Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.[Br:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:25]=1)=[O:23].S(C)C.Br>C1(C)C=CC=CC=1.CB1OB(C)OB(C)O1.C1COCC1>[Br:20][CH2:21][C@@H:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:25]=1)[OH:23]
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: Br
Agent: CB1OB(C)OB(C)O1
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Solvent: CSC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A 25 mL round bottom flask with magnetic stirbar and toluene-filled Dean-Stark trap with reflux condenser and gas bubbler, was charged with (R)-α,α-diphenyl-2-pyrrolidinemethanol (1.13 g, 4.46 mmol) and trimethylboroxine (418 μL, 2.99 mmol) in toluene (11 mL) under N2. The mixture was stirred at ambient temperature for ~30 minutes and then heated to reflux for 2.75 hours. Upon cooling, this solution was added to a stirred ~-13° C. THF (185 mL) solution under N2 containing 2-bromo-1-[4-phenylmethoxy-3-[(methylsulfonyl)amino]phenyl]ethanone (14.25 g, 36 mmol). To this was added 5.2 mL of 10.1M BH3.Me2S (52 mmol) over ~5 minutes, keeping T≤-11.6° C. Upon completion of the reaction, HBr was bubbled through the solution until the pH was ~1 whereupon a solution of 50 mL MeOH in 100 mL methyl tert-butyl ether was carefully added. The mixture was washed with H2 O (4×100 mL=400 mL) (until the final wash had pH~4-5), diluted with EtOAc (50 mL), dried over Na2SO4. After solvent removal in vacuo, 12.84 g (90%) of crude title compound was obtained in 86% purity with an ee of 96.9%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[H-].[Na+].[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12]Br>CN(C)C=O>[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12][O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOCc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
In a 50 ml flask, under a nitrogen atmosphere, 2-(N,N-dimethylamino)ethanol (1.319 g, 4.92 mmol) was dissolved in N,N-dimethylformamide (16 ml). Sodium hydride (60%, 335 mg, 8.37 mmol) was added and the mixture was stirred at ambient temperature for about twenty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (1.319 g, 4.92 mmol) as a solution in N,N-dimethylformamide (3 ml). The resulting mixture was stirred at ambient temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and diethyl ether. The aqueous fraction was back extracted with diethyl ether. The organic fractions were combined, washed with brine (7×) and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was used without further purification.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-:21].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:15][CH2:16][CH2:17][C:18]([C:10]1[CH:9]=[CH:8][C:7]2[S:6][C:5]3[C:14](=[CH:1][C:2]([C:18](=[O:19])[CH2:17][CH2:16][Cl:21])=[CH:3][CH:4]=3)[CH2:13][C:12]=2[CH:11]=1)=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: [Cl-]
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(CCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCl)ccc1S2
Temperature: -20 °C

Procedure:
To a mixture of 99.2 g (0.5 mole) of thioxanthene, 158.5 g (1.25 mole) of 3-chloropropionyl chloride, and 3 liters of previously dried methylene chloride, chilled to -20° C., is slowly added 146.7 g (1.1 mole) of aluminum chloride over a 30 minute period while maintaining the temperature at below -10° C. Following the addition of aluminum chloride the reaction mixture is slowly permitted to rise to room temperature and then refluxed for an additional 4 hours. The reaction mixture is cooled to room temperature and decomposed by cautiously pouring into 2 liters of an ice-water mixture. The liquid layers are separated and the aqueous layer re-extracted with methylene chloride. The combined organic layers are evaporated to a small volume and cooled. The desired 2,7-bis(3-chloropropionyl)thioxanthene which separates on standing is recrystallized from acetone to yield the desired product having a m.p. of 175°-7° C.
