Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH:3]1[C:8]2[C:9]([CH3:15])=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[CH2:6][CH:5]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:4]1.[Br:22]Br.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:22][C:11]1[CH:10]=[C:9]([CH3:15])[C:8]2[CH:3]([CH2:2][Br:1])[O:4][CH:5]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:6][C:7]=2[C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C)c2c1CC(C1CCCCC1)OC2CBr
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(Br)cc(C)c2c1CC(C1CCCCC1)OC2CBr
Yield: 55 %

Procedure:
A solution of 2.04 g (5.8 mmol) of 1-bromomethyl-3-cyclohexyl-3,4-dihydro-5-methoxy-8-methyl-1H-2-benxopyran (the product of Step 2 of Example 33) in 20 mL of dry methylene chloride was cooled to 0° C. and treated with 0.38 mL (7.4 mmol) of bromine. The resultant solution was stirred for 25 minutes at 0° C. and then poured into 30 mL of a saturated aqueous solution of sodium bisulfite. The cloudy mixture was extracted with 200 mL of diethyl ether and the organic extract was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized from hexane/ether to afford 1.36 g (55% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:24]([N:26]([CH3:30])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([N:26]([CH3:30])[C:27]([N:13]1[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[CH2:10][CH:11]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:12]1)=[O:28])[CH3:25]
Reactant: CCN(C)C(=O)Cl
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
250 mg (0.74 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 117 mg (0.96 mmol, 1.3 eq.) of ethyl(methyl)carbamoyl chloride were reacted according to General Method 3. Yield: 215 mg (74% of theory)
Reaction SMILES: [CH2:1]([NH:8][S:9](=[O:12])(=O)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][S:9]([Cl:14])(=[O:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)NCc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)NCc1ccccc1

Procedure:
A stirred mixture of benzylsulfamic acid (73 g), PCl5 (81 g) in toluene (540 ml) is heated to 40°-50° C. for one hour and refluxed for about 3 hours. The cooled mixture is filtered through Celite and the filtrate concentrated in vacuo to remove the toluene affording the desired product as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.[OH:11]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:11])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: OO
Reactant: Clc1cnc2c(c1)CCC2
Solvent: CC(=O)O
Product: [O-][n+]1cc(Cl)cc2c1CCC2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-6,7-dihydro-5H-[1]pyrindine (3.03 g, 19.7 mmol) in acetic acid (19.7 ml) was treated at room temperature with hydrogen peroxide (3.45 ml, 39.5 mmol). The mixture was heated to 70° C. and stirred at this temperature overnight. After completion, the reaction mixture was allowed to cool and was concentrated at reduced pressure. Water was added and the mixture was evaporated again. This procedure was repeated another 2 times. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, then dried over sodium sulphate and evaporated at reduced pressure. The crude 3-chloro-6,7-dihydro-5H-[1]pyrindine 1-oxide was obtained as dark green crystals (2.07 g, 62%). (calculated) C8H8ClNO [169.61]; (found) [M+H]+=170.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:22](=[O:23])[C:21]4[CH:25]=[C:26]([O:29][C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:28][C:20]=4[F:19])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1cc(OC(F)(F)F)ccc1F
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cc(OC(F)(F)F)ccc1F
Yield: 11.7 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-fluoro-5-trifluoromethoxy-benzoyl chloride to afford the title compound (11 mg, 11.7%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=5.9 Hz), 6.91-6.94 (m, 1H, Harom), 7.41-7.44 (m, 2H, Harom), 7.50-7.53 (m, 2H, Harom), 7.67-7.69 (m, 1H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 10.65 (s, 1H, NHamide), 11.18 (s, 1H, NHPy7), 11.39 (s, 1H, NHPy9). LC-MS, tR=4.65 minutes, m/z: 449.08 (M+H)+, calculated for C20H13N4O4F4. HRMS (EI): m/z [M+H] calculated for C20H13N4O4F4: 449.0873; found: 449.0873.
Reaction SMILES: FC1C=CC=CC=1CCN[C:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12].[CH2:19]([C:26]1([N:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(N=C=NC(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)C>[CH2:19]([C:26]1([N:33]([CH3:34])[CH3:35])[CH2:31][CH2:30][CH:29]([NH:32][C:11](=[O:12])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CCCC(=O)NCCc1ccccc1F
Reactant: CN(C)C1(Cc2ccccc2)CCC(N)CC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C1(Cc2ccccc2)CCC(NC(=O)CCCC(=O)O)CC1

