Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].O.Cl([O-])(=O)(=O)=O.[Na+].Cl([O-])(=O)(=O)=O.[C:14]1([N:20]2[CH:24]=[C:23]([CH:25]=[N+](C)C)[C:22]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:14]1([N:20]2[CH:24]=[C:23]([CH:25]=[O:1])[C:22]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O
Reactant: C[N+](C)=Cc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: O=Cc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1

Procedure:
The procedure described in the foregoing Example (54d) was modified, by omitting the direct hydrolysis with a mixture of ice and water. Instead, the reaction mixture was diluted by the addition of 500 milliliters methanol, and by the addition of a solution of 65 grams sodium perchlorate-monohydrate in methanol, [[1-phenyl-3-(p-chlorophenyl)-pyrazol-4-yl]-methylene]-dimethylammonium perchlorate, having a melting point of 256°-258° C., was nearly quantitatively precipitated. This product was thereafter subjected to alkaline hydrolysis in a manner similar to that described in Example (54d) to produce the 1-phenyl-3-(p-chlorophenyl)-pyrazol-4-aldehyde.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:27])([F:26])[F:25])=[N:17]3)[CH2:8][C@@H:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C.[CH3:36][NH2:37].[C-]#N.[Na+]>CCO>[CH2:28]([C@H:7]1[CH2:8][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:27])([F:25])[F:26])=[N:17]3)[CH2:10][CH2:11][N:6]1[CH2:5][C:4]([NH:37][CH3:36])=[O:3])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Reactant: CN
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Reaction time: 48 h
Yield: 63 %

Procedure:
A solution of [(S)-2-Benzyl-4-(8-methoxy-2-trifluoromethyl-quinolin-5-yl)-piperazin-1-yl]-acetic acid ethyl ester in a ˜33% methylamine solution in EtOH (5 mL) was treated with catalytic amount of sodium cyanide and allowed to stir for 48 h. The reaction mixture was then evaporated, washed with water and air dried to afford the title compound as a yellow solid (68 mg, 63%). LC/MS (Method B) 2.82 min, [M+1]+ 472.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:13][OH:14])[NH:8]CCOC)=[N:4][O:5][N:6]=1.O.[OH-].[K+].[C:18]([O:21][CH2:22]C)(=O)[CH3:19]>CCCCCC>[OH:14][N:13]=[C:7]([C:3]1[C:2]([NH:1][CH2:19][CH2:18][O:21][CH3:22])=[N:6][O:5][N:4]=1)[NH2:8]
Reactant: CCOC(C)=O
Reactant: COCCNC(=NO)c1nonc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: COCCNc1nonc1C(N)=NO
Temperature: 100 °C
Yield: 81 %

