Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.Cl[CH2:13][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:13][C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]3[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=3[N:15]=2)[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncnc2c1c(I)nn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (11.0 g, 41.1 mmol), 2-(chloromethyl)-1-phenyl-1H-benzo[d]imidazole (10.0 g, 41.4 mmol) and K2CO3 (6.0 g, 43.4 mmol) in DMSO (60 mL) was stirred at room temperature overnight. Then the mixture was added H2O (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE:EtOAc=2:1) to give 141 (10.0 g, yield 52%) as a yellow solid. LCMS (ESI), M+H+=466.04. 1HNMR (400 MHz, CDCl3) δ 5.783 (s, 2H), 5.785 (s, 2H), 7.068-7.090 (q, J=0.8 Hz, 1H), 7.088-7.307 (m, 3H), 7.362-7.422 (m, 4H), 7.800-7.822 (d, J=0.8 Hz, 1H), 8.219-8.221 (d, J=1.2 Hz, 2H)
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@H:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol, US2005/20572 A1, 2005) in DCM (20 mL) was added tert-butyl [trans-3-(aminooxy)cyclopentyl]methylcarbamate 116 (0.32 g, 1.39 mmol), 1-hydroxybenzotriazole (0.18 g, 1.33 mmol), and 1-ethyl-(3-dimethylamino propyl)carbodiimide hydrochloride (0.26 g, 1.36 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 6 hours, then concentrated in vacuo to provide a residue which was subjected to chromatography to olive 117 (0.45 g, contains some byproduct) as a white foam.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:34])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:30](=[CH:31][CH:32]=1)[O:29][C:13]1([CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[CH2:15][CH2:14]1)[CH2:12][C:11]2=[O:33].Cl>O1CCOCC1.O>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:16]2[CH2:17][CH2:18][C:13]3([CH2:12][C:11](=[O:33])[C:10]4[C:30](=[CH:31][CH:32]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:34])=[O:4])[CH:9]=4)[O:29]3)[CH2:14][CH2:15]2)=[CH:21]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4ccccc34)CC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4ccccc34)CC1)O2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4 M NaOH (0.081 ml, 0.325 mmol) was added to a solution of (E)-3-{1′-(1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (140 mg, 0.325 mmol) in dioxane (2 ml) and water (1 ml) and the mixture was stirred at RT for 10 h. The pH was brought to 4 with 2 M HCl and the solvent was removed under vacuum to give (E)-3-{1′-(1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid. The crude compound (135 mg) was dissolved in THF (12 ml). TEA (0.092 ml, 0.66 mmol), EDC (126 mg, 0.66 mmol) HOBT (44 mg, 0.33 mmol) and NH2OTHP (48 mg, 0.41 mmol) were added and the mixture was stirred at RT overnight. The solvent was removed and the residue was partitioned between DCM and water. The organic phase was dried over Na2SO4, evaporated and the crude product was purified by column chromatography (eluent: DCM/MeOH/NH4OH 96:4:0.4). The resulting (E)-3-{1′-(1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide was dissolved in DCM and treated with HCl/Et2O for 3 h. The precipitate was filtered and washed with DCM to give (E)-3-{1′-(1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride as a white solid (40 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C(=O)O)ccc1C
Yield: 104.7 %

Procedure:
In a similar manner to Step 1 of Example 347, 3-hydroxy-4-methylbenzoic acid (2.00 g, 13.1 mmol) was suspended in dichloromethane (50 mL), and the suspension was treated with diisopropylethylamine (13.7 mL, 78.6 mmol) and chloromethyl methyl ether (5.00 mL, 65.8 mmol). The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (50 mL), and the solution was treated with 2 mol/L aqueous potassium hydroxide solution (50 mL). The solvent was evaporated under reduced pressure. The residue was added with 4 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-methoxymethoxy-4-methylbenzoic acid (2.69 g).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][CH3:14])[O:12][C:8]=2[C:7]([C:15]([OH:17])=O)=[CH:6][CH:5]=1.[CH2:19]([C:21]1[C:25]([NH2:26])=[C:24]([CH3:27])[O:23][N:22]=1)[CH3:20]>C(OCC)C.CCCCCC>[CH2:19]([C:21]1[C:25]([NH:26][C:15]([C:7]2[C:8]3[O:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=3[C:4]([O:3][CH:2]([F:1])[F:18])=[CH:5][CH:6]=2)=[O:17])=[C:24]([CH3:27])[O:23][N:22]=1)[CH3:20]
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Reactant: CCc1noc(C)c1N
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(CC)noc3C)c2o1
Yield: 54.6 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (0.20 g) and 3-ethyl-5-methylisoxazol-4-ylamine (0.20 g). Purification by column chromatography on silica eluting 20-50% ethyl acetate in heptane afforded, after trituration with diethyl ether-hexane, the title compound as a white solid (0.155 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:29])[CH2:19][CH2:20][CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31]>C(#N)C>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:30](=[O:31])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH3:29])[CH2:19][CH2:20][CH2:21][S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:12][C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(N)c(CCNCCCN(C)CCCSc2ccccc2)cc1OC
Solvent: CC#N
Product: COc1cc2c(cc1OC)NC(=O)N(CCCN(C)CCCSc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(2-(2-amino-4,5-dimethoxyphenyl)-ethylamino)-propyl]-N-[3-(phenylthio)-propyl]-methylamine and carbonyldiimidazole in acetonitrile analogously to Example 56.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)=[CH:11][C:5]=2[C:4](=[O:31])[O:3]1.[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:33]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([CH3:1])([CH3:32])[O:3][C:4](=[O:31])[C:5]=2[CH:11]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCC=O
Reactant: CCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Yield: 74.7 %