Procedure:
As described for Example 341, 0.95 mg 4-[2-(2-fluorophenyl)ethylcarbamoyl]butyric acid and 0.87 1-benzyl-N,N-dimethylcyclohexane-1,4-diamine were converted in 5 ml DMF in the presence of 0.59 ml N,N-diisopropylcarbodiimide and 0.50 g 1-hydroxybenzotriazole and the crude product (1.65 g yellow solid) similarly isolated. 720 mg of the non-polar diastereoisomer of glutaric acid (4-benzyl-4-dimethylaminocyclohexyl)amide was obtained by column chromatography on silica gel (3.0×20 cm) with 450 ml diethyl ether, followed by 450 ml diethyl ether/methanol (V:V=4:1) and 450 ml diethyl ether/methanol (V:V=1:1), was dissolved in 25 ml 2-butanone, 25 ml ethyl acetate and converted into the corresponding hydrochloride by adding 28 μl water and 198 μl chlorotrimethylsilane (657 mg of vitreous solid).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-phenylphenol (5.00 g), methyl bromoacetate (3.1 ml) and potassium carbonate (8.1 g) in DMF was stirred at room temperature. After five hours, the reaction mixture was diluted with water (100 ml) and then extracted with ether. The combined organic layers were washed with aqueous sodium carbonate followed by brine and then dried, filtered and evaporated to give crude methyl (3-phenylphenoxy)acetate (7.2 g) as a pale yellow liquid, 1H NMR (CDCl3) delta 3.8 (3H,s), 4.7 (2H,s), 6.8-7.6 (9H,m) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Cl:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[Cl:22])=[CH:6][CH:7]=1
Reactant: Oc1ccc(C(=Cc2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Oc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1

Procedure:
Combine (E and Z)-1-[(4-hydroxy)phenyl]-1,2-diphenyl-ethylene [Cacchi et al, Tet. Lets. 25, 3137-3140 (1984)] (0.90 g, 3.31 mmol) and N-chlorosuccinimide (0.486 g, 3.64 mmol) in chloroform (20 mL). Heat to reflux and allow to stir at reflux for 48 hours. Evaporate in vacuo. Chromatograph on silica gel eluting with 20% ethyl acetate/hexane to give the title compound as a solid: mp; 127°-129° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13](=O)([O-])O.[Na+]>CO.S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
15 g (0.09 mol, 1 eq) of 3-(4-hydroxyphenyl)propanoic acid are dissolved in 50 ml of methanol and 4 drops of sulfuric acid are added. The reaction mixture is stirred for 16 hours at room temperature. The reaction is stopped by addition of 50 mL of saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 14.9 g of methyl 3-(4-hydroxyphenyl)propanoate are obtained. Yield=92%
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6].[S:21](Cl)(Cl)=O>>[C:2]([C:3]1[S:21][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH:4]=1)(=[O:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(NC(=O)CCC(=O)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(-n2sc(C(=O)c3ccccc3)cc2=O)cc1
Yield: 77 %

Procedure:
A solution of 4-oxo-4-phenyl-N-p-tolyl-butyramide 28 (252 mg, 0.944 mmol) in thionyl chloride (1 mL) was stirred for 16 h at room temperature. Excess thionyl chloride was removed under vacuum and the residue was purified by flash silica gel column chromatography (hexane:ethyl acetate=10:1 to 4:1) to give the compound 29 (216 mg, 77%). 1H-1-NMR (CDCl3, 300 MHz) δ 2.40 (s, 3H), 6.82 (s, 1H), 7.28 (m, 2H), 7.54 (m, 4H), 7.71 (m, 1H), 7.96 (m, 2H). HRMS: calculated for C17H14NO2S (M+H)+296.0745. Found 296.0762.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[OH:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11]
Reactant: Oc1cccc(O)c1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(O)c1
Yield: 74.9 %

