Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[CH2:28]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1oc2cc(OCc3ccccc3)ccc2c(=O)c1-c1ccccc1

Procedure:
10 g of 7-hydroxy-2-methyl-isoflavone, 10 g of anhydrous potassium carbonate, 1 g of potassium iodide and 12.5 g of benzyl chloride are boiled in 200 ml of anhydrous acetone for 2 hours with stirring, under a reflux condenser. On subjecting the mixture to steam distillation, the crude product precipitating from the water is filtered, dried, and recrystallized from a mixture of 100 ml of methanol and 40 ml of acetone, affording white needle crystals of 7-benzyloxy-2-methyl-isoflavone, m.p. 139°-141° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[CH:8][C:9]([N-:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])=[CH:5][CH:4]=1.[C:21]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:22][C:23]([O:25]CC)=O.[O-]CC.[Na+]>COCCOCCOC>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([CH:7]2[CH2:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:23](=[O:25])[CH:22]2[C:21]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCC[N-]C(=O)C=Cc1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCCCCN1C(=O)CC(c2ccc(C(F)(F)F)cc2)C(C(=O)OCC)C1=O
Yield: 54.8 %

Procedure:
105 mmol 4-trifluoromethylcinnamoyl-N-pentylamide, 116 mmol diethyl malonate, and 285 mmol sodium ethoxide were refluxed in a 1:1 touene/diglyme mixture for 7 h, cooled and washed with dilute HCl and water. Evaporation at 2 torr gave a dark red oil, which was purified by column chromatography on silica to give 23 g 4-(4-trifluoromethyl-phenyl)-3-ethoxycarbonyl-1-pentylpiperidine-2,6-dione as a reddish oil. 57 mmol 4-(4-trifluoromethylphenyl)-3-ethoxycarbonyl-1-pentylpiperidine-2,6-dione in 100 ml THF was slowly added with stirring to a suspension of 260 mmol LiAlH4 in 100 ml THF maintaining the temperature at 10° C., followed by stirring at room temperature overnight. Excess hydride was destroyed by addition of water, followed by 500 ml 4 N HCl. The THF was removed by evaporation, the aqueous phase was extracted by methylene chloride, and the organic phase was washed with 4 N NaOH, dried, and evaporated. Column chromatography on silica yielded the pure compound, which was crystallized from EtOAc. Compound (93). Yield 3.7 g. M.p. 112°-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH3:19])=[CH:6][N:5]=[C:4]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(OC)ccc2OC)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Product: COc1ccc(OC)c(C(=O)c2cnc(NC3CCN(C(C)=O)CC3)nc2N)c1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,5-dimethoxyphenyl)-methanone (Example 329) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(2,5-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 400.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:17][CH:10]3[CH2:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH2:13][CH:9]3[CH:8]2[CH2:18][O:19][CH3:20])[C:3]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C(O)C>[CH:14]([N:12]1[CH2:13][CH:9]2[CH:8]([CH2:18][O:19][CH3:20])[CH:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=5)[N:26]=[CH:25][N:24]=4)[C:3]3=[O:21])[CH2:17][CH:10]2[CH2:11]1)([CH3:16])[CH3:15]
Reactant: COCC1C2CN(C(C)C)CC2CC1N1CCC(N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCC1C2CN(C(C)C)CC2CC1N1CCC(Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O