Reaction SMILES: C(N1CCN([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=3)[N:10]=2)CC1)C.C([Mg]Br)C.[CH2:30]([O:32]CC)[CH3:31].[Cl-].[NH4+].[O:37]1CCCC1>>[O:32]1[CH2:30][CH2:31][O:25][CH:24]1[C:21]1[CH:20]=[CH:19][C:18]([C:11]2[NH:10][C:9](=[O:37])[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=2)=[CH:23][CH:22]=1
Reactant: CCN1CCN(c2nc(-c3ccc(C=O)cc3)cc3sccc23)CC1
Reactant: CCOCC
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: O=c1[nH]c(-c2ccc(C3OCCO3)cc2)cc2sccc12

Procedure:
To a solution of 4-(4-ethylpiperazin-1-yl)-6-(4-formylphenyl)thieno-[3,2-c]pyridine (0.20 g) in tetrahydrofuran (20 ml) was added 3M ethylmagnesium bromide/diethyl ether solution (0.5 ml), and the mixture was reacted at room temperature for 30 min. To the resulting reaction solution was added an aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried. The resulting product was filtered through NH silica gel and washed with ethyl acetate. The filtrate was concentrated, to give 0.17 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][CH2:29][CH2:30]Cl)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:27][CH2:26][O:28][CH2:29][CH3:30])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(-c2ccc(O)cc2)c1
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCCOc1ccc(-c2cc(C(=O)OC)ccc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
A solution of methyl 6-(benzyloxy)-4′-hydroxybiphenyl-3-carboxylate (5.0 g, 15.0 mmol), 2-chloroethyl ethyl ether (2.1 mL, 19.1 mmol) and potassium carbonate (3.1 g, 22.4 mmol) in N,N-dimethylformamide (50 mL) was stirred at 60° C. for 24 hr. 2-Chloroethyl ethyl ether (2.0 mL, 18.2 mmol) and potassium carbonate (3.0 g, 21.8 mmol) were further added to the reaction solution, and the mixture was stirred at 60° C. for 2 days. The reaction solution was diluted with ethyl acetate, washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:3) to give the title compound (6.0 g, yield 99%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4](Cl)[C:3]=1C(OCC)=O.[BrH:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([Br:25])[CH:3]=1
Reactant: CCOC(=O)c1c(Cl)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: Br
Solvent: CC(=O)O
Product: Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 5-amino-4-carboethoxy-3-chloro-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (3.3 g), hydrobromic acid (45%; 30 ml) and acetic acid (50 ml) was boiled under reflux for 18 h. The mixture was evaporated to low bulk and basified with sodium hydroxide solution (2M), and the product was filtered off, dried (2.9 g) and recrystallized from a mixture of ethanol and water to give 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (2.5 g), m.p. 132.5°-134° C. in the form of a colorless solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=[O:4])[CH:2]=[CH2:3].[CH2:11]1[S:15](=[O:17])(=[O:16])[O:14][CH2:13][CH2:12]1.C[C:19]([CH3:21])=[O:20]>>[CH3:9][N+:8]([CH3:10])([CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:13][CH2:12][CH2:11][S:15]([OH:14])(=[O:17])=[O:16].[CH3:7][N+:8]([CH2:21][C:19]([OH:14])=[O:20])([CH3:10])[CH3:9]
Reactant: O=S1(=O)CCCO1
Reactant: C=CC(=O)OCCN(C)C
Reactant: CC(C)=O
Product: C=CC(=O)OCC[N+](C)(C)CCCS(=O)(=O)O
Product: C[N+](C)(C)CC(=O)O
Temperature: 30 °C
Reaction time: 8 h

Procedure:
10 g of N,N-dimethylaminoethyl acrylate (CPS Chemical Company, Old Bridge, N.J.) is dissolved in approximately 150 mL of acetone in a 250 mL round bottom flask containing a magnetic stir bar. To this solution is added 8.35 g of propane sultone (Aldrich). The flask is equipped with a reflux condenser and heated at 30° C. with stirring overnight. In the morning, the resulting white solid is isolated by filtration, washed twice with diethyl ether, and dried under vacuum in a desiccator for 24 hours. A 13C NMR spectrum of the product is consistent with the structure of the sulfobetaine monomer.
