Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][N:20]([CH:23]([C:25]([O:27]CC)=[O:26])[CH3:24])[CH2:19][CH2:18][N:17]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:16][CH2:15][N:14]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][N:20]([CH:23]([C:25]([OH:27])=[O:26])[CH3:24])[CH2:19][CH2:18][N:17]([C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH2:16][CH2:15][N:14]([C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)N1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C(=O)O)N1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
33.7 g (50 mmol) of 1,4,7-tris-(benzyloxycarbonyl)-10-(1-ethoxycarbonylethyl)-1,4,7,10-tetrazacyclododecane is dissolved [in] 300 ml of dioxane and mixed with 140 ml of 5% aqueous NaOH solution and stirred for 24 hours at room temperature. After neutralization with concentrated HCl, it is evaporated to the dry state. The residue is taken up in 250 ml of ethyl acetate and extracted twice with 250 ml each of 1N HCL solution. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]([O:18][C:19](C)(C)C)=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC.O>CO.CCCCCC.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CC(C)(C)OC(=O)COCCCCCCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)COCCCCCCCCCCCCBr
Yield: 76.9 %

Procedure:
To 1.3 mmol of 3 in methanol (20 ml) was added a catalytic amount of p-toluenesulfonic acid and the solution was stirred under reflux for 5 hr. Ether (20 ml) and water (20 ml) were added, and the organic layer washed successively with water and brine, dried (MgSO4), and evaporated under reduced pressure. The product 5 (1 mmol, 77%) was isolated as an oil by column chromatography (hexane/ethyl acetate 9:1−>3:1). TLC (hexane/ethyl acetate 3:1) Rf=0.6. 1H-NMR 1.2-1.65 (m, 20H, CH2), 3.41 (t, 2H, C(15)H2), 3.50 (t, 2H, C(4)H2), 3.72 (s, 3H, —COO—CH3), 3.94 (s, 3H, C(2)H2).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:7]=1[Br:15])(=[O:3])[CH3:2].N1CCOCC1>CO.[Pt]=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[Br:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc([N+](=O)[O-])c1Br
Agent: O=[Pt]
Solvent: CO
Solvent: C1COCCN1
Product: CC(=O)OCc1cccc(N)c1Br
Yield: 115.5 %

Procedure:
A mixture of 5.7 grams (0.022 mole) of 2-bromo-3-nitrophenylmethyl acetate, 0.1 gram of platinum oxide and 2.0 ml of morpholine in 200 ml of methanol was hydrogenated using a Parr hydrogenator. The hydrogenation required 2.25 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give 6.2 grams of 3-amino-2-bromophenylmethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH2:37])=[O:36])(OC(C)(C)C)=O.[ClH:41].O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:41].[NH:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH2:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CCCN1

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-L-prolineamide (1,250 mg, 2.33 mmols) was dissolved in 10 ml of dichloromethane, and 5 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at room temperature for 1 hour. One-hundred milliliters of diethyl ether were added thereto, and the mixture was filtered. The resulting powder was purified through medium-pressure liquid chromatography (ODS, mixture of water and acetonitrile at a ratio of 70:30). The product was recrystallized three times with a mixture of chloroform and ethyl acetate at a ratio by volume of 1:10 to produce 465 mg (0.980 mmols) of the final product in a yield of 42%.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[Cl:19])[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.Br>C(O)(=O)CC>[Cl:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][NH:10][CH2:11]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cccc(Cl)c3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Clc1cccc2c1CNC2

Procedure:
1H-NMR (CDCl3) δ: 7.33 and 7.76 (each 2H, ABq, J=10Hz, tosyl group ARM-H), 7.08-7.25 (3H, m, isoindoline ARM-H), 4.58 (4H, s, 2 x --CH2N--), 2.40 (3H, s, CH3) (3) The procedure of Reference Example 6-(3) was followed using 12.32 g of 2-(p-toluenesulfonyl)-4-chloroisoindoline, 10 g of phenol, 150 ml of 48% hydrobromic acid, and 20 ml of propionic acid. Through purification of the crude product by vacuum distillation 3.1 g of 4-chloroisoindoline was produced.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][C:3]1=[O:12]>C(O)(=O)C.[Zn]>[Br:11][C:8]1[CH:9]=[C:10]2[CH2:2][C:3](=[O:12])[NH:4][C:5]2=[N:6][CH:7]=1
Reactant: O=C1Nc2ncc(Br)cc2C1(Br)Br
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(Br)cnc2N1
Yield: 31.3 %

