Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=[O:15])[NH:7][CH2:8][C:9]2[C:14]/1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:3].[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27]C(N)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:3]([NH:2][CH:4]=[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][NH:7][C:6]3=[O:15])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)/C=C1/C(=O)NCc2ccccc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Product: O=C1NCc2ccccc2C1=CNc1ccc(CN2CCCCC2)cc1
Yield: 15.8 %

Procedure:
A solution of 0.400 g (1.98 mmol) of (4E)-4-[(Dimethylamino)methylene]-1,4-dihydro-3(2H)-isoquinolinone and 0.300 g (1.58 mmol) of 4-piperidin-1-ylmethyl-phenylamine in 4 mL of N,N-dimethylformamide (DMF) is heated at 125° C. for 3 h. The solvent is removed and the residue is slurried with Et2O and filtered. The Et2O soluble material is evaporated, redissolved in a small volume of PhCH3 and chilled. A precipitate is collected, boiled with MeOH (ca 20 mL) and filtered. The filtrate is evaporated and the residue is recrystallized from a minimum volume of MeOH. The resulting solid is collected, washed with cold MeOH and Et2O and dried in vacuo to yield 0.087 g (13%) of yellow crystals: mp 188-189° C. (dec); 1H NMR (DMSO-d6) δ 11.5 (d, 1H, J=11.8 Hz), 8.04 (d, 1H, J=11.8 Hz), 7.66 (m, 2H), 7.20 (s, 5H), 7.08 (m, 2H), 4.41 (s, 2H), 3.34 (s, 2H), 2.29 (s(br), 4H), 1.46 (m, 6H); HRMS (ESI) m/e calcd for C22H25N3O 348.20704. found 348.20704 (M+H)+1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:16]([C:20](OCC)=[O:21])[NH:17][C:18](=[O:19])[C:7]1=[CH:6]2.Cl.[NH2:26][OH:27].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:16]([C:20]([NH:26][OH:27])=[O:21])[NH:17][C:18](=[O:19])[C:7]1=[CH:6]2
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2cc3c(=O)[nH]c(C(=O)NO)nc3nc2cc1OC
Temperature: 95 °C
Yield: 74 %

Procedure:
Ethyl 7,8-dimethoxypyrimido-[4,5-b]quinolin-4(3H)-one-2-carboxylate (200 mg., 6.08 millimoles) is added to a solution of hydroxylamine hydrochloride (69 mg., 100 millimoles) and triethylamine (100 mg., 100 millimiles) in absolute ethanol (50 ml.). The mixture is heated at 95° C. overnight in a bomb and then cooled. The insoluble yellow solid is filtered off, washed with hot ethanol and dried to provide 143 mg. (74%) of the title product. M.P. 337° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[N:4]=1.[C:17]1([C:23]2[N:24]=[C:25]([N:28]3[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29]3)[S:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:23]2[N:24]=[C:25]([N:28]3[CH2:32][CH2:31][CH:30]([C:33]([NH:11][C:10]4[CH:12]=[CH:13][CH:14]=[C:8]([C:5]5[N:4]=[C:3]([C:2]([F:15])([F:1])[F:16])[O:7][N:6]=5)[CH:9]=4)=[O:34])[CH2:29]3)[S:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C1CCN(c2nc(-c3ccccc3)cs2)C1
Reactant: Nc1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(Nc1cccc(-c2noc(C(F)(F)F)n2)c1)C1CCN(c2nc(-c3ccccc3)cs2)C1
Yield: 28 %

Procedure:
This compound was synthesized from 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline and 1-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxylic acid as described for example 37 step 3 (20 mg, yield 28%). 1H NMR (400 MHz, MeOD) δ 8.47 (t, J=1.8 Hz, 1H), 7.88-7.81 (m, 3H), 7.57-7.53 (t, J=7.9 Hz, 1H), 7.39-7.35 (m, 2H), 7.30-7.25 (m, 2H), 6.90 (s, 1H), 3.90-3.86 (m, 1H), 3.82-3.78 (m, 1H), 3.76-3.71 (m, 1H), 3.64-3.58 (m, 1H), 3.47-3.39 (m, 1H), 2.46-2.40 (m, 2H). MS (ESI) m/z: Calculated for C23H18F3N5O2S: 485.11. found: 486.0 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:18])[CH2:13][C@@H:12]1C.[CH3:20][C@H]1N[C@@H](C)CN(C2C=CC([N+]([O-])=O)=CC=2)C1>>[CH3:18][N:14]1[C@H:13]([CH3:20])[CH2:12][N:11]([C:3]2[CH:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][CH:4]=2)[CH2:16][C@@H:15]1[CH3:17]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1C
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1C
Yield: 106 %