Procedure:
To a solution of (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (0.5 g, 1.7 mmol) and 3-hydroxyphenol (0.2 g, 2.1 mmol) in 20 mL of acetonitrile (CH3CN) was added potassium carbonate (0.35 g, 2.6 mmol). The reaction mixture was stirred under reflux and concentrated in a vacuum to remove the solvent. The residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum to remove the solvent. The concentrate was purified by silica gel chromatography to afford (E)-methyl 2-(2-((3-hydroxyphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (0.4 g, yield 74%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1.CC(O)C.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:17][O:16][C:13]1[N:14]=[CH:15][C:10]([NH:9][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:11][CH:12]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: COc1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2cc(N)ncn2)cn1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol), 5-amino-2-methoxypyridine (0.62 g, 5 mmol) and 2-propanol (5 mL) is shaken for 36 h at 90° C. After cooling to room temperature, the reaction mixture is distributed between half-saturated Na2CO3-solution and ethyl acetate. The organic layer is dried over Na2SO4 and evaporated. The solid residue is washed consecutively with CH3OH, ethyl acetate and CH2Cl2 and dried in vacuo.
Reaction SMILES: FC1C(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)C(C)=CC=1.[F:17][C:18]1[C:19]([CH3:28])=[C:20]([C:24](I)=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:17][C:18]1[C:19]([CH3:28])=[C:20]([C:24]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]
Reactant: Cc1c(F)ccc(I)c1C(=O)O
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Product: Cc1c(F)ccc(-n2nccn2)c1C(=O)O

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 3-fluoro-6-iodo-2-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([NH:17][C:18](=O)[CH2:19][CH2:20]1)=[CH:15][CH2:14]3)[CH3:2]>C(O)(=O)C.[Pt]=O>[CH3:9][C@:8]12[CH2:25][CH2:24][C@H:23]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]4[C@:21]3([CH3:22])[CH2:20][CH2:19][CH:18]=[N:17]4)[C@@H:10]1[CH2:11][CH2:12][C@@H:7]2[O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27]
Reactant: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N=CCC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The product of Step D, above, and platinum oxide (35 mg) in glacial acetic acid (2 ml) was hydrogenated at 40 psi for 22.5 hours. The mixture was filtered through a pad,of celite. The filtrate was concentrated and the residue purified via preparative TLC using one silica gel plate (1000μ) developed with EtOAc to give the title product (Rf =0.22; mp 170°-172° C.).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[C:14]([O:24][CH3:25])[CH:13]=2)[CH2:4][CH2:3]1.[H][H]>CO.[C].[Pd]>[CH3:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:26])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])=[C:14]([O:24][CH3:25])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1OCCN(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1OCCN(C)C

Procedure:
0.05 g of 10% palladium-carbon was added to a solution of 1 g of N-(cis-4-methylcyclohexyl)-4-(2-dimethylaminoethoxy)-3-methoxycinnamamide (Example 107) in 50 ml of methanol. The solution was vigorously stirred for 16 hours under normal-pressure hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 0.93 g of N-(cis-4-methylcyclohexyl)-3-[4-(2-dimethylaminoethoxy)-3-methoxyphenyl]propionamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH3:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:23].Cl.Cl.NC[C@H](N1CCN(CC2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)CC1)C(O)=O>>[ClH:23].[ClH:23].[ClH:23].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:19][CH2:20]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCN1CCN([C@@H](CNC(=O)OC(C)(C)C)C(=O)OC)CC1
Reactant: NC[C@@H](C(=O)O)N1CCN(Cc2ccc(F)cc2)CC1
Agent: Cl
Product: COC(=O)[C@H](CN)N1CCN(Cc2ccc(F)cc2)CC1

Procedure:
In a manner similar to example 2-3, starting from 5.3 g (13.4 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate, 5.4 g (100%) of (S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate trihydrochloride are obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][C:14](OC)=O)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].BrC[C:26]1C=C[CH:29]=[C:28]([Cl:32])[CH:27]=1>C1COCC1>[Cl:32][C:28]1[CH:29]=[C:13]([CH:14]=[CH:26][CH:27]=1)[CH2:12][S:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[N:7][CH:6]=1
Reactant: COC(=O)CCSc1cnc(OC)c(OC)c1
Reactant: Clc1cccc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
To a cooled solution of methyl 3-[(5,6-dimethoxypyridin-3-yl)sulfanyl]propanoate (Intermediate 7, 257 mg, 1 mmol) in THF (6 ml) at −45° C. was added potassium tert-butoxide (123 mg, 1.10 mmol). After stirring at −45° C. for 20 minutes, 1-(bromomethyl)-3-chlorobenzene (0.16 ml, 1.20 mmol) was added and the reaction mixture was stirred with warming to room temperature for 2 hours. The resulting mixture was partitioned between ethyl acetate (15 ml) and water (15 nil) and the resulting organic layer was washed with brine (15 ml), dried (MgSO4), filtered and concentrated in vacuo to give yellow oil. Purification by column chromatography (SiO2; 0-10% ethyl acetate in petrol) gave 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine as a yellow oil (244 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:28]4[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=4)=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:21]([F:22])([F:24])[F:23]
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(O)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(Oc3ccnc(Cl)n3)ccc21