Procedure:
4-Amino-N′-hydroxy-N-(2-methoxyethyl)-1,2,5-oxadiazole-3-carboximidamide (248.0 g, 1.23 mol) was mixed with water (1 L). Potassium hydroxide (210 g, 3.7 mol) was added. The reaction was refluxed at 100° C. overnight (15 hours). TLC with 50% ethyl acetate (containing 1% ammonium hydroxide) in hexane indicated reaction completed (product Rf=0.6, starting material Rf=0.5). LCMS also indicated reaction completion. The reaction was cooled to room temperature and extracted with ethyl acetate (3×1 L). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (201 g, 81%) as a crude off-white solid. LCMS for C6H12N5O3 (M+H)+: m/z=202.3 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1 H), 6.22 (s, 2 H), 6.15 (t, J=5.8 Hz, 1 H), 3.45 (t, J=5.3 Hz, 2 H), 3.35 (m, 2 H), 3.22 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20].S(Cl)(Cl)=O.[CH:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[NH:33][CH2:32][C:31]=12.C(N(CC)CC)C>O1CCCC1.ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8]([N:33]2[C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH2:36][N:30]3[CH:29]=[CH:28][CH:27]=[C:31]3[CH2:32]2)=[O:10])[CH:7]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cc(-c2ccccc2C(F)(F)F)c(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(-c2ccccc2C(F)(F)F)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A stirred solution of the 2-chloro-2′-trifluoromethyl-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step B (3.46 g, 10.46 mmol) in tetrahydrofuran (20 mL) containing a catalytic amount of N,N-dimethylformamide was treated dropwise with thionyl chloride (1.36 g, 11.51 mmol). The reaction mixture was stirred for 2 hours, and then added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.92 g 10.46 mmol) in tetrahydrofuran (20 mL) containing triethylamine (2.32 g, 23 mmol). The reaction mixture was stirred for 2 hours, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Trituration of the residue with acetone gave 3.14 g of the title compound. Recrystallization from acetone/hexane provided white crystals, m.p. 208–210° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li]CCCC.C[O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:32]2[CH:33]=[CH:34][C:29]([C:28]([OH:36])=[O:27])=[CH:30][CH:31]=2)=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: COc1ccc(Br)cc1OCCCCc1ccccc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1OCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (2.9 g, 8.65 mmol, 1.0 eq) 1-methoxy-2-(4-phenyl-1-butoxy)-4-bromobenzene in 30 ml of dry THF at -78° C. was added (3.81 ml, 9.52 mmol, 1.1 eq) 2.5M n-BuLi. After stirring 15 minutes at -78° C. (10.4 ml, 10.4 mmol, 1.2 eq) 1.0M ZnCl2 in ether was added and the mixture allowed to warm to room temperature over 35 minutes. Tetrakis(triphenylphosphine)palladium(O) (500 mg, 0.43 mmol, 0.05 eq) and (2.27 g, 8.65 mmol, 1.0 eq) methyl-4-iodobenzoate were added to the reaction and the mixture allowed to stir at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuo, costripped with CHCl3, and chromatographed on a silica gel column eluting with ethyl acetate-hexane (0-10%) to afford 2.61 g, 76%, of a yellow solid. Hydrolysis of the ester according to the method of Example 4 gave the title compound, M.P.: 178°-179° C. Elemental analysis calculated for C24H24O4 : C, 76.56; H, 6.43. Found: C, 76.06; H, 5.92.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]1=O.[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28]C(O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][C:2]([O:1][CH2:5][CH2:4][OH:3])=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1
Reactant: Oc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
1,3-Dioxolan-2-one (1093 mg, 12.41 mmol) was added to 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (907 mg, 2.48 mmol) and potassium carbonate (686 mg, 4.97 mmol) in DMF (10 mL). The resulting mixture was stirred at 80° C. for 16 hours. The reaction mixture was evaporated to dryness, the residue redissolved in DCM (100 mL) and the solution washed with water (100 mL). The aqueous washings were re-extracted with DCM (100 mL), then the combined organic phases were washed with saturated brine (50 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (695 mg, 68%).
Reaction SMILES: [H-].[Na+].C(O)(=O)C(O)=O.[CH3:9][N:10]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20](C(F)(F)F)=[CH:19][CH:18]=2)[C@H:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:11]1.[F:33]C1C=CC(F)=CC=1>CN(C=O)C>[F:33][C:20]1[CH:21]=[CH:22][C:17]([O:16][C@@H:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][C@H:12]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(F)cc1
Reactant: CN1CC[C@@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of 0.6 g of sodium hydride, 3.83 g of sodium hydride, 3.83 g of trans-1-methyl-3-phenyl-4-piperidinol of Example 1 and 30 ml of anhydrous DMF is heated to 90° C. for 1.5 hours, then cooled to room temperature. A solution of 2.85 g of p-difluorobenzene in 20 ml of DMF is added all at once; the mixture is stirred at 70°-80° C. under nitrogen for 48 hours. The mixture is cooled and partitioned between ether and saturated aqueous NaCl solution. The aqueous phase is extracted with ether, and the combined ether extracts are washed with water and saturated aqueous NaCl solution and then concentrated in vacuo to an oil. This material is dissolved in 200 ml of dichloromethane, and the solution is extracted with 2 N HCl solution. The dichloromethane phase is successively washed with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to afford an oil which crystallizes upon standing. This material is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent to obtain trans-4-(4-fluorophenoxy)-1-methyl-3-phenylpiperidine, m.p. s 67°, 69.5°-71.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1cnccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cnccn2)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with pyrazin-2-amine (500 mg, 5.3 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1335 mg, 5.3 mmol), Pd2(dba)3 (229 mg, 0.25 mmol), XantPhos (289 mg, 0.50 mmol), cesium carbonate (3.26 g, 10 mmol) and 1,4-dioxane (50 mL). After three cycles of vacuum/argon flush, the mixture was stirred at 100° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 162a (420 mg, 30%) as a yellow solid. MS-ESI: [M+H]+ 281.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[N:38]1[CH:39]=[CH:40][CH:41]=[N:42][C:37]=1[O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Reactant: Clc1ncccn1
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(Oc3ncccn3)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 2-chloro-pyrimidine
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)([CH3:3])[CH3:2].BrC1C=CC=[C:15]([O:19]C(C)C)C=1>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:15]=[O:19])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1Br
Reactant: CC(C)Oc1cccc(Br)c1
Product: CC(C)Oc1ccccc1C=O
Yield: 70 %

