Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16]1C=CC(S(O)=O)=C[C:17]=1C(O)=O.ICCC>C(O)CC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH2:16][CH3:17])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Solvent: CCCI
Solvent: CCCO
Product: CCCS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 3 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and 1-iodopropane in 20 ml propanol/20 ml water and obtained in 3% yield. MS (m/e): 261.1 (MH−, 100%).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][C@H:18]1[C:29]([O:31]C)=[O:30])=[O:6])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:25]([O:24][C:22]([N:20]1[CH2:21][C@H:17]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([F:15])([F:16])[F:14])[C:7]=2[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])[C@H:18]([C:29]([OH:31])=[O:30])[CH2:19]1)=[O:23])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)c1c([C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of (±)-cis-1-tert-butyl 3-methyl 4-(2-(isopropoxycarbonyl)-3-(trifluoromethyl)phenyl)pyrrolidine-1,3-dicarboxylate (0.90 g, 1.96 mmol) in 20 mL of 2:1 THF/H2O was added lithium hydroxide (52 mg, 2.15 mmol). The reaction mixture was allowed to stir at ambient temperature for 2 h. The reaction was partitioned between 1:1 hexane/EtOAc and dilute aq Na2CO3. The organic layer was discarded. The aqueous layer was acidified with 12 N HCl and extracted with EtOAc. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated to afford 0.75 g (86%) of the title compound as a white foam, which was pure enough to be used without purification. LRMS (ES)+: 446 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([Cl:12])[CH:6]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][CH3:22])=[C:18]([OH:20])[CH:19]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:20][C:18]2[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=2[O:21][CH3:22])=[C:7]([Cl:12])[CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(Cl)cc1O
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Product: COc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 7 step (ii) and 5-chloro-2-methoxy phenol. Yield 4.0 g
Reaction SMILES: C1(C(C2C=CC=CC=2)C2CCN(CCCCC3C=NC=CC=3)CC2)C=CC=CC=1.C([O-])(=O)/C=C\C([O-])=O.[C:38]1([C:44]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:45][CH:46]2[CH2:51][CH2:50][N:49]([C:52](=O)[CH2:53][CH2:54][CH2:55][C:56]3[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=3)[CH2:48][CH2:47]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[C:63]1([C:44]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:45][CH:46]2[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][CH2:54][CH2:55][C:56]3[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=3)[CH2:50][CH2:51]2)[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: O=C(CCCc1cccnc1)N1CCC(C=C(c2ccccc2)c2ccccc2)CC1
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])/C=C\C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCc2cccnc2)CC1
Yield: 91.1 %

Procedure:
The title compound was prepared in a manner similar to that employed for 3-[4-[4-(diphenyl methyl)-1-piperidinyl]butyl]pyridine (1:1)-(Z)-2-butenedioate salt (Ex. 16) starting with 5.0 g of 4-(2,2-diphenylethenyl)-1-[1-oxo-4-(3-pyridinyl)butyl]piperidine and 7.2 mL of a 3.5M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene. The analytically pure base was obtained from hexanne, mp 54°-56° C. Analysis Calculated for C28H32N2 : C, 84.80; H, 8.13; N, 7.06. Found: C. 84.61; H, 7.92; N, 7.05. Evaporation of the hexane filtrates provided 4.4 g of crude 3-[4-[4-(2,2-diphenylethenyl)-1-piperidinyl]butyl]pyridine, which was dissolved in 50 mL of hot ethanol and treated with 1.28 of fumaric acid. Dilution with 50 mL of ether provided 4.1 g (67%) of salt, mp 163°-165° C. Analysis Calculated for C28H32N2.C4H4O4 : C, 74.97; H, 7.08; N, 5.46. Found: C, 74.69; H, 7.07; N, 5.44.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[O:14]([CH2:13][CH2:12][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCOc1ccccc1
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C1c2ccccc2CN1CCOc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
A mixture of 2,3-dihydroisoindol-1-one (0.066 g, 0.5 mmol,), 2-(bromoethoxy)benzene (0.121 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(2-phenoxy-ethyl)-2,3-dihydro-isoindol-1-one (0.099 g, 78%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.05 (t, 2H), 4.26 (t, 2H), 4.64 (s, 2H), 6.92 (m, 3H), 7.22-7.60 (m, 5H), 7.88 (d, 1H), GC-MS: m/z 253 (M)+.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](SC)[N:11]=[CH:12][C:7]=2[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[N:11]=[CH:12][C:7]=2[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(SC)nc21
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C)CC3)nc21
Temperature: 110 °C
Yield: 116.9 %