Procedure:
Crude cis-1,2,6-trimethyl-4-(4-nitrophenyl)piperazine (5.55 g, 106% recovery) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,4,5-trimethylpiperazine from cis-3,5-Dimethyl-1-(4-nitrophenyl)piperazine (4.91 g, 20.8 mmol). LCMS-ESI (m/z): calcd for C13H19N3O2, 249; [M+H]+ found, 250.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](O)[N:7]=[CH:6]2.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[N:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2nc(O)ncc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(Cl)ncc2c1
Yield: 90 %

Procedure:
6-methoxyquinazolin-2-ol (1eq) and phosphorus oxychloride (2-10eq) was refluxed for 2 hours. The reaction mixture was concentrated and neutralized with sodium carbonate, which was then filtered off. The concentrate was partitioned between ethyl acetate and water. The organic layer was then washed with brine dried and concentrated. The crude was subjected to column chromatography (10% Acetone in hexane) to afford 2-chloro-6-methoxyquinazoline as a beige color solid in 90% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[OH:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:12]=[CH:13][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: OCCCOc1ccc(CO)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1ccc(OCCCO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of the above 3-(4-hydroxymethyl-phenoxy)-propan-1-ol (1.50 g, 8.23 mmol) in acetonitrile (25 mL) is added N-methylmorpholine-N-oxide (1.50 g, 12.38 mmol) followed by tetrapropylammonium perruthenate (140 mg, 0.43 mmol). The dark solution is stirred at rt for 2 h before the solvent is removed in vacuo. The crude product is purified by column chromatography on silica gel (heptane/EA) to give 4-(3-hydroxy-propoxy)-benzaldehyde. 1H NMR (D6-DMSO): δ 9.83 (s, 1H), 7.85-7.81 (m, 2H), 7.12-7.07 (m, 2H9, 4.56 (t, J=5.3 Hz, 1H), 4.14 (t, J=6.4 Hz, 2H), 3.57-3.51 (m, 2H), 1.88 (p, J=6,4 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[OH:11])[CH2:9][C@H:4]2[O:3]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:18]([O:11][CH:10]([C@H:8]1[O:7][C@@H:5]2[O:6][C:2]([CH3:17])([CH3:1])[O:3][C@@H:4]2[CH2:9]1)[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)O[C@H]2O[C@H](C(O)C3CCCC3)C[C@H]2O1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)O[C@H]2O[C@H](C(OC(=O)c3ccccc3)C3CCCC3)C[C@H]2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a solution of [(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-cyclopentyl-methanol (compound 11a, 1.2 g, 5.0 mmol), TEA (3.2 g, 31.2 mmol) and DMAP (100 mg) in DCM (50 mL) was added benzoyl chloride (1.4 g, 10.0 mmol) slowly at 0° C. The mixture was stirred at 25° C. for 4 hours and then quenched by saturated NaHCO3 solution. The reaction mixture was extracted with EtOAc (100 mL) twice. The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:5 EtOAc in petroleum ether) to afford 1.4 g of [[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-cyclopentyl-methyl] benzoate (compound 11b) as a colourless oil.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[C:36]([F:44])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH2:32]([NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[C:36]([F:44])[CH:35]=1)[CH3:33]
Reactant: CCN(C[C@@H](N)c1ccc(C(F)(F)F)c(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(C(F)(F)F)c(F)c1