Procedure:
To a solution of 290 mg (0.81 mMol) 6-hydroxy-benzooxazole-3-carboxylic acid (4-chloro-3-trifluoromethyl-phenyl)-amide (Step 1.3) and 134 mg (0.90 mMol) 2,4-dichloropyrimidine in 15 ml NMP, 377 mg (1.78 mMol) K3PO4 are added. After 2 h at rt the reaction mixture is dissolved in EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2→CH2Cl2/EtOAc 9:1) gives the title compound: m.p.: 140-142° C.; MS: [M+1]+=471/473.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16]2.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH:19]=2)[CH:14]=1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: O=[N+]([O-])c1ccccc1I
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2cc(-c3ccccc3[N+](=O)[O-])ccc2c1
Temperature: 110 °C
Reaction time: 7 h
Yield: 42.8 %

Procedure:
To a suspension of 2-iodo-1-nitrobenzene (2.5 g), (6-methoxynaphthalen-2-yl)boronic acid (2.9 g) and tetrakis(triphenylphosphine)palladium(0) (600 mg) in toluene (50 ml) was added an aqueous solution of 2N sodium carbonate (15 ml) under a nitrogen atmosphere, and the solution was stirred for 7 hours at 110° C. Ethyl acetate was added thereto, the solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.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>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=3)[CH:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1oc(-c2cccc(Br)c2)nc1CCO
Reactant: OB(O)c1ccc(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: CCCO
Product: Cc1oc(-c2cccc(-c3ccc(F)cc3)c2)nc1CCO
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
2-[2-(3-Bromo-phenyl)-5-methyloxazol-4-yl]ethanol (1.0 g, 3.54 mmol) (see Ex. 2, Part D) and para-fluorophenyl boronic acid (744 mg, 5.32 mmol) were stirred in n-PrOH (10 mL) under nitrogen, to which 2M Na2CO3 (3.54 mL) was added. The mixture was heated at 85° C., and after Pd(PPh3)4 (41 mg, 0.0354 mmol) was added, the reaction proceeded for 0.5 h. Once the reaction mixture had cooled to room temperature, it was concentrated and taken up in CH2Cl2 (20 mL), then washed with 0.5M NaOH (20 mL). The aqueous layer was back-extracted with CH2Cl2 (10 mL), combined organics were washed with 1M NaOH (10 mL), followed by H2O (10 mL), then dried over Na2SO4, and concentrated to a crude solid. Recrystallized from ethyl acetate:hexanes (1:1) and vacuum oven-dried at 50° C. to yield a tan solid (375 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.96 (d, J=7.6 Hz, 1H) 7.63–7.59 (m, 3H), 7.50 (t, J=7.6 Hz, 1H), 7.18–7.13 (m, 2H) 3.95 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H), 2.37 (s, 3H); MS (EI) 298.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9]([C:11]1[S:12][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][CH:15]=1)=[O:10]>>[C:16]([C:13]1[S:12][C:11]([C:9](=[O:10])[CH2:6][C:2]#[N:1])=[CH:15][CH:14]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccc(C(C)(C)C)s1
Product: CC(C)(C)c1ccc(C(=O)CC#N)s1
Yield: 86 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 5-tert-Butyl-thiophene-2-carboxylic acid methyl ester (3.0 g, 15.0 mmol, 1.0 eq). The crude product was extracted with DCM and used in the following step without further purification (2.7 g, yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:34]1[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]1)=[O:20])=[N:5]2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(F)c(F)cc4nc3OC)CC2)c1
Yield: 70 %

Procedure:
Ethyl N-(6,7-difluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 70%). MS (ESI) m/z 460 ([M+H]+).