Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:30]([O:32][CH2:33][C:34](Cl)=O)[CH3:31]>C(Cl)(Cl)Cl>[CH2:30]([O:32][CH2:33][C:34]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:31]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A solution of ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate (9.25 g, 30.7 mmol) in chloroform (100 mL) was cooled to 0° C.; triethylamine (5.13 mL, 36.8 mmol) was added. Ethoxyacetyl chloride (4.51 g, 36.8 mmol) was then added dropwise over a period of five minutes. The reaction was allowed to warm to ambient temperature, heated at reflux overnight, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 93:7 dichloromethane:methanol) to provide 7.73 g of ethyl 6-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[SH:20][C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:20][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: Sc1ncccn1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1oc(Sc2ncccn2)nc1-c1ccc(Cl)cc1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (2.00 g), 2-mercaptopyrimidine (819 mg), anhydrous potassium carbonate (1.10 g) and N,N-dimethylformamide (10 ml) was heated to 100-110° C. and stirred for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then concentrated, the residue was subjected to silica gel column chromatography, and methyl 4-(4-chlorophenyl)-2-(2-pyrimidinylsulfanyl)-5-oxazolepropionate was obtained as a yellow oil (1.42 g, 57%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH3:3][N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:11]=2)[CH2:8][CH2:9]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(C#N)cc23)CC1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
NaH (26 mg, 1.07 mmol) was added in several batches to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (200 mg, 0.76 mmol) in DMF (2 mL) at 0-5° C., and the mixture was maintained for 1 hour at room temperature. Benzenesulfonyl chloride (222 mg, 1.24 mmol) was then added, and the resulting solution was maintained at room temperature for an additional 4 hours. The mixture was filtered, and the filter cake was washed with ethanol (2×10 mL) and diethylether (2×10 mL) to afford 250 mg (86%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole-5-carbonitrile as a white solid. 1H NMR (DMSO) δ 8.41 (s, 1H), 8.14 (d, 2H), 8.07 (d, 2H), 7.78 (d, 1H), 7.71 (d, 2H), 7.61 (t, 1H), 6.35 (s, 1H), 3.79 (2H), 3.34 (s, 2H), 2.80-2.87 (m, 5H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][C:30](O)=[O:31].[Cl:34][C:35]1[CH:60]=[CH:59][C:38]2[N:39]3[C:43]([CH2:44][NH:45][CH2:46][C:37]=2[CH:36]=1)=[N:42][N:41]=[C:40]3[CH:47]1[CH2:52][CH2:51][N:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[CH2:49][CH2:48]1>ClCCl>[NH3:8].[Cl:34][C:35]1[CH:60]=[CH:59][C:38]2[N:39]3[C:43]([CH2:44][N:45]([C:30](=[O:31])[CH2:29][CH2:28][N:27]([CH3:33])[CH3:26])[CH2:46][C:37]=2[CH:36]=1)=[N:42][N:41]=[C:40]3[CH:47]1[CH2:48][CH2:49][N:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[CH2:51][CH2:52]1
Reactant: CN(C)CCC(=O)O
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)CCC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Product: N
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.52 mmol) was added to a solution of 3-dimethylaminopropionic acid hydrochloride (80 mg, 0.52 mmol) in dichloromethane (5 ml) and the solution was stirred for 15 minutes. The amine from example 4 (100 mg, 0.26 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The mixture was partitioned between dichloromethane and aqueous sodium bicarbonate solution, and the layers were separated. The organic phase was dried over magnesium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1), to afford the title compound as a white solid (110 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:12][CH:13]=2)=[O:29])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: c1cnc2nc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(-n2cnc3cccnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from imidazo[4,5-b]pyridine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 1.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][CH2:7][C@H:8]([N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])[CH3:9].N1C=CC=CC=1.[CH3:22][N:23]1[CH:27]=[C:26]([C:28]2[CH:33]=[C:32]([O:34][C:35]3[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=3)[CH:31]=[CH:30][N:29]=2)[CH:25]=[N:24]1>C(Cl)Cl.CCOC(C)=O>[CH3:5][O:6][CH2:7][C@H:8]([N:10]1[CH2:14][CH2:13][N:12]([C:11]([NH:41][C:38]2[CH:37]=[CH:36][C:35]([O:34][C:32]3[CH:31]=[CH:30][N:29]=[C:28]([C:26]4[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=4)[CH:33]=3)=[CH:40][N:39]=2)=[O:15])[C:1]1=[O:2])[CH3:9]
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: O=C(Cl)Cl
Reactant: COC[C@@H](C)N1CCNC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC[C@@H](C)N1CCN(C(=O)Nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cn2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
Phosgene (15% in toluene, 1.75 mL, 2.449 mmol) was treated with a solution of (R)-1-(1-methoxypropan-2-yl)imidazolidin-2-one (155 mg, 0.980 mmol) and pyridine (116 mg, 1.470 mmol) in DCM (2 mL), stirred at RT for 15 min, then concentrated to dryness. The residue was dissolved in DCM (2 mL), treated with a solution of Example A2 (131 mg, 0.490 mmol) and TEA (248 mg, 2.449 mmol) in DCM (2 mL) and stirred at RT for 4 h. The mixture was treated with EtOAc, washed with satd. NaHCO3, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford (R)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (38 mg, 17%). 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.22-8.21 (m, 1 H), 8.06-8.05 (m, 1 H), 7.95 (d, J=0.7 Hz, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 6.69 (dd, J=5.7, 2.4 Hz, 1 H), 4.10-4.09 (m, 1 H), 3.84 (s, 3 H), 3.81-3.79 (m, 2 H), 3.40-3.39 (m, 4 H), 3.26 (s, 3 H), 1.09 (d, J=6.9 Hz, 3H); MS (ESI) m/z: 452.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].Cl>O1CCOCC1.CO>[CH3:12][CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][NH:22][CH2:23]4)[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)no2)cc1C#N
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,1-dimethylethyl 5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 6, 512 mg, 1.11 mmol) and 4M HCl in dioxane (20 ml) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo to give a pale yellow solid, which was redissolved in MeOH. This solution was applied to an SCX-3 cartridge (10 g), and the product eluted with 1% NH3 in MeOH. Concentration gave a yellow oil, that became a solid on standing overnight (366 mg). 1H NMR (400 MHz, d6-DMSO) δ 8.38 (1H, d), 8.32 (1H, dd), 7.94 (1H, d), 7.32-7.17 (2H, m), 7.13 (1H, m), 4.80 (1H, sept), 4.10 (2H, s), 3.20-3.14 (4H, m), 1.48 (6H, d); m/z (ES) 361 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:17]([N:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:13]1)=[O:11].C[Mg+].[Br-].[CH3:32]COC(C)=O>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:13][CH:14]([C:16]2[C:17]([N:22]3[CH2:27][CH2:26][C:25]([OH:28])([CH3:32])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:15]1)=[O:11]
Reactant: CCOC(C)=O
Reactant: O=C1CCN(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCN(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 1-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-one (150 mg, 0.40 mol, SCHEME 13, Ex. 13.1) in 20 mL of THF was added CH3MgBr (0.60 mol, 3 M in ether) dropwise at 0° C. The mixture was stirred for 1 h at RT and then quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give crude product which was purified by prep. TLC (EtOAc:Petrol ether=1:1) to give (1H-benzoimidazol-2-yl)-{3-[3-(4-hydroxy-4-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone (0.109 g, 0.28 mmol, 70% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O)#[N:2].[CH2:10]([O:12][C:13](=[O:32])[CH:14]([C:20](=[O:31])[CH:21]([O:23][C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=1)[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].C(=O)([O-])[O-:34].[K+].[K+]>CS(C)=O>[CH2:10]([O:12][C:13](=[O:32])[CH:14]([C:20](=[O:31])[CH:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:34][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:26][CH:25]=1)[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(F)cc1
Reactant: N#Cc1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 84.7 %