Procedure:
The title compound was prepared following procedure described in Example 23, step b) from 2,2-dimethyl-6-({4-[(4-propylphenyl)ethynyl]benzyl}amino)-4H-1,3-benzodioxin-4-one (660 mg; 1.55 mmol) and hexanal (Aldrich, 279.41 μl, 2.33 mmol). Purification of the crude (880 mg) by flash chromatography using silica gel (EtOAc/c-Hex, 5:95 then 10:90) gave 590 mg (75%) of the title compound as a beige powder. HPLC, Rt.: 6.37 min (purity: 61.9%), 1H NMR (CDCl3) δ: 7.42 (m, 4H), 7.12-7.19 (m, 5H), 6.78 (m, 2H), 4.48 (s, 2H), 3.34 (t, J=7.6 Hz, 2H), 2.57 (t, J=7.8 Hz, 2H), 1.68 (s, 6H), 1.61 (m, 4H), 1.24 (m, 6H), (0.91 (t, J=7.3 Hz, 3H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:27]([CH:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[CH:26]=1)[CH3:24]
Reactant: CCc1ccc(O)c(C(C)c2ccccc2)c1
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Product: CCc1ccc(Oc2cc(F)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(C(C)c2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethyl-2-(1-phenyl-ethyl)-phenol as in Example 18 to afford 0.078 g (29%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C32H31O4F 498, found 499 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[C:7](=[N:9][OH:10])[NH2:8].[C:15](OC(=O)C)(=O)[CH3:16]>>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[C:7]1[N:8]=[C:15]([CH3:16])[O:10][N:9]=1
Reactant: NC(/C=C/c1cccc(Cl)c1F)=NO
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(/C=C/c2cccc(Cl)c2F)no1
Reaction time: 2 h
Yield: 75.6 %

Procedure:
6.4 g (0.03 mol) of (E)-3-chloro-2-fluoro-cinnamamide oxime are introduced into 50 ml of acetic anhydride and the mixture is stirred for 2 hours at reflux temperature. The entire batch is subsequently concentrated in vacuo, the residue is stirred with sodium carbonate solution and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and the solvent is distilled off. 5.1 g (75.6% of theory) of (E)-3-(3-chloro-2-fluoro-styryl)-5-methyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:29])[CH:3]=1.[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:31]#[C:30][CH:32]4[CH2:34][CH2:33]4)=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:29])[CH:3]=1
Reactant: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c(Cl)cc1F
Yield: 46.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 using N-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-90, 0.200 g, 0.370 mmol), ethynylcyclopropane (0.050 g, 0.75 mmol), TBAF (0.360 g, 1.13 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (3.0 mL) at 80° C. to afford 0.080 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.77 (br s, 9H), 0.92 (br s, 2H), 1.10 (s, 3H), 1.57 (m, 1H), 4.30 (d, J=5.4 Hz, 2H), 7.43-7.50 (m, 3H), 7.65 (d, J=5.4 Hz, 2H), 7.77 (d, J=5.1 Hz, 2H), 12.57 br s, 1H); MS (m/z): 467.36 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: CC(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a solution of 4-hydoxybenzaldehyde (4.0 g, 32.8 mmol) in dry DMF (100 mL) was added 2-bromopropane (6.0 g, 49.2 mmol) and potassium carbonate (6.8 g, 49.2 mmol). The resulting reaction was heated to 100° C. and stirred for 3 hours. The reaction was quenched by adding excess water and partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. Purification on silica gel with 15% ether/hexane afforded the title compound (5.0 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@@H:4]2[C@H:7]([CH:8]=1)[C:6](=[CH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2.N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:34]([CH3:37])([O-:36])=[O:35]>>[CH3:1][C:2]1[CH2:3][C@@H:4]2[C@H:7]([CH:8]=1)[C@@:6]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH2:37][N+:34]([O-:36])=[O:35])[CH2:5]2
Reactant: C[N+](=O)[O-]
Reactant: CC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 6 h