Procedure:
A mixture of 3-amino-1-(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-yl)-pyrrolidin-2-one, 4-chloro-6-trifluoromethylquinazoline (see Armarego et al., J. Chem. Soc. B, 1967, 449) and triethylamine in ethanol is heated at reflux until the reaction is complete. The resulting solution is concentrated under vacuum yielding a residue. The residue is purified by reverse phase HPLC and lyophilization providing the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:8][N:7]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]([CH2:25][C:26](=[O:27])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1OCC(F)(F)F
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CC(=O)Nc2ccc(Cl)cn2)c(C(=O)OCC)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 260 mg 4-(2,2,2-Trifluoro-ethoxy)-1H-pyrazole-3,5-dicarboxylic acid diethyl ester in 4 ml absolute DMF 33.5 mg of a 60% suspension of NaH in mineral oil were added under an argon atmosphere. The mixture was stirred for 15 min at RT. Then 209 mg 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture stirred for 2 h at RT. After concentration in vacuo the residue was directly subjected to the next reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([N:19]=[C:20]=[S:21])(=O)C1C=CC=CC=1>CC(C)=O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:20]([NH2:19])=[S:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: NC(=S)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 mL) was reacted with benzoylisothiocyanate (9.88 g, 60. mmol) at RT for about 4 h. The resulting solid was filtered and treated with 2 N NaOH in THF (120 mL). The mixture was refluxed for about 6 h and allowed to warm to RT. The solvent was evaporated off under vacuum. The residue was diluted with water (20 mL) and neutralized to pH 7 with 1N HCl. The resulting solid was filtered and dried under vacuum to afford 5-indolylthiourea (55-2). 5-Indolyl thiourea (0.01 mol) and ethyl bromopyruvate (0.011 mol) were dissolved in 3 mL ethanol and held at reflux for 2 h. The reaction was cooled, the crystalline ethyl 2-(1H-indol-5-ylamino)thiazole-4-carboxylate (55-3) was collected by filtration and washed with ethanol. Refluxing the mixture of ethyl esters with the NaOH-ethanol solution gave 2-(1H-indol-5-ylamino)thiazole-4-carboxylic acid (55-4) which was used directly in next steps. To a mixture of the crude acid (2.5 mmol), EDCI (2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol) in CH2Cl2 (30 mL) was added HNCH3OCH3HCl salt (2.6 mmol) and stirring continued at RT for overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 2-(1H-indol-5-ylamino)-N-methoxy-N-methylthiazole-4-carboxamide (55-5) (45.6% yield for overall 5 steps). At −78° C., to a solution of 5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0 mmol) in 30 mL THF was charged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol) under Ar2 protection and stirred for 10 min Weinreb amide (1 mmol) in 10 ml, THF was added to lithium reagent and allowed to stir at RT for 2 h. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 55 (51.7% yield). 1H NMR (300 MHz, CDCl3) δ 8.29 (br, 1H), 7.68 (d, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28˜7.26 (m, 1H), 7.15˜7.12 (m, 1H), 6.55 (m, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 432.1 (M+Na)+, 408.0 (M−H)−.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[O:20])[CH2:15]1>>[F:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:27]=1)[C:23]([NH:22][CH2:21][C:19](=[O:20])[NH:18][CH:16]1[CH2:17][N:14]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[S:13][CH:12]=[N:11][CH:10]=3)[CH2:3][CH2:4]2)[CH2:15]1)=[O:35]
Reactant: O=C1CCC(O)(c2cncs2)CC1
Reactant: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cncs3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-thiazol-5-yl-cyclohexanone, as prepared in Example 40 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-5-fluoro-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:27])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][C:11]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[N:4][CH:3]=1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:27])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:34][CH2:33][CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:19])=[CH:12][C:11]=2[C:20]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])=[N:4][CH:3]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)Cc1ccc(NC(=O)Nc2ncc(Cl)s2)c(C(=O)C2CCCC2)c1
Product: CS(=O)(=O)CCNC(=O)Cc1ccc(NC(=O)Nc2ncc(Cl)s2)c(C(=O)C2CCCC2)c1
Yield: 70.2 %