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][C:12]([CH2:14][CH2:15][C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)=[CH:13][C:6]2=[N:5][C:4]=1[N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([O-])=[O:31])[CH2:25]1)=O.FC(F)(F)COP([CH2:45][C:46]([O:48][CH3:49])=[O:47])(=O)OCC(F)(F)F.C1CCN2C(=NCCC2)CC1.[Cl-].[Li+]>O1CCCC1>[CH:30]([CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:4]2[N:5]=[C:6]3[CH:13]=[C:12]([CH2:14][CH2:15][C:16]4[S:17][CH:18]=[C:19]([CH:21]([CH3:22])[CH3:23])[N:20]=4)[CH:11]=[CH:10][N:7]3[C:8](=[O:9])[C:3]=2/[CH:1]=[CH:45]/[C:46]([O:48][CH3:49])=[O:47])[CH2:25]1)=[O:31]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)c(N4CCCC(C(=O)[O-])C4)nc3c2)n1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(N2CCCC(C=O)C2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-{3-Formyl-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}-3-piperidylformate (94.0 mg, 0.207 mmol) and bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonoate (0.131 ml, 0.620 mmol) were dissolved in tetrahydrofuran (2 ml), added with DBU (0.085 ml, 0.620 mmol) and lithium chloride (26.3 mg, 0.620 mmol), and then the mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.[S:19](S([O-])=O)([O-:22])(=[O:21])=[O:20].[Na+:26].[Na+]>C(#N)C.O>[OH:16][CH:15]([C:14]1[CH:17]=[CH:18][C:11]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=2)=[CH:12][CH:13]=1)[S:19]([O-:22])(=[O:21])=[O:20].[Na+:26]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CSc1cccc(S)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CSc1cccc(Sc2ccc(C(O)S(=O)(=O)[O-])cc2)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
A solution of 3-(methylthio)benzenethiol as prepared in Preparation 8 (290 g, 1.856 mol) in acetonitrile (3 L) was sparged with nitrogen for 1 hour and then treated with 4-fluorobenzaldehyde (196 mL, 1.856 mol) followed by acetonitrile (150 mL, used as a line wash). The resulting solution was treated with 1,1′,3,3′-tetramethylguanidine (256 mL, 2.04 mol) followed by acetonitrile (150 mL used as a line wash) and heated to 50° C. under nitrogen for 16 hours. The resulting solution was allowed to cool to ambient temperature and diluted with ethyl acetate (3 L) and washed with hydrochloric acid (2M aqueous solution, 1.5 L) and sodium bicarbonate (1 M aqueous solution, 3 L) and brine (half saturated, 1.5 L). The resulting solution was concentrated by distillation at atmospheric pressure to a volume of 2 L and diluted with acetonitrile (3 L). the resulting solution was concentrated by distillation at atmospheric pressure to a volume of 2 L and diluted with acetonitrile (3 L) and concentrated by distillation at atmospheric pressure to a final volume of 3 L. The resulting solution was cooled to ambient temperature and treated with a solution of sodium metabisulfite (377 g, 1.982 mol) in water (3 L). After stirring at ambient temperature for 48 hours the resulting suspension was filtered and the solid collected was washed with water (2-fold 2.5 L) and acetonitrile (2-fold 2.5 L). The solid was suspended in acetonitrile (2 L) and stirred at ambient temperature for 18 hours after which time the suspension was filtered and the solid was washed with acetonitrile (2-fold 1 L) and dried in vacuo at 50° C. to give the title compound as a white solid, 55% yield, 368.7 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH:24]12[CH2:30][CH:27]([CH:28]=[CH:29]1)[C:26](=[O:31])[NH:25]2>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[C:26](=[O:31])[CH:27]4[CH2:30][CH:24]3[CH:29]=[CH:28]4)=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: O=C1NC2C=CC1C2