Procedure:
Tert-butyl(±)-(1S,5R)-3-methylbicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.21 g, 5.50 mmol) was dissolved in nitromethane (7 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 mL, 6.0 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 6 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (1.14 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)=[CH:4][CH:3]=1.[Br:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH:37]=O)=[O:36])=[CH:31][CH:30]=1.FC(F)(F)C(O)=O>>[Br:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH:37]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:36])=[CH:31][CH:30]=1
Reactant: O=CC(=O)c1ccc(OCCBr)cc1
Reactant: Fc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(OCCBr)cc1)C1c2ccc(OCc3ccccc3)cc2CCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
To a solution of (4-fluorophenyl){2-[3-(phenylmethoxy)phenyl]ethyl}amine (0.643 g, 2.0 mmol) and [4-(2-bromoethoxy)phenyl]glyoxal (0.617 g, 2.4 mmol) was added trifluoroacetic acid (0.342 g, 3.0 mmol). The reaction stirred at room temperature for 4 hours. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (SiO2, 20% ethyl acetate/hexane) to provide the title compound (0.879 g, 78% yield): 1H NMR (CDCl3) 8.00 (d, 2H), 7.40 (m, 4H), 7.18 (m, 1H), 7.07 (d, 1H), 6.79-6.92 (m, 8H), 5.85 (s, 1H), 5.02 (s, 2H), 4.33 (t, 2H), 3.71 (m, 1H), 3.64 (t, 2H), 3.47 (m, 1H), 3.07 (m, 1H), 2.87 (m, 1H); ES-MS (m/z) 560 [M+H]+.
Reaction SMILES: C(N(CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=CC=C(C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[NH:47]1[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48]1>>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:24]([N:47]3[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48]3)[C:25]3[C:20](=[CH:9][CH:14]=[N:15][CH:16]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NC1CCNC1
Product: NC1CCN(c2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccncc23)C1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-naphthyridine) and pyrrolidin-3-amine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 9.26 (s, 1 H), 8.28-8.20 (d, J=6.4 Hz, 1 H), 8.05-7.98 (d, J=8 Hz, 1 H), 7.90-7.82 (d, J=7.2 Hz, 1 H), 7.70-7.60 (m, 2 H), 7.50-7.42 (t, J=7.2 Hz, 1 H), 6.14 (s, 1 H), 5.26 (s, 2 H), 4.70-4.50 (m, 2 H), 4.20-4.10 (m, 2 H), 4.10-4.00 (m, 1 H), 3.90-3.78 (m, 2 H), 3.60-3.52 (t, J=2.8 Hz, 2 H), 2.60-2.48 (m, 1 H), 2.35-2.25 (m, 1 H).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc(-c2ccccc2)ncn1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccccc2)ncn1
Yield: 93.5 %

Procedure:
Crude 4-hydroxy-6-phenylpyrimidine (3.65 g) was heated to reflux with phosphoryl chloride (40 ml) for 90 minutes. The reaction mixture was cooled and then concentrated under reduced pressure to afford a brown solid. The brown solid was partitioned between water and ether and the combined ether extracts washed with brine, dried and evaporated to give 4-chloro-6-phenylpyrimidine (2.18 g, 93.5% pure by GC analysis) as a yellow solid which was used directly in the next stage.
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]([CH2:6][C@@H:7]([CH2:12][C:13]([O-:15])=O)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[Cl:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[NH:64]1[CH2:69][CH2:68][CH:67]([N:70]2[CH2:79][C:78]3[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=3)[NH:72][C:71]2=[O:80])[CH2:66][CH2:65]1>CN(C=O)C>[NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]([CH2:6][C@@H:7]([CH2:12][C:13](=[O:15])[N:64]2[CH2:65][CH2:66][CH:67]([N:70]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[NH:72][C:71]3=[O:80])[CH2:68][CH2:69]2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[Cl:22]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.0 g (8.83 mmol) 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and 3.05 g (9.5 mmol) TBTU, 1.28 g (9.47 mmol) HOBT in 1.7 mL (9.76 mmol) ethyldiisopropylamine and 1100 mL DMF was stirred for 1 h at RT. Then 2.2 g (9.51 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one were added and the reaction solution was stirred overnight at RT. The reaction mixture was evaporated down i.vac., the residue was taken up in DCM, washed with 10% citric acid solution and 15% K2CO3 solution and dried over Na2SO4. The desiccant was eliminated by filtering through activated charcoal; after elimination of the solvent the desired product was obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C[n+]1ccn(C(=O)N2CCCCC2)c1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCCCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (45%). HPLC-MS m/z=367.02 (M+1), Rt: 4.9 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=1.O[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:17][CH:16]=1>>[N:24]1([CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:13][CH2:12][C:10]3[N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[S:8][CH:9]=3)=[CH:16][CH:17]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: OCc1csc(-c2cccnc2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1cncc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)cs2)c1
Yield: 35 %

Procedure:
In substantially the same manner as in Working Example 146, 2-(3-pyridyl)-4-thiazolylmethanol was mesylated, which was allowed to react with 1-[3-(4-hydroxyphenyl)propyl]imidazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-pyridyl)thiazole. The yield was 35%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 67-68° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11]\[OH:12])[CH:3]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2cccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)c2)cc1

Procedure:
In analogy to example 22, from (E)-3-(3-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 12) and (4-methylsulfonylphenyl)boronic acid was prepared the title compound as a colorless oil, MS (ESI+): m/z=457.3 ([M+H]+).