Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[OH:6][CH:7]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9][CH2:8]1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O.CCOCC>[Si:16]([O:6][CH:7]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9][CH2:8]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC1CCC(O)CCC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1CCC(O[Si](C)(C)C(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.9 %

Procedure:
Imidazole (2.45 g, 31.6 mmol) is added to a solution of (±) 5-hydroxy-2-methylcycloheptanone (2.03 g, 14.3 mmol) in dimethylformamide (35 ml) at 0° C. followed by t-butyldimethylsilyl chloride (2.38 g, 15.7 mmol) under nitrogen. The mixture is stirred at room temperature for 17 hours and then diluted with ether (100 ml) and washed three times with water. After drying (Na2SO4), the ether is removed in vacuo to afford (±) 5-t-butyldimethylsilyloxy-2-methylcycloheptanone (3.7 g, 100%). IR (neat)μ: 5.88 (C=O); NMR (CDCl3)δ: 0.1 (s, 6H, Si(CH3)0.93 [s, 9H, Si(CH3)2 --C(CH3)3 ], 1.1 (d, J=2--CH3), 3.6-4.2 (m, 1H, 5-H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([NH2:25])=O.C[O-].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1Cc2c(C(N)=O)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 0.17 h

Procedure:
22.8 g Ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate (V)were suspended under stirring and argon atmosphere in 91.2 ml 1,4-dioxane. 14.1 ml Formamide and 13.9 ml sodium methanolate were successively added to yield a clear light-orange solution, which turned to a white suspension after 10 minutes. This suspension was stirred two hours at 30° C. 200 ml deionized water were added in one portion and 1,4-dioxane was distilled off at 40° C. under reduced pressure. The remaining white suspension was stirred two hours at 0° C. and filtered. The precipitate (7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide (VI)) was washed with 50 ml deionized water three times and dried under reduced pressure for 18 hours at 80° C. Crude product: 19.43 g as a white powder. m.p.>250° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[S:26][C:27]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=4[N:29]=3)=[CH:23][CH:24]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(Br)c([N+](=O)[O-])c4)cc3)sc2c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 4-bromo-3-nitrobenzoic acid (0.24 g, 0.976 mmol) and thionyl chloride (5 ml) was heated under reflux for 3 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride, 2-(4-aminophenyl)-6-methoxybenzothiazole (0.25 g, 0.976 mmol) and Hunig's base (0.151 g, 1.17 mmol) in dry THF (10 ml) to give the title compound (0.368 g, 78%) as small yellow crystals after work-up and recrystallisation from DMF.
Reaction SMILES: [Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11](Cl)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=O.C([SH:21])C.C(=O)([O-])[O-].[K+].[K+].C(O[CH2:31][CH3:32])C>CN(C=O)C>[Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([CH2:31][CH3:32])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[S:21]
Reactant: CCOC(=O)c1ccc(Cl)c(OCCOC)c1Cl
Reactant: CCS
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=S)c1ccc(CC)c(OCCOC)c1Cl

Procedure:
A solution of 10 g (34 mmole) ethyl 2,4-dichloro-3-(2-methoxyethoxy)benzoate, 10 g (4 eq) ethanethiol and 10 g (2 eq) potassium carbonate in 100 ml DMF was heated (approximately 100° C.) for 2 hours, then let cool overnight. Added 400 ml diethyl ether and washed with 100 ml water (two times), 100 ml 10% HCl and 100 ml 10% NaOH. Dried (MgSO4) and reduced under vacuum. Yield 10 g (31 mmole) of an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7](=O)[C:8](OC)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[F:14][C:15]1[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[N:25][CH:26]=[C:21]2[C:20]([C:27](=[NH:30])[NH:28][NH2:29])=[N:19]1>C(O)C>[F:14][C:15]1[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[N:25][CH:26]=[C:21]2[C:20]([C:27]2[N:28]=[N:29][C:7]([C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:30]=2)=[N:19]1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncncc23)nc1O
Yield: 21.5 %