Procedure:
11.9 g of cyano-phenol and 32.6 g of diethyl-2-(4'-fluoro-phenoxy)-propionyl-malonate are dissolved in 150 ml of dimethyl sulfoxide, whereupon 13.8 g of potassium carbonate are added and the reaction mixture is stirred at 60° C. for 6 hours. The reaction mixture is filtered and the filtrate is evaporated. Thus 36 g of the desired compound are obtained, yield 86%.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=O)=[C:24]([F:33])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:47]1([CH2:53][S:54]([NH2:57])(=[O:56])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:53]([S:54]([NH:57][C:30](=[O:32])[CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][CH2:20][C:16]2[CH:15]=[C:14]([C:10]3[C:9]([CH3:34])=[CH:8][C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:12][C:11]=3[CH3:13])[CH:19]=[CH:18][CH:17]=2)=[CH:23][C:24]=1[F:33])(=[O:56])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)NS(=O)(=O)Cc4ccccc4)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
To a solution of 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]propanoic acid (0.186 g, 0.400 mmol) in tetrahydrofuran (5 mL) was added 1,1′-carbonyldiimidazole (97.3 mg, 0.600 mmol), and the mixture was heated under reflux under a nitrogen atmosphere for 1 hr. After cooling the reaction mixture, 1-phenylmethanesulfonamide (91.5 mg, 0.480 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.0897 mL, 0.600 mmol) were added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (0.189 g, yield 76%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[C:15](=[O:16])[CH2:14][O:13][C:12]2=[O:17])=[CH:5][CH:4]=1.[CH3:20][NH2:21]>CO.O1CCCC1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:17])[O:13][CH2:14][C:15]([NH:21][CH3:20])=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1COC(=O)N1CCc1ccc(C(F)(F)F)cc1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCc1ccc(C(F)(F)F)cc1
Reaction time: 12 h