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)C5C=CC4C5)cc3)CC2)c(C)c1
Yield: 15.1 %

Procedure:
Using (4-bromophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (747 mg) described in Preparation Example 170 and 2-azabicyclo[2.2.1]hept-5-en-3-one (218 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (121 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH3:13])[CH:6]=[C:7]([I:10])[C:8]=1[OH:9].Cl.[NH2:16][OH:17].[OH-].[Na+].C(O)C>O>[OH2:9].[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=[N:16][OH:17])[CH2:12][CH3:13])[CH:6]=[C:7]([I:10])[C:8]=1[OH:9]
Reactant: CCC(=O)c1cc(I)c(O)c(CN)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(=NO)c1cc(I)c(O)c(CN)c1
Temperature: 25 °C
Yield: 180.5 %

Procedure:
A mixture of 2.0 g of 3'-aminomethyl-4'-hydroxy-5'-iodopropiophenone and 1.2 g of hydroxylamine hydrochloride is added to 10 ml of 4N sodium hydroxide solution and 3.5 ml of ethanol, and then the mixture is refluxed with heating for 45 minutes. After cooling to room temperature, 15 ml of water is added to the reaction mixture. After filtration of the mixture, the filtrate is stirred under ice cooling and adjusted to pH 7.5 with concentrated hydrochloric acid. The white fine powder precipitated is collected by filtration, washed with cold water and dried to give 2.0 g of 3'-aminomethyl -4'-hydroxy-5'-iodopropiophenone oxime monohydrate, melting at 167°-168° C. with decomposition.
Reaction SMILES: CS(O[CH:6]([CH3:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH:6]([CH3:16])[CH2:7][NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 85 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)propan-2-yl methanesulfonate (10.0 g, 39.5 mmol) in DMF (100 mL) at RT was added NaN3 (7.7 g, 118.5 mmol). The reaction mixture was stirred at 85° C. for 24 h, cooled to RT, diluted with cold water (300 mL) and extracted with diethyl ether (3×300 mL). The combined organic layers were washed with saturated NaHCO3 (2×200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-azidopropylcarbamate (7.0 g, 88.6%) as a light yellow oil. 1HNMR (CDCl3): δ3.6 (m, 1H, CH), 3.25 (m, 1H, CH2), 2.9 (m, 1H, CH2), 1.49 (s, 9H, CH3 1.2 (d, 3H, CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH3:19]>CN(C)C=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH2:17][CH2:18][CH3:19])=[CH:3][C:2]=1[F:1]
Reactant: CCCI
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a solution of 3,4-difluoro-phenol (20 g, 154 mmol) in N,N-dimethylformamide (70 mL) was added potassium carbonate (30 g, 217 mmol) and iodopropane (50 g, 293 mmol, Aldrich). The reaction mixture was heated at refluxing for 48 h. The crude was cooled to room temperature and filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:8) to give 1,2-difluoro-4-propoxy-benzene as a colorless oil (Yield 17 g, 100%).