Procedure:
584 mg (3.103 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate were initially charged in 12 ml of ethanol and heated to reflux. Subsequently, 590 mg (2.069 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 12 ml of ethanol were added and the mixture was boiled under reflux overnight. After cooling, the mixture was filtered, the filtercake was washed with a little ethanol and the filtrate was concentrated. The residue was stirred with 10 ml of acetonitrile. 188 mg of the target compound were obtained (purity 93%; 20% of theory).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26](O)=[O:27])[CH:20]=4)[NH:15]3)[CH:10]=[C:11]([F:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29]1([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:31][CH2:30]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26]([NH:35][S:32]([CH:29]5[CH2:31][CH2:30]5)(=[O:34])=[O:33])=[O:27])[CH:20]=4)[NH:15]3)[CH:10]=[C:11]([F:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(C2CCCCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cc(F)cc(C2CCCCC2)c1
Temperature: 65 °C
Yield: 20.6 %

Procedure:
A mixture of 2-(3-cyclohexyl-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (60 mg, 0.16 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (45 mg, 0.24 mmol), 4-dimethylaminopyridine (29 mg, 0.24 mmol), cyclopropane sulfonamide (58 mg, 0.48 mmol) in dichloromethane (10 mL) was heated at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(3-cyclohexyl-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (16 mg, 20%) as a light yellow solid: LC/MS m/e calcd for C27H33FN2O3S (M+H)+: 485.6, observed: 485.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=2)[C:9](=[O:11])[CH3:10])[CH:2]=1.[CH3:33][I:34]>>[I-:34].[C:9]([N:8]([CH2:7][C:3]1[CH:2]=[N+:1]([CH3:33])[CH:6]=[CH:5][CH:4]=1)[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:17]=1)(=[O:11])[CH3:10]
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(N(Cc2cccnc2)C(C)=O)cc1
Product: CCCCCCCCCCCCCCOc1ccc(N(Cc2ccc[n+](C)c2)C(C)=O)cc1
Product: [I-]
Temperature: 95 °C
Yield: 102.2 %

Procedure:
A mixture of 2.3 g of product from Example 142 and 37.21 g of methyl iodide is heated, in a sealed tube, at 95° C. for 13 hours. The reaction is concentrated in vacuo to give 3.11 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[C:6]([O:15][CH3:16])[CH:5]=1)(=[NH:3])[NH2:2].CN(C)C=O.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[ClH:24].[C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([Cl:24])=[O:11])=[C:6]([O:15][CH3:16])[CH:5]=1)(=[NH:3])[NH2:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=N)N)ccc1OCC(=O)O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1cc(C(=N)N)ccc1OCC(=O)Cl
Product: Cl
Reaction time: 2 h

Procedure:
A suspension of 6.15 g of 4-amidino-2-methoxy-phenoxyacetic acid in 60 ml of benzene and 10 ml of thionyl chloride was combined with 0.2 ml of dimethylformamide and heated. After 2 hours at 65° C, a well stirrable, colorless suspension had formed. The precipitate was isolated, washed with benzene and di-isopropylether and dried. 6.5 g of 4-amidino-2-methoxy-phenoxyacetyl chloride-hydrochloride melting at 155° to 156° C (decomposition) were obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14](=[O:28])[N:15]([CH:25]([CH3:27])[CH3:26])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].N1C=CC=CC=1.Cl>ClCCl>[Cl:12][C:13]1[C:14](=[O:28])[N:15]([CH:25]([CH3:26])[CH3:27])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH:21]([OH:24])[CH2:22][O:23][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC(C)n1ncc(NCC(O)CO)c(Cl)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)CNc2cnn(C(C)C)c(=O)c2Cl)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1.60 g of p-toluenesulfonyl chloride was added to a mixture comprising 2.09 g of 4-chloro-5-(2,3-dihydroxypropylamino)-2-i-propyl-3(2H)pyridazinone prepared in Reference Example 6, 12 ml of pyridine and 20 ml of dichloromethane, under cooling with ice. The mixture was stirred for 6 hours, and then left to stand for 2 days in an ice chamber. The reaction mixture was acidified to a pH of about 2 by adding cooled dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a colorless oily substance. The oily substance was purified by silica gel column chromatography, and 2.45 g of the above identified compound was obtained as a colorless viscous oily substance from the eluate with choroform-methanol (25:1, v/v).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.CC(O)=O>O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Temperature: 100 °C
Yield: 76.2 %