Procedure:
A solution of 0.75 g (2.74 mmol) of 3-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3-oxazolidine-2,4-dione obtained in step 2.1., in 10 ml of methanol is admixed with 8 ml (16.47 mmol) of a solution (2M) of methylamine in tetrahydrofuran. Stirring is continued at ambient temperature for 12 hours.
Reaction SMILES: [C:1]([O:4][C:5]1[C:24]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])=[C:23]([O:30][CH2:31][O:32][CH3:33])[CH:22]=[C:21]([O:34][CH2:35][O:36][CH3:37])[C:6]=1[C:7](=[O:20])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][C:5]1[C:24]([CH2:25][CH:26]=[C:27]([CH3:28])[CH3:29])=[C:23]([O:30][CH2:31][O:32][CH3:33])[CH:22]=[C:21]([O:34][CH2:35][O:36][CH3:37])[C:6]=1[C:7](=[O:20])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2OC(C)=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 46.1 %

Procedure:
An ethanol solution (100 ml) of the 9.89 g of the 2'-acetoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone obtained as the intermediate in Specific Example 18 was added into a suspension of 5.0 g of 5% palladium/carbon in 70 ml of ethanol, in which a hydrogen gas had been sufficiently absorbed in advance, and hydrogen was absorbed by stirring the mixture at 0° C. under atmospheric pressure in a hydrogen gas atmosphere for 1.5 hours with 430.55 ml of a hydrogen gas. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography [280 g of 230-400 mesh silica gel; n-hexane/ethyl acetate (5/1); 0.3 kg/cm2 ]. Fractions of 100 ml were collected and the 30th to 52nd fractions to obtain 4.58 g (yield=46.1%) of 1-[2-acetoxy-4,6-bis(methoxymethoxy)-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxymethoxyphenyl)-1-propanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([C:34]([F:37])([F:36])[F:35])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)[C:11]([F:13])([F:14])[F:12])[O:8][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([C:34]([F:35])([F:37])[F:36])[CH:27]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(c1ccc(Oc2ccc(C=O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 214, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one(Example 151, step 7) was reacted with 4-fluoro-2-(trifluoromethyl)benzaldehyde in the presence of cesium carbonate to give the title compound as a colorless oil. MS (m/e, ISP neg. ion)=532.0 [M−H+].
Reaction SMILES: S1C(C2C=CN=C([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)N=2)=CC2C=CC=CC1=2.[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[CH:35]=[C:34]([C:36]3[C:41]([Cl:42])=[CH:40][N:39]=[C:38](Cl)[N:37]=3)[S:33][C:32]=2[CH:44]=1>>[ClH:42].[ClH:42].[ClH:42].[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[CH:35]=[C:34]([C:36]3[C:41]([Cl:42])=[CH:40][N:39]=[C:38]([NH:12][CH2:13][CH2:14][CH2:15][N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)[N:37]=3)[S:33][C:32]=2[CH:44]=1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Reactant: Clc1ncc(Cl)c(-c2cc3ccc(Br)cc3s2)n1
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(Br)cc4s3)n2)CC1
Product: Cl