Procedure:
A mixture containing 1.33 g of 5,8-dihydro-8-ethyl-2-methylthio-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 1.30 g of 4-methylpiperazine, and 20 ml of dimethyl sulfoxide was heated at 110°C for 1 hour with stirring. The separated solid was collected by filtration, washed with ethanol, and recrystallized from dimethylformamide to give 1.86 g of the product, as nearly coloress needles, m.p. 232 - 233°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(N)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 1,3-diaminobenzene were reacted to give N2-(3-aminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 11.89 min.; purity: 97.6%; MS (m/e): 312.05 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:6]=1)=[O:4].[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27]Cl>C1COCC1.O.[NH4+].[Cl-]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]([O:15][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[N:10]=1)=[O:4]
Reactant: COC(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: COCCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)nc(C(=O)OC)nc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
A solution of 4,6-bis-(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxylic acid methyl ester (4.0 g, 15.0 mmoles) in 50 mL of THF is added to a suspension of NaH (0.39 g, 16.5 mmoles) in THF (50 mL) at 0° C. When addition is complete, the reaction mixture is stirred at 0° C. for 15 minutes. 2-methoxyethoxymethyl chloride (2.0 g, 16.5 mmoles) is added and the solution is warmed to room temperature. The reaction mixture is stirred at room temperature overnight. It is diluted with 100 mL H2O and 100 mL of saturated aqueous NH4Cl. The layers are separated, and the aqueous phase is washed with Et2O (3×100 mL). The combined organic phases are washed with 100 mL brine and dried over MgSO4. Evaporation of Et2O gives 5.3 g (100%) of the desired ester as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC>C(OCC)C.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>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([Cl:12])[N:11]=[C:2]([C:25](=[O:27])[CH3:26])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)nc(C(C)=O)c1
Reaction time: 8 h

Procedure:
Add methyl 2,6-dichloroisonicotinate (3.0 g, 15.0 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (105 mg, 0.15 mmol) and toluene (10 mL) in a previously nitrogen filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(1-ethoxyvinyl)tin (5.57 mL, 16.5 mmol) under nitrogen and heat the sealed mixture at 100° C. overnight with vigorous stirring. Cool the reaction to room temperature, dilute with diethyl ether and filter through a filtering agent. Concentrate to near dryness and dilute the residue with THF (10 mL). Add dropwise 5 N HCl (5 mL) and stir the mixture overnight. Concentrate to near dryness and extract the organic material by diethyl ether, partitioning with water. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the title compound as a solid over two steps (47%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:17]([O:21][C:22]1[CH:32]=[CH:31][C:25]([CH:26]=[CH:27][C:28](O)=O)=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([O:21][C:22]1[CH:23]=[CH:24][C:25](/[CH:26]=[CH:27]/[C:28]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:31][CH:32]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CCCCOc1ccc(C=CC(=O)O)cc1
Product: CCCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CCC)c(=O)n3CCC)cc1
Yield: 63.6 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.21 g (14.6 mmol) of 4-butoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.47 g (yield 64%) of Compound 51 as white needles.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O[C:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A mixture of 4-nitrophenylboronic acid pinacol ester (4.5 g; 18.1 mmol; 1.2 eq.), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (5.0 g; 15.1 mmol; 1.0 eq.) and sodium carbonate (1.07 g, 10.1 mmol, 5 eq.) were dissolved in DME (50 mL) and water (25 mL). The mixture was degassed for 5 min with nitrogen before the addition of Pd(PPh3)4 (349 mg; 0.30 mmol; 0.02 eq.) and heated at 80° C. O/N. Water (100 mL) was added and aqueous phase was extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (EtOAc:heptane, 10.90) to give the title compound as a yellow solid (3.3 g, 72%). 1H NMR (300 MHz, DMSO-d6) δ 8.24-8.17 (m, 2H), 7.65-7.68 (m, 2H), 6.45 (brs, 1H), 4.06 (m, 2H), 3.56 (t, 2H), 2.55-2.48 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][Li].[Cl-].[Cl-].[CH3:10][Ga+2:11]>CCCCC.C1C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][Ga:11]([CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:10]
Reactant: C[Ga+2]
Reactant: [Li]CCCN(C)C
Agent: [Cl-]
Solvent: CCCCC
Solvent: c1ccccc1
Product: CN(C)CCC[Ga](C)CCCN(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g of 3-dimethylaminopropyllithium (53.7 mmol) are suspended in 40 ml of pentane, and a solution of 4 g of methylgallium dichloride (25.7 mmol) in 20 ml of benzene is added dropwise. The mixture is first stirred at room temperature for one hour and then boiled under reflux for 6 hours. After cooling, the lithium chloride and excess lithium salt are filtered off and the solvent is stripped off in vacuo. The residue which remains is sublimed in vacuo at an oil bath temperature of 60° C. Bis-(3-dimethylaminopropyl)methylgallium is obtained as a white solid of melting point 52° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(O)CCC.CCCCCC>[F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[N:4]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: ClCCNCCCl
Reactant: Nc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCCCO
Product: Fc1cc(F)c(N2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.8 %