Procedure:
To a mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (887.5 mg, 2.067 mmol) and K3PO4 (1494 mg, 7.038 mmol), 1,4-dioxane (10.0 mL) was added, followed by water (10.0 mL). The mixture was heated at 100° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL). AcOH (1313 mg, 21.86 mmol) was added to adjust the pH to 5. The mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-15% MeOH in DCM) to give the sub-title compound as a yellow solid (632.0 mg, 76%). LCMS calc. for C18H14BrN2O4(M+H)+: m/z=401.0. found 401.0.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)CC1C=CC=CC=1)[C:2]1C=CC=CC=1.N#N.[H][H].C(OC(=O)C)(=[O:42])C.C(N(CC)CC)C>[Pd].CC(C)=O>[CH3:2][C:1]([NH:8][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)=[O:42]
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Yield: 75.6 %

Procedure:
(S)-5-((dibenzylamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.95 g, 2 mmol) and 0.1 g 10 wt % Pd—C were added to 20 mL acetone and the air was replaced with N2. The reaction went on under 5 Mpa hydrogen at room temperature for 5 hours. After filtered, acetic anhydrid (0.24 g, 2.4 mmol) and triethylamine (2.0 g, 20 mmol) were added and reacted for 2 hours at room temperature. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, most part of the solvent was evaporated, frozen crystallized and filtered to provide the crude product. The crude product was recrystallized with ethyl acetate to provide 0.51 g of linezolid in 75% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][NH:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:30]Br>C(Cl)Cl.O>[Br:30][C:6]1[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])=[N:8][CH:9]=[N:10][C:5]=1[NH:4][CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1]
Reactant: BrBr
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(NCC(C)(C)C)ncn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(NCC(C)(C)C)c2Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of 3-{6-[(2,2-dimethyl-propyl)-amino]-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (0.45 g, 1.37 mmol) in methylene chloride (10 mL), was added sat. aq. sodium bicarbonate (2 mL) and bromine (0.07 mL, 1.37 mmol). The resulting mixture was stirred at room temperature for 18 hours, and the reaction was then diluted with water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography using 2% methanol in DCM as eluent to afford the product (314 mg, yield 56%). MS (m/z): 406 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1OC)[CH2:6][CH2:7][OH:8].[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18]N)[CH3:15].[CH2:23]([OH:31])[CH2:24][C:25]1[CH:30]=CC=CC=1>>[C:17]([O:20][CH2:21][CH3:22])(=[O:16])[CH2:18][C:3]([CH3:11])=[O:2].[CH2:14]([O:16][C:23](=[O:31])[CH2:24][C:25]1([CH3:30])[C:4]2[C:5](=[CH:9][CH:10]=[CH:11][CH:3]=2)[CH2:6][CH2:7][O:8]1)[CH3:15]
Reactant: OCCc1ccccc1
Reactant: CCOC(CN)OCC
Reactant: COc1ccc(CCO)cc1OC
Product: CCOC(=O)CC(C)=O
Product: CCOC(=O)CC1(C)OCCc2ccccc21

Procedure:
In the same manner but replacing 3,4-dimethoxyphenethyl alcohol and aminoacetaldehyde diethyl acetal with equivalent amounts of phenethyl alcohol, Khafagy and Lambooy, cited above, and ethyl acetoacetate, respectively, 1-methyl-1-isochromanacetic acid ethyl ester, νmaxCHCl3 1720 cm-1, nmr (CDCl3) δ1.5, 2.85, is obtained. Likewise, replacement with equivalent amounts of 1-naphthaleneethanol, M. Mousseron and Nguyen-Phuoc-Du. Bull. Soc. Chim. Fr., 91 (1948), and ethyl acetoacetate, gives 1,2-dihydro-4-methyl-4H-naphtho[2,1-c]-pyran-4-acetic acid ethyl ester, νmaxCHCl3 1720 cm-1, nmr (CDCl3) δ1.5. Hydrogen bromide is a preferred acid catalyst for these latter two preparations.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[CH:30][N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=2)=[CH:24][CH:23]=1.[C:41]([O:45][C:46]([N:48]1[CH2:52][CH2:51][CH2:50][CH:49]1[C:53]1[NH:54][C:55]([C:58]2[CH:63]=[CH:62][C:61](B3OC(C)(C)C(C)(C)O3)=[CH:60][CH:59]=2)=[CH:56][N:57]=1)=[O:47])([CH3:44])([CH3:43])[CH3:42].C(COC)OC>C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:41]([O:45][C:46]([N:48]1[CH2:52][CH2:51][CH2:50][CH:49]1[C:53]1[NH:54][C:55]([C:58]2[CH:63]=[CH:62][C:61]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[N:10][CH:9]=4)=[CH:4][CH:3]=3)=[CH:60][CH:59]=2)=[CH:56][N:57]=1)=[O:47])([CH3:44])([CH3:42])[CH3:43].[C:41]([O:45][C:46]([N:48]1[CH2:52][CH2:51][CH2:50][CH:49]1[C:53]1[NH:54][C:55]([C:58]2[CH:63]=[CH:62][C:61]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[CH:30][N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=4)=[CH:24][CH:23]=3)=[CH:60][CH:59]=2)=[CH:56][N:57]=1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: C[Si](C)(C)CCOCn1cncc1-c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(Br)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cn(COCC[Si](C)(C)C)cn4)cc3)cc2)[nH]1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cncn4COCC[Si](C)(C)C)cc3)cc2)[nH]1
Temperature: 80 °C