Procedure:
The title compound was prepared as in Example 257A but employing 2-iso-propyloxybromobenzene in lieu of 1-bromo-3-isopropoxybenzene. Purification on silica, gel with 10% ether/hexane afforded the title compound (2.3 g, 70%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([CH:10]=1)[CH2:7][C:8]#[N:9].Br[C:17]1[C:22]([O:23][CH2:24][O:25][CH3:26])=[CH:21][CH:20]=[CH:19][N:18]=1.C1(C)C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([CH:10]=1)[CH:7]([C:17]1[C:22]([O:23][CH2:24][O:25][CH3:26])=[CH:21][CH:20]=[CH:19][N:18]=1)[C:8]#[N:9]
Reactant: COCOc1cc(Cl)c(Br)cc1CC#N
Reactant: COCOc1cccnc1Br
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(Cl)c(Br)cc1C(C#N)c1ncccc1OCOC
Temperature: 0 °C
Yield: 71.2 %

Procedure:
To a suspension of 5-bromo-4-chloro-2-methoxymethoxybenzyl cyanide (10.4 g), 2-bromo-3-methoxymethoxy pyridine (7.81 g) and sodium p-toluenesulfinate (12.7 g) in THF (150 ml) was added, at room temperature, sodium hydride (3.63 g). The mixture was heated for 2 hours under reflux under argon atmosphere. The reaction mixture was cooled by aeration, which was poured into ice-water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, dried (anhydrous magnesium sulfate) and concentrated. The crystal obtained was washed with cyclohexane/isopropyl ether (5:1) to give 2-(5-bromo-4-chloro-α-cyano-2-methoxymethoxybenzyl)-3-methoxymethoxypyridine (10.9 g) (Compound C-15). The physical properties and spectrum data are shown in Table 9 and Table 12.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (33%).
Reaction SMILES: [CH3:1][N:2]1[O:9][CH2:8][C:7]2([CH3:10])[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2>O>[CH3:1][N:2]1[O:9][CH2:8][C:7]2([CH3:10])[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2N(C)OCC2(C)C1
Solvent: O
Product: CN1OCC2(C)CNCC12