Procedure:
A mixture of 2,4,5-trifluoroaniline (2.94 g, 20 mmol) and bis(2-chloroethyl)amine hydrochloride (3.56 g, 20 mmol) in butanol (10 mL) was heated at reflux for 24 hours. The mixture was cooled to room temperature, sodium carbonate (2.33 g, 22 mmol) was added, and the mixture was heated again at reflux. After 2 days, the mixture was cooled to room temperature, hexane (15 mL) and 3 N NaOH (25 mL) were added, and the resulting layers were separated. The aqueous layer was extracted with chloroform (3×25 mL) and the combined organic fractions were flashed over a column of silica gel. The silica gel was further eluted with a gradient of chloroform to chloroform/methanol (4:1). The solvent was removed from the combined fractions with Rf=0.20 [silica gel, chloroform/methanol (4:1)], giving the title compound as a yellow oil (1.028 g, 4.76 mmol, 24%). ESI-MS m/z 217 (MH+).
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17]CC)=[CH:13][N:12]=2)=[CH:7][CH:6]=1.C(OC(C)CCC1C=CC(C2N=CC(OCC)=CN=2)=CC=1)(=O)C.[OH-].[Na+]>C(O)COCCO>[OH:1][CH:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: CCOc1cnc(-c2ccc(CCC(C)O)cc2)nc1
Agent: CCOc1cnc(-c2ccc(CCC(C)OC(C)=O)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CC(O)CCc1ccc(-c2ncc(O)cn2)cc1
Yield: 161.5 %

Procedure:
2.9 g of (-)-2-[4-(3-hydroxy-1-butyl)phenyl]-5-(ethoxy)pyrimidine, 3.1 g of (-)-2-[4-(3-acetoxy-1-butyl)phenyl]-5-(ethoxy)pyrimidine, 8 g of sodium hydroxide and 60 ml of diethylene glycol were reacted in an analogous manner to Example 1(c) to give 4.2 g of (-)-2-[4-(3-hydroxy-1-butyl)phenyl]-5-hydroxypyrimidine.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[C:7]([C@@H:9]([NH:13][S@](C(C)(C)C)=O)[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=1.[ClH:22].O1CCOCC1>>[ClH:22].[F:20][C:2]([F:1])([F:21])[C:3]1[N:8]=[C:7]([C@@H:9]([NH2:13])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=1
Reactant: CCC[C@H](N[S@@](=O)C(C)(C)C)c1cccc(C(F)(F)F)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCC[C@H](N)c1cccc(C(F)(F)F)n1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
(S,S)-2-Methyl-propane-2-sulfinic acid 1-(6-trifluoromethyl-pyridin-2-yl)-butylamide (290 mg, 0.92 mmol) is treated with HCl in dioxane (4.0 N solution, 10 mL, 40 mmol) at room temperature and stirred for 30 min. The reaction mixture is concentrated in vacuo to afford (S)-1-(6-trifluoromethyl-pyridin-2-yl)-butylamine hydrochloride (200 mg, 88%) which is used without further purification [note: the enantiomeric purity (% ee) has not been determined].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:12].[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].CCOC(C)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:12][S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)Cl
Reactant: NC1CCc2c(Cl)ccc(F)c21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)NC1CCc2c(Cl)ccc(F)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-7-fluoro-2,3-dihydro-1H-inden-1-amine (CAS No. 1337690-24-0, 371 mg, 2.00 mmol) and TEA (0.697 mL, 5.00 mmol) in DCM (10 mL) was added sulfamoyl chloride (462 mg, 4.00 mmol) at 0° C. The reaction mixture was stirred for 3 hours at room temperature. To the reaction mixture were added AcOEt and water, and the layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo and the residue was purified by silicagel column chromatography (gradient 20% to 33% AcOEt in n-heptane) to afford the title compound (165 mg, 0.623 mmol) as a racemate.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[NH:13][C:12]1=[O:21])[CH2:8]2.I[CH3:23]>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH2:16][C:17]([F:20])([F:18])[F:19])[N:13]([CH3:23])[C:12]1=[O:21])[CH2:10]2
Reactant: CI
Reactant: O=c1[nH]c(CC(F)(F)F)cn1C1C2CC3CC(C2)CC1C3
Product: Cn1c(CC(F)(F)F)cn(C2C3CC4CC(C3)CC2C4)c1=O