Procedure:
Compound 29 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a pale yellow solid. LC/MS [423 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.93 (d, J=3.7 Hz, 1H), 9.25 (d, J=7.8 Hz, 1H), 9.01 (d, J=4.5 Hz, 1H), 8.54 (s, 1H), 8.39 (d, J=4.5 Hz, 1H), 8.19 (d, J=3.8 Hz, 1H), 7.73 (t, J=7.9 Hz, 1H), 7.62 (d, J=12.0 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 5.51 (q, J=4.9 Hz, 1H), 3.20 (dd, J=12.5, 8.1 Hz, 1H), 3.03 (dd, J=12.4, 5.2 Hz, 1H), 2.70-2.53 (m, 2H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30]CC3C=CC=CC=3)=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CCO.C1COCC1.[Pd]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]2[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(O)cc1
Yield: 95.3 %

Procedure:
A solution of 2-(4-acetamidophenyl)-6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.190 g, 0.386 mmol) in 2 mL of EtOH/THF (1:1) was debenzylated with 10% Pd/C under an H2 atmosphere as described in Example 30. F to provide the title compound (0.148 g, 95% yield): ES-MS (m/z) 403 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.COCCOC.C([O-])(O)=O.[Na+]>CCOC(C)=O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[C:11]([Cl:10])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: Fc1cnc(Cl)nc1Cl
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: COCCOC
Product: Fc1cnc(Cl)nc1-c1cccnc1Cl
Temperature: 80 °C

Procedure:
To 2,4-dichloro-5-fluoropyrimidine (500 mg, 2.99 mmol), 2-chloropyridine-3-boronic acid (707 mg, 4.49 mmol), Pd(PPh3)4 (346 mg, 0.30 mmol) was added DME (9.0 mL) and 1 M NaHCO3 (3.0 mL). The mixture was heated overnight in a sealed tube at 80° C., cooled to RT, diluted with EtOAc, and washed with water and saturated Na2CO3. The organic layer was dried over Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to provide 2-chloro-4-(2-chloro-pyridin-3-yl)-5-fluoro-pyrimidine. MS m/z=244, 246 [M]+ and [M+2]+. Calc'd for C9H4Cl2FN3: 244.06.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(O)(=O)C.O>O>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH:3]=[O:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)#[N:18]
Reactant: COC=Cc1ccc(-c2ccc(C#N)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(-c2ccc(CC=O)cc2)cc1
Temperature: 100 °C
Yield: 104.2 %

Procedure:
A mixture of 4.9 g of 4'-(2-methoxyvinyl)-4-biphenylcarbonitrile and 80 ml of glacial acetic acid/water (vol. 2:1) was heated to reflux for 1.5 hours at 100° C. bath temperature. The reaction mixture was subsequently poured into 150 ml of water and extracted three times with 100 ml of methylene chloride each time. The organic phases were washed with 100 ml of water and with 100 ml of saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated. There were obtained 4.8 g of (4'-cyano-4-biphenylyl)acetaldehyde as a yellowish, crystalline residue which was processed without additional purification; Rf-value (toluene/ethyl acetate vol. 90:10) 0.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH2:16])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:17]N1C(=O)CCC1=O>>[Cl:17][C:11]1[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[C:4]([C:10]=1[NH2:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1c(N)ccc(OC)c1OC
Reactant: O=C1CCC(=O)N1Cl
Product: CCOC(=O)c1c(N)c(Cl)cc(OC)c1OC
Yield: 55 %

Procedure:
Following the procedure employed in Example 27, treatment of ethyl 2,3-dimethoxy-6-aminobenzoate with N-chlorosuccinimide gave a 55% yield of the title compound after EtOH crystallization; mp 60-62%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ON=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a solution of 4-chlorobenzaldehyde (10.0 g) in chloroform (350 mL), hydroxylamine hydrochloride (10.2 g) was added and the mixture was stirred at room temperature for 18 hours in an argon atmosphere. After adding 2 mol/L hydrochloric acid (200 mL), three extractions were conducted with chloroform. The combined organic layers were washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was crystallized with a liquid mixture of n-hexane and chloroform to give 1-(4-chlorophenyl)-N-hydroxymethaneimine as a colorless solid (9.27 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: OCCCCCCBr
Reactant: COc1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 76 %