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine, the title compound is synthesized from 4-(6-bromobenzo[b]thiophen-2-yl)-2,5-dichloropyrimidine and isolated as a light orange solid. ES+(m/z) 480 (35C1, 79Br), 482 ([37Cl, 79Br] and [35Cl, 81Br]) and 484 (37Cl, 81Br) [M(free base)+H].
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]([OH:12])=O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2[CH:18]=1.CCN=C=NCCCN(C)C.NC1C=CC=CC=1>C1COCC1>[C:1]([NH:5][S:6]([CH2:9][C:10]([NH:19][C:17]1[CH:18]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:12])(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)CC(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of compound 2-(N-tert-butylsulfamoyl)acetic acid (5 g, 25.6 mmol.) in dry THF (20 mL) was added HOBt (13.8 g, 102.4 mmol.) and EDCI (18.3 g, 102.4 mmol.). Then aniline (3.6 g, 38.4 mmol.) was added successively. The reaction mixture was stirred overnight at room temperature. TLC analysis showed the reaction complete. The mixture was quenched by adding water and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated. The residue was purified by column chromatography (PE:EtOAc=2:1) to afford 2-(N-tert-butylsulfamoyl)-N-phenylacetamide (3.5 g, 51%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].[H][H].Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1>CN(C=O)C>[CH2:3]([O:7][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[CH2:4][CH2:5][CH3:6]
Reactant: Brc1nccs1
Reactant: [H][H]
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1nccs1
Yield: 36.6 %

Procedure:
A suspension of NaH (6.7 mmol, 0.27 g, 60% dispersion) in dry DMF was stirred with butanol (6.09 mmol, 0.55 mL) under argon until evolution of hydrogen ceased. 2-Bromothiazole (6.09 mmol, 0.55 mL) was added and after 15 minutes the mixture was heated to reflux. After 48 hours the reaction was quenched with water and extracted with ethyl acetate (4x). The organic phases were combined, dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (hexane followed with 1% ethyl acetate) to afford 0.35 g (37%) of 2-(1-butoxy)thiazole as an amber oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:10]=[CH:9][CH:8]=[CH:7]N=1)=[N+:2]=[N-:3].[CH:11](N(CC)C(C)C)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2([C:45]([F:48])([F:47])[F:46])[O:32][N:31]=[C:30]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]([C:43]#[CH:44])=[CH:35][CH:34]=3)[CH2:29]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1>CN(C=O)C.[Cu]I>[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2([C:45]([F:46])([F:48])[F:47])[O:32][N:31]=[C:30]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]([C:43]4[N:3]=[N:2][N:1]([CH2:4][C:5]5[CH:11]=[CH:7][CH:8]=[CH:9][N:10]=5)[CH:44]=4)=[CH:35][CH:34]=3)[CH2:29]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: [N-]=[N+]=NCc1ncccn1
Reactant: C#Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: CCN(C(C)C)C(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(-c3cn(Cc4ccccn4)nn3)c3ccccc23)=NO1
Reaction time: 16 h

Procedure:
CuI (88 mg) is added to a solution of 2-azidomethyl-pyrimidine (62 mg), N,N-diisopropylethylamine (DIPEA, 2.0 ml) and 5-(3,5-dichloro-phenyl)-3-(4-ethynyl-naphthalen-1-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole (100 mg) in DMF (1.0 ml). After 16 hours at room temperature, the reaction is quenched with a saturated solution of NaHCO3 and extracted with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 2-(4-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalen-1-yl}-[1,2,3]triazol-1-ylmethyl)-pyridine as a beige foam. (compound 1.27, Table 1).
Reaction SMILES: C(O)/C=C\CO.[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]#[C:17][CH2:18][OH:19])=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([NH:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][OH:19])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC#CCO
Agent: OC/C=C\CO
Product: CC(C)(C)OC(=O)NC/C=C\CO
Yield: 30 %

Procedure:
The title compound was synthesized from cis-2-butene-1,4-diol in an overall yield of 30% according to the procedure used for 4-tert-butoxycarbonylamino-2-butyn-1-ol