 0.5 h

Procedure:
To a solution of dimethylsulfoxide (390 mg, 5 mmol) in methylene chloride (25 ml) under N2 cooled to -78° C. is added a solution of oxalyl chloride (630 mg, 5 mmol) in methylene chloride (2 ml). The mixture is allowed to stir at -78° for 30 minutes, then a solution of ethyl 1-methyl-2-hydroxymethyl)-4-(3-methylphenoxymethyl)pyrrole-5-carboxylate (1.63 g, 5 mmol) in CH2Cl2 (5 ml) is added. The resulting solution is stirred for 1 hour, then triethylamine (500 mg, 5 mmol) is added. The reaction is followed by TLC until complete. The resulting solution is washed with water (2×25 ml) then saturated brine, and dried over anhydrous sodium sulfate. The crude product is purified by preparative HPLC to afford ethyl 1-methyl-2-formyl-4-(3-methylphenoxymethyl)pyrrole-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:21]=[CH:22][CH:23]=1)#[CH:17]>C1COCC1.C(Cl)Cl.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>[Cl:1][C:2]1[N:7]=[C:6]([C:17]#[C:16][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1cccc(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C#Cc2ccnc(Cl)n2)c1)C(F)(F)F
Temperature: 50 °C

Procedure:
To a mixture of 2,4-dichloropyrimidine (14.5 g, 97.5 mmol), dichlorobis(triphenyl-phosphine)palladium(II) (1.3 g, 2.6 mmol), and copper(I) iodide (25 mg, 0.13 mmol) in degassed THF was added triethylamine (34 mL, 263 mmol), and the mixture was heated to 50° C. A solution of N-(3-ethynyl-phenyl)-2,2,2-trifluoro-acetamide (14 g, 65 mmol) in THF was added to the mixture over 45 min. After several h, the reaction was cooled to rt and diluted with DCM. The organic mixture was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified through silica to give the title compound as an off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 11.43 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 8.00 (s, 1H), 7.80 (d, J=4.8 Hz, 1H), 7.76 (m, 1H), 7.54-7.52 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](Br)[CH:3]=1.C([Li])CCC.[CH2:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:17]1[O:19][CH2:18]1>O1CCCC1.[Cu]Br.CSC.B(F)(F)F.CCOCC>[CH2:21]([O:20][CH2:16][C@@H:17]([OH:19])[CH2:18][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(F)cc1Br
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Agent: [Cu]Br
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CSC
Product: COc1ccc(F)cc1C[C@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a solution of 4-fluoro-2-bromanisole (12.6 ml, 0.1 mol) in anhydrous tetrahydrofuran at −78° C. was added n-butyllithium (39 ml, 2.5 M in hexane) and the resulting mixture was allowed to stir at −78° C. for 3 h. Copper(I) bromide-dimethylsulfide (10.0 g, 0.05 mol) was then added at −78° C. and the reaction mixture was allowed to warm to 40° C. over 2 h. Benzyl(S)-(+)-glycidyl ether (3.71 ml, 0.025 mol) was added at −60° C. followed by boron trifluoride diethyl etherate (0.15 ml, 1.2 mmol) and the reaction mixture was allowed to warm to room temperature over 12 h. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) afforded 5.0 g (70%) of (S)-1-benzyloxy-3-(5-fluoro-2-methoxy-phenyl)propan-2-ol as a colorless oil. HRMS ESI m/e 308.1666 [M+NH4]+, Calc'd m/e 308.1662 [M+NH4]+; [α]D25=+8.1 (c 0.89% in methanol).