Procedure:
13 g (60.6 mmol) of ethyl 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 33 g of Ba(OH)2.8H2O in 330 ml of water overnight. The BaCO3 is filtered off with suction, K2CO3 is added to the filtrate, the solid is filtered off with suction again and the filtrate is extracted ten times with 100 ml of CHCl3 each time. The extracts are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCC[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 98 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3S,4S)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and triethylamine in DMF yielding tert-butyl (3S,4S)-4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (98%). LCMS (m/z): 453.3 (MH+); LC Rt=4.01 min.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=1)[C:14]#[N:15].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[C:7](=[O:8])[C:6]2[C:5](=[CH:1][CH:2]=[CH:3][CH:9]=2)[NH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:14]2[NH:29][N:28]=[N:27][N:15]=2)[CH:16]=[C:17]([O:19][CH2:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(COc2cc(C#N)cc(OCC3CCOCC3)c2)[nH]ccc1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(COc2cc(OCC3CCOCC3)cc(-c3nnn[nH]3)c2)[nH]c2ccccc2c1=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
To a solution of 3-[(3-methyl-4-oxo-1,4-dihydropyridin-2-yl)methoxy]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzonitrile (100 mg) in DMF (2 mL) were added sodium azide (18 mg) and ammonium chloride (15 mg), followed by stirring at 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 1M aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was adjusted to a pH of 2 by adding 1M hydrochloric acid, followed by extraction with chloroform and a mixed solvent of chloroform-methanol (5:1). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (developer: chloroform/methanol=6/1) and washed with ethyl acetate to obtain 3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1H-tetrazol-5-yl)phenoxy]methyl}quinolin-4(1H)-one (37 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[CH:22][N:21]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:19][C:20]1[CH:25]=[C:24]([O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=3[CH:11]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CSc1nc2ccc(O)cc2s1
Reactant: Fc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Temperature: 55 °C
Reaction time: 8 h
Yield: 109.6 %

Procedure:
To the mixture of 2-(methylthio)benzo[d]thiazol-6-ol (1 g, 5.08 mmol) and cesium carbonate (4.55 g, 14 mmol) in 15 ml of NMP was added 2-chloro-4-fluoropyridine (1.32 mg, 10 mmol). The reaction mixture was stirred at 55° C. for overnight. The reaction mixture was poured into 80 ml of aq. saturated NaHCO3 and extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with aq. 0.1M NaHSO4 (60 ml), water (2×60 ml) and brine (60 ml), then dried over MgSO4, filtered and evaporated in vaccuo to give 6-(2-chloropyridin-4-yloxy)-2-(methylthio)benzo[d]thiazole (1.72 g) as brown oil that carried on to next step without purification. ES/MS m/z 308.9 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH:18]([CH:20]([CH3:22])[CH3:21])[NH:17][C:16](=[O:23])[CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:19][CH:18]([CH:20]([CH3:22])[CH3:21])[NH:17][C:16](=[O:23])[CH2:15]4)[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: CC(C)C1CN(CCc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC(=O)N1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CC(=O)NC(C(C)C)C3)n(C)c2n1
Temperature: 120 °C
Yield: 44.8 %

Procedure:
A mixture of 4-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-6-isopropylpiperazin-2-one (90 mg, 0.21 mmol), 2-ethylbenzimidazole (35 mg, 0.24 mmol), Pd2(dba)3 (4.9 mg, 2.5 mol %), Xphos (10.2 mg, 10 mol %) and Cs2CO3 (104 mg, 0.32 mmol) in dioxane (2.0 mL) was purged with argon gas then heated at 120° C., for 19 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 20-90%) to give 522 (50 mg, 44%) as a pale beige solid. LCMS: (Method I): RT 2.90 min; [M+H]+ 532.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1 H), 7.84-7.78 (m, 1 H), 7.32-7.28 (m, 2 H), 5.82 (s, 1 H), 4.62-4.07 (m, 4 H), 3.86 (t, J=4.7 Hz, 4 H), 3.78 (s, 3 H), 3.47-3.23 (m, 4 H), 3.08-2.99 (m, 4 H), 3.01-2.93 (m, 2 H), 2.40 (dd, J=11.7, 8.9 Hz, 1 H), 1.79-1.67 (m, 1 H), 1.47 (t, J=7.5 Hz, 3 H), 0.98 (d, J=6.8 Hz, 3 H), 0.95 (d, J=6.88 Hz, 3 H)