Reaction SMILES: C(S[C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:28][C@H:29]([CH3:32])[CH2:30][OH:31])[N:10]=1)C1C=CC=CC=1.Cl[C:34]1[C:39]([C:40](OO)=O)=[CH:38][CH:37]=[CH:36][CH:35]=1.[S:44]([O-:48])([O-:47])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:40]([S:44]([C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[C:11]([NH:28][C@H:29]([CH3:32])[CH2:30][OH:31])[N:10]=1)(=[O:48])=[O:47])[C:39]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(OO)c1ccccc1Cl
Reactant: O=S([O-])([O-])=S
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(SCc2ccccc2)n1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(S(=O)(=O)Cc2ccccc2)n1

Procedure:
To a solution of the product of step ii) (6.8 g) in DCM (300 ml) was added nm-chloroperbenzoic acid (8 g) at ambient temperature with stirring. After 6 h a concentrated solution of sodium thiosulphate (50 ml) was added and the organic phase collected. The organic phase was then washed with saturated sodium bicarbonate solution (×2) followed by brine. The organic phase was dried (MgSO4) and the solvent evaporated to leave the subtitle compound as a colourless foam. Yield: 7.0 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[C:14]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C#N)ccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a stirring suspension of 11A (0.34 g, 1.86 mmol) and K2CO3 (0.283 g, 2.05 mmol) in DMF (3 mL) was added iodomethane (0.127 mL, 2.05 mmol). After the addition, the reaction mixture was stirred at rt for 16 h, then partitioned between H2O and CH2Cl2. The separated CH2Cl2 layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 5% to 40% EtOAc/hexane to yield the title compound (0.22 g) as a solid.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH:28]=1)=[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[O:19][N:20]=2.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:18]2[O:19][N:20]=[C:16]3[CH:15]=[CH:14][C:13]([CH:34]([C:33]4[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=4)[OH:35])=[CH:28][C:17]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
nBuLi 1.6M in hexane (0.112 mol) was added dropwise at −70° C. under N2 flow to a mixture of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.097 mol) in THF (300 ml). The mixture was stirred at −70° C. for 15 min. A mixture of 4-fluoro-benzaldehyde (0.112 mol) in THF (100 ml) was added dropwise. The mixture was stirred at −70° C. for 30 min, then hydrolized and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was taken up in diethyl ether and DIPE. The precipitate was filtered off, washed and dried, yielding 9.2 g (26.8%) of 3-(3-chlorophenyl)-α-(4-fluorophenyl)-2,1-benzisoxazole-5-methanol (intermediate 1), mp. 171° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: c1cn(-c2nccc(N3CCCCC3CCNCc3ccc4c(c3)OCO4)n2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCC1CCCCN1c1ccnc(-n2ccnc2)n1)Cc1ccc2c(c1)OCO2
Reaction time: 16 h
Yield: 48.2 %

Procedure:
Alternatively, to THF (3 mL) was added N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (8 mg, 0.03 mmol), Hünig's base (8 mg, 0.06 mmol), and methanesulfonyl chloride (4.5 mg, 0.04 mmol). After stirring for 16 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH. 19/1) to give 7 mg (51%) of N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-N-(methylsulfonyl)piperidine-2-ethanamine (the compound of formula (Iff)); 1H NMR (CDCl3) δ 8.10 (s, 1), 7.78 (d, 1), 7.13 (s, 1), 6.82 (s, 1), 6.72 (s, 2), 6.30 (d, 1), 5.94 (s, 2), 4.23 (m, 3), 3.20 (m, 2), 2.80 (s, 3), 1.14 (m); MS: 485.7 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([Cl:8])=[O:7])[CH:3]=[N:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>O1CCOCC1>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:4]3[CH:3]=[N:2][O:1][CH:5]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)c1cnoc1
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)c4cnoc4)CC3)nc(N)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of isoxazole-4-carbonyl chloride (1.06 g., 8.08 mmole) in dioxane (8 ml.) was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.34 g., 8.08 mmole) in dioxane (200 ml.). The mixture was stirred at room temperature for 20 hours. Filtration gave the title compound, which, after recrystallization from methanol, had a m.p. of 225°-260° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2)[OH:29]
Reactant: COc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: CC(C=O)c1ccc(Cl)cc1Cl
Product: COc1ccc(-n2ncc3cc(C(O)C(C)c4ccc(Cl)cc4Cl)ccc32)cc1

Procedure:
In analogy to Example 186, 5-bromo-1-(4-methoxy-phenyl)-1H-indazole was reacted with 2-(2,4-dichloro-phenyl)-propionaldehyde to give 2-(2,4-dichloro-phenyl)-1-[1-(4-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-ol which was oxidized to 2-(2,4-dichloro-phenyl)-1-[1-(4-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-one and converted further to the title compound. Off-white foam. MS (m/e)=495.1 [M+H+].