Procedure:
2-{4-[3-(5-Chloro-thiazol-2-yl)-ureido]-3-cyclopentanecarbonyl-phenyl}-N-(2-methanesulfonyl-ethyl)-acetamide (180 mg, 70%) was prepared from {4-[3-(5-chloro-thiazol-2-yl)-ureido]-3-cyclopentanecarbonyl-phenyl}-acetic acid (204 mg, 0.5 mmol) and 2-methanesulfonyl-ethylamine (62 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [NH2:1][C:2]([CH3:27])([CH3:26])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[CH3:26][C:2]([NH:1][C:35](=[O:37])[CH3:36])([CH3:27])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(=O)Cl
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a solution of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine (6.5 g, 17.5 mmol), prepared in Part A of Example 45, in dichloromethane (200 mL) was cooled to 0° C.; triethylamine (4.87 mL, 35.0 mmol) and acetyl chloride (1.37 mL, 19.2 mmol) were sequentially added. The reaction was stirred at 0° C. for 30 minutes, allowed to warm to ambient temperature, and stirred for three hours. The reaction was washed with saturated aqueous sodium bicarbonate (2×) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N-[1,1-dimethyl-2-(3-nitro-7-benzyloxyquinolin-4-ylamino)ethyl]acetamide as a yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([CH3:14])[CH2:11][CH:12]=[O:13])=[CH:2]1.CC(=CC)C.[O-:20]Cl=O.[Na+]>C(O)(C)(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([CH3:14])[CH2:11][C:12]([OH:20])=[O:13])=[CH:2]1
Reactant: [O-][Cl+][O-]
Reactant: CC(CC=O)c1c[nH]c2ccccc12
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(CC(=O)O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(1H-Indol-3-yl)-butanal (130 mg, 0.690 mmol) was dissolved in tert-butyl alcohol (27 mL) and 2-methyl-2-butene (4.7 mL) and subsequently was stirred for 10 min. To this solution was added an aqueous solution (4.7 mL) of NaClO2 (75 mg, 0.83 mmol) and NaH2PO4 (115 mg, 0.830 mmol) in one portion. The reaction mixture was stirred at room temperature for 12 h. The organics were removed by concentrating in vacuo. The residue was diluted with 10 mL of H2O, and adjusted to a neutral pH with 1M HCl. Extraction with EtOAc (3×10 mL), drying over Na2SO4, and concentration in vacuo provided 3-(1H-indol-3-yl)-butanoic acid. TMS-diazomethane was added dropwise to a solution of the crude 3-(1H-indol-3-yl)-butanoic acid in methanol (7 mL) until a yellow color persisted. The residual TMS-diazomethane was quenched by the dropwise addition of acetic acid until the yellow color disappeared. The reaction was then treated with an excess of saturated aqueous sodium bicarbonate, extracted with Et2O (3×20 ml), dried over Na2SO4 and purified by silica gel chromatography (20:80 EtOAc/hexanes to provide (R)-3-(1H-indol-3-yl)-butyric acid methyl ester. [α]D=−7.6 (c=1.0 benzene); reported rotation for (S)-3-(1H-indol-3-yl)-butyric acid methyl ester [α]D=+10.9 (c=2.12, benzene).
Reaction SMILES: [N+:1]([C:4]1[CH:51]=[CH:50][C:7]([CH2:8][CH:9]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-])=O)=[CH:43][CH:42]=2)[C:10]([O:12][CH:13]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:34]3[CH2:33][CH2:32][C@@:31]3([CH3:39])[C@H:19]4[CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Zn].CO.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[C:10]([O:12][CH:13]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:34]3[CH2:33][CH2:32][C@@:31]3([CH3:39])[C@H:19]4[CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]2)=[O:11])=[CH:50][CH:51]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC(=O)C(Cc5ccc([N+](=O)[O-])cc5)Cc5ccc([N+](=O)[O-])cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC(=O)C(Cc5ccc(N)cc5)Cc5ccc(N)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 69.3 %