Procedure:
Using 5 g (25 mmol) of 4-methoxy-4'-hydroxybiphenyl, 50 ml of ethanol, 4.52 g (25 mmol) of 6-bromo-1-hexanol and a NaOH aqueous solution (1.05 g (26.2 mmol) of NaOH/3 ml of water), synthetic treatment was carried out in the same manner as in Example 1. The obtained crystals were recrystallized from methanol to obtain 5.71 g (yield: 76%) of 4-methoxy-4'-(6-hydroxyhexyloxy)biphenyl (13) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:25])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:25])=[CH:34][CH:35]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: CCN(CC)CCOC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: CCN(CC)CCOC(=O)c1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)cc1

Procedure:
2850 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 2440 mg of the product obtained in step 1 above are added. 30 mg of the expected product are thus obtained.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[OH:34][C:28]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[OH:21])[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:32][CH2:33]1
Reactant: COC(=O)C(CCBr)(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1C1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCN1CCC(O)(c2ccccc2O)CC1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 29.1 %

Procedure:
In 50 mL of anhydrous dimethylformamide were dissolved 2.24 g (6.7 mmol) of methyl 4-bromo-2,2-diphenylbutyrate and 1.30 g (6.7 mmol) of 4-(2-hydroxyphenyl)-4-piperidinol. To the resulting solution was added 1.07 g (10 mmol) of sodium carbonate, followed by stirring under heating at 50° C. for 35 hours. The residue obtained by distilling off the solvent under reduced pressure was dissolved in ethyl acetate, followed by washing with water and drying. The residue obtained by concentrating the solvent under reduced pressure was purified by chromatography on a silica gel column, whereby 870 mg (yield: 29.2%) of methyl 4-(4-hydroxy-4-(2-hydroxyphenyl)piperidino)-2,2-diphenylbutyrate was obtained.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]([CH3:40])([CH3:39])[CH2:12][C:13]1[N:14]=[C:15]([CH:24](O)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[N:16]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH:17]=1>C(Cl)Cl>[CH3:10][C:11]([CH3:40])([CH3:39])[CH2:12][C:13]1[N:14]=[C:15]([CH:24]([F:7])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[N:16]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH:17]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)Cc1ccc(-c2ccccn2)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(F)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethylaminosulfur trifluoride (0.1 mL, 0.8 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-[1-hydroxy-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (for synthesis see Example 1) (71 mg, 0.16 mmol) in methylene chloride (5 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-[1-fluoro-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[H][H]>[Ru]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9]
Reactant: OCCc1ccccn1
Reactant: [H][H]
Agent: [Ru]
Product: OCCC1CCCCN1
Temperature: 10 °C

Procedure:
Low pressure hydrogenations were carried out by charging solvent, 2-pyridineethanol, and different quantities of various ruthenium supported catalysts into a pressure vessel capable of agitation, agitating the resulting mixture and pressurizing the vessel and its contents to 500 psi with hydrogen. Under constant hydrogen pressure and continued agitation, the reaction mixture was either heated to a constant reaction temperature or heated to an initial reaction temperature with incremental increases of 10° C. to a final reaction temperature. Reactions were allowed to continue until hydrogen uptake ceased. The pressure vessel and its contents were cooled, vented and the catalyst removed with vacuum filtration. Upon distillation of the filtrate, 2-piperidineethanol was obtained and analyzed on a gc column (6′ CW 20M 160° C.) to provide product yield and composition of the distillate. The results are provided in Table II.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:32][CH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[O:39])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:32].[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:33][C:34]3[CH:48]=[CH:47][C:37]([C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=[O:39])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: CN1CCN(C(=O)c2ccc(CCl)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccc(C(=O)N6CCN(C)CC6)cc5)cc4)cc3)n(C)c(=O)c12
Yield: 13.2 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (406 mg), 1-(4-chloromethylbenzoyl)-4-methylpiperazine hydrochloride (1.119 g) and potassium carbonate (739 mg) in DMF (10 ml) was stirred at room temperature for 40 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane: methanol =9:1) and treated with hydrogen chloride/ethyl acetate to provide the title compound as colorless solid (86 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:9]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2csc(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
After a mixture of ethyl 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (595 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2.5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (538 mg, yield: 95%). This was recrystallized from ethanol-hexane. Melting point: 109–110° C.