Procedure:
To a stirred solution of 3,3,5-tribromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (2.0 g, 5.4 mmole) in acetic acid (50 mL) at RT was added Zn metal. The reaction became exothermic and was cooled by the use of an ice bath during the initial 30 minutes. After 5 hr the reaction was filtered through celite®, and the filter pad was washed with EtOAc. The filtrate was concentrated under vacuum and neutralized with saturated aqueous NaHCO3 solution. The neutralized aqueous filtrate was then extracted with EtOAc (2×200 mL), and the combined organic extracts were dried over Na2SO4 and concentrated to a solid. The solid was washed with hexanes and dried under high vacuum to give the title compound (0.36 g, 32%): MS (ES) m/e 215 (M+H)+. This was used without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][C:16]1[C:21]([CH2:22]Br)=[C:20]([F:24])[CH:19]=[CH:18][C:17]=1[F:25]>CN(C)C=O>[F:24][C:20]1[CH:19]=[CH:18][C:17]([F:25])=[C:16]2[C:21]=1[CH2:22][N:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH2:15]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Fc1ccc(F)c(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3c(F)ccc(F)c3C2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A solution of 4-toluenesulphonamide (2.44 g, 14.28 mmol) in N,N-dimethylformamide (10 ml) was added dropwise to a vigourously stirred suspension of sodium hydride (1.2 g, 60 wt % in mineral oil, 30.0 mmol) in anhydrous N,N-dimethylformamide (60 ml). The mixture was stirred at room temperature for 1 hour, at 110° C. for 1 hour and was then cooled to 60° C. and a solution of 2,3-bis-bromomethyl-1,4-difluorobenzene (4.28 g, 14.28 mmol) in N,N-dimethylformamide (30 ml) was added dropwise. The mixture was stirred at 60° C. for 1 hour and then at room temperature for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and 1M hydrochloric acid. The organic layer was separated, washed with 5% aqueous potassium carbonate solution, the organics were separated and the solvent removed in vacuo. The residue was rinsed with diethyl ether, filtered and the solids sucked dry under reduced pressure to afford 4,7-difluoro-2-(toluene-4-sulfonyl)isoindoline (2.46 g, 56%) as a pale tan solid. 1H NMR (DMSO-d6) 7.82 (2H, d), 7.43 (2H, d), 7.15 (2H, dd), 4.66 (4H, s), 2.36 (3H, s). MS: [M+H]+ 310.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[CH:9][CH:10]=3)[N:5]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)[nH]c1cc(F)ccc12
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c3ccc(F)cc3n(CC3CO3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a stirred solution of 2,7-difluoro-9H-carbazole (0.400 g, 2.0 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.156 g, 2.4 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.326 mL, 3.9 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.47 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.93 (dd, 2H, J=8.4, 5.4 Hz), 7.14 (dd, 2H, J=9.9, 2.4 Hz), 6.99 (td, 2H, J=9.0, 2.4 Hz), 4.60 (dd, 1H, J=15.9, 2.7 Hz), 4.25 (dd, 1H, J=15.9, 5.1 Hz), 3.35 (m, 1H), 2.86 (t, 1H, J=4.5 Hz), 2.57 (dd, 1H, J=4.8, 2.7 Hz).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([CH2:18][N:19]([CH3:31])[CH2:20][CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)=[CH:16][N:15](C3CCCCO3)[N:14]=2)=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]>Cl>[CH3:31][N:19]([CH2:18][C:17]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:12][CH:11]=2)=[N:14][NH:15][CH:16]=1)[CH2:20][CH2:21][NH:22][CH3:23]
Reactant: C=C(C)C(=O)Nc1ccc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: C=C(C)C(=O)Nc1ccc(-c2n[nH]cc2CN(C)CCNC)cc1
Yield: 81.4 %

Procedure:
A solution of tert