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 1-adamantan-2-yl-4-(2,2,2-trifluoro-ethyl)-1,3-dihydro-imidazol-2-one (obtained in example 16, 100 mg) by alkylation with iodomethane (71 mg). 1-Adamantan-2-yl-3-methyl-4-(2,2,2-trifluoro-ethyl)-1,3-dihydro-imidazol-2-one was obtained as a light yellow solid (72 mg). MS (EI): 314.2 (M+).
Reaction SMILES: [NH2:1][CH:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].[ClH:11].[CH3:12][CH2:13]O>>[NH2:1][CH:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([O:6][CH2:12][CH3:13])=[O:5].[ClH:11]
Reactant: CCO
Reactant: CC(C)C(N)C(O)C(=O)O
Agent: Cl
Product: CCOC(=O)C(O)C(N)C(C)C

Procedure:
Treat 3-Amino-2-hydroxy-4-methylpentanoic acid (0.89 g, 6.05 mmol) (Peet, N. P. et al., J. Med. Chem., 33, 394 (1990)) in CH3CH2OH (25 mL and then 20 mL) with gaseous HCl. Concentrate and dry over KOH pellets to give the title compound.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.C([O:32][B:33](OC(C)C)[O:34]C(C)C)(C)C.Cl>C1COCC1>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([B:33]([OH:34])[OH:32])=[C:18]([F:22])[C:17]=2[F:23])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)c(F)c2F)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
After 2.72 g of the 4-n-octyloxy-2', 3'-difluorobiphenyl was dissolved in 20 ml of a dried THF, the solution thus formed was cooled down to -70° C. under a nitrogen atmosphere and added dropwise with 5.5 ml of butyllithium (1.6 mol/liter hexane solution). The solution was continuously stirred at the same temperature for 2 hours, and then added dropwise with a THF solution containing 3.21 g of triisopropylborate. After the solution was stirred at an ambient temperature for 12 hours, it was added with 7.7 ml of a 10% aqueous hydrochloric acid solution and further stirred for 1 hour. Then, the same after-treatments as in [1] in Example 1 were repeated to obtain 2.27 g of 4-(p-n-octyloxyphenyl)-2,3-difluorobenzene boronic acid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:3]1[C:2]([N:14]2[CH2:15][CH2:16][CH:11]([O:10][CH3:9])[CH2:12][CH2:13]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC1CCNCC1
Reactant: Clc1ncccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC1CCN(c2cccnc2Cl)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A round-bottomed flask was charged with 3-bromo-2-chloropyridine (620 mg, 3.22 mmol), 4-methoxy-piperidine (371 mg, 3.22 mmol), tris(dibenzylideneacetone)dipalladium(0) (147 mg, 0.161 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (186 mg, 0.322 mmol), and sodium tert-butoxide (464 mg, 4.83 mmol) in toluene (6442 μL), sealed and then sparged with argon for 5 min. The reaction mixture was heated at 100° C. with stirring for 2 h. After cooling to RT, the reaction mixture was filtered through a pad of celite and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 40% EtOAc in hexane, to provide 2-chloro-3-(4-methoxypiperidin-1-yl) as orange oil. MS (ESI, pos. ion) m/z: 226.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: CC(C)CN(c1ccc(I)cc1)c1ncccn1
Product: COC(=O)C(C/C=C/c1ccc(N(CC(C)C)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 63.8 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (143 mg) was reacted with N-(4-iodophenyl)-N-isobutylpyrimidin-2-amine (167 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(isobutyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (159 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=1/1) was used for purification.