Procedure:
2.62 g (3.75 mmol) Cholest-5-en-3-yl 2-(4-nitrobenzyl)-3-(4-nitrophenyl)-propanoate and 0.79 g (14.77 mmol) ammonium chloride were suspended in 90 ml of a mixture consisting of methanol:water 9:1. 4.90 g (74.96 mmol) zinc powder was then added in 10 minutes. The reaction mixture was then allowed to react at 45° C. for 6 hours and partitioned between dichloromethane and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. First chromatography of the residue on 50 g silica gel using toluene:ethyl acetate 1:1 as eluant and second chromatography on 50 g silica gel using tert.butyl methylether as eluant yielded 1.66 g Cholest-5-en-3-yl 2-(4-aminobenzyl)-3-(4-aminophenyl)-propanoate as white powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)([OH:13])[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32]CC)=[CH2:31])CCC.Cl.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[C:11]([C:8]1[N:6]2[N:7]=[C:2]([C:30](=[O:32])[CH3:31])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)([OH:13])[CH3:12]
Reactant: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncc(C(C)(O)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
In a flask was charged with tetrakis-(triphenylphosphine)-palladium (51 mg, 0.044 mmol) under nitrogen. A solution of 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoroquinolin-6-yl)ethanol (150 mg, 0.44 mmol) in DMF (10 mL) was added. The system was purged with nitrogen gas three times and tributyl-(1-ethoxy-vinyl)-stannane (0.16 ml, 0.46 mmol) was added. The temperature was increased to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, 3N HCl was added and the mixture was stirred for additional 4 hrs. Water was added and the mixture was then extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in CH2Cl2) to afford 70 mg (yield: 41%) title compound. LCMS (method B): [MH]+=351, tR=2.01 min.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CN(CC(O)c1csc(C(F)(F)F)n1)C(C)Cc1ccc(OCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.21 g (0.005 mol) of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine is dissolved in 10 ml of butan-2-one, and 0.5 ml of ethyl bromoacetate and 0.5 g of potassium carbonate are added, and the mixture is stirred at room temperature for 16 hours. The inorganic products are removed by filtration, and the solvent is removed by distillation. The remaining oil is purified on a silica gel column using toluene/ethyl acetate=85.15 as eluant. A colourless oil is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:31])[C:18]3[C:13](=[CH:14][C:15]([O:32]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH3:28][O:27][C:24]1[N:23]=[C:22]([O:29][CH3:30])[C:21]([C:20]2[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:10][CH:9]=3)[O:12][C:13]3[C:18]([C:19]=2[CH3:31])=[CH:17][CH:16]=[C:15]([OH:32])[CH:14]=3)=[CH:26][N:25]=1
Reactant: COc1ncc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)c(OC)n1
Reactant: C1COCCN1
Product: COc1ncc(C2=C(C)c3ccc(O)cc3OC2c2ccc(OCCN3CCOCC3)cc2)c(OC)n1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and morpholine as the starting material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.[CH2:13](O)[CH2:14][OH:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7]3([O:15][CH2:14][CH2:13][O:11]3)[C:6]=2[CH:12]=1
Reactant: OCCO
Reactant: O=C1CCSc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc2c(c1)C1(CCS2)OCCO1
Yield: 78.8 %

Procedure:
14.7 g (0.060 mol) of the title compound of Step B, 11 mL (0.19 mol) of ethylene glycol (purchased from Aldrich Chemical Company), and 0.4 g (2.10 mmol) of p-toluenesulfonic acid monohydrate (purchased from Aldrich Chemical Company) were added to 125 mL of toluene. The solution was stirred at reflux under nitrogen overnight, and was then washed with 1M sodium carbonate (2×250 mL), followed by water (2×250 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to dryness to yield 13.58 g of the title compound of Step C as an oil. 1H NMR (CDCl3): δ2.2 (m,2H), 3.16 (m,2H), 4.1 (m,2H), 4.2 (m,2H), 7.0-7.6 (3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>S(=O)(=O)(O)O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C1=COCCC1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC2CCCCO2)cc1

Procedure:
To a solution of 0.64 mL (2 mmol) of 1-(2-trimethylsiloxyethoxy)-1-trimethylsiloxy-2-methyl-lpropene, 0.55 mL of tetrabutylammonium biacetate (0.04 M in THF), and 0.06 mL of bis(dimethylamino)methylsilane in 40 mL of THF was added dropwise a solution of 20 g (72.5 mmol) of 4-tetrahydropyranyloxybenzyl methacrylate (purified by passing over a column of basic alumina in hexane solution, followed by evaporation of the hexane under reduced pressure) in 30 mL of THF. When the exothermic polymerization was finished, and the temperature had returned to room temperature, the reaction mixture was poured into methanol. Filtration gave 19 g of poly(4-tetrahydropyranyloxybenzyl methacrylate). GPD: Mn =9390, Mw =11,500, MwMn =1.23. DSC: Tg =62.3° C., with a decomposition endotherm at 250.5° C. TGA: rapid loss of 24.74% of weight at 248.1° C. The monomer was prepared from methyl 4-hydroxybenzoate by reaction with an excess of 3,4-dihydro-2H-pyran in the presence of sulfuric acid catalyst to give methyl 4-(2-tetrahydropyranyloxy)benzoate, which was then reduced with lithium aluminum hydride in THF solution to give 4-(2-tetrahydropyranyloxy)benzyl alcohol. Esterification with methacrylyl chloride and triethylamine in dichloromethane solution gave 4-tetrahydropyranyloxybenzyl methacrylate, m.p. 36° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: C1CCNCC1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCCCN4CCCCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and piperidine were converted to yield 3-(4-Bromo-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole as white solid, MS: 445(MH+, 1Br).