Procedure:
A mixture of 1:1 mixture of 5-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole and 4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (0.145 g), 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.150 g, prepared according to WO2008021927 A2) and Pd(PPh3)4 (0.020 g) in aq. K2CO3 solution (0.51 mL)/dimethoxyethane (1.5 mL) was heated at 80° C. for 18 hours. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) to give a 1:1 mixture 2-(5-{4′-[3-(2-Trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-(5-{4′-[1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.0998 g): LCMS-ESI+: calc'd for C33H44N5O3Si: 586.82 (M+H+). Found: 586.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[Cl:14][C:15]1[CH:27]=[C:26]([O:28][CH2:29][CH:30]=[C:31]([Cl:33])[Cl:32])[CH:25]=[C:24]([Cl:34])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:14][C:15]1[CH:27]=[C:26]([O:28][CH2:29][CH:30]=[C:31]([Cl:33])[Cl:32])[CH:25]=[C:24]([Cl:34])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][N:23]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1
Reactant: NOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc(C=NOCCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of 0.14 g of 4-(trifluoromethyl)benzaldehyde and 10 ml of pyridine was added 0.30 g of O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.37 g (yield, 95.6%) of 4-(trifluoromethyl)benzaldehyde O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)oxime, nD21.0 1.5387.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[C:27]([O:28][CH3:29])=[CH:26][C:11]([CH2:12][CH2:13][NH:14][C:15](=O)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][C:9]=1[OH:30]>C(Cl)(Cl)Cl>[ClH:3].[CH3:29][O:28][C:27]1[CH:26]=[C:11]2[C:10](=[C:9]([OH:30])[C:8]=1[O:7][CH3:6])[C:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[N:14][CH2:13][CH2:12]2
Reactant: COc1ccc(CC(=O)NCCc2cc(O)c(OC)c(OC)c2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC2=NCCc3cc(OC)c(OC)c(O)c32)cc1
Product: Cl
Temperature: 55 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
Phosphoryl chloride (5.42 ml, 58.1 mmol) was added to a chloroform (100 ml) solution of N-(4,5-dimethoxy-3-hydroxyphenethyl)-4-methoxyphenylacetamide (6.71 g, 19.4 mmol) at room temperature, and the mixture was stirred under a nitrogen atmosphere at 55° C. for 16 hours. The solvent and excess phosphoryl chloride were removed under reduced pressure, and the resultant residue was recrystallized from methanol-ether to give 6.05 g (yield: 86%) of the captioned compound as colorless needles.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>C(Cl)Cl>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Temperature: 0 °C

Procedure:
trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol) was dissolved in CH2Cl2 (1.5 ml) and the solution was cooled to 0° C. Et3N (139 mg, 1.37 mmol) and methanesulfonyl chloride (78 mg, 0.68 mmol) were added and the reaction mixture was stirred over night at room temperature. H2O was added and the product was extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent was evaporated. Purification by flash chromatography over silica gel (CH2Cl2/MeOH/25% NH3 aq 140:10:1) yielded the title compound as a white solid (78 mg, 56%), MS (ISP) m/z=407.2 [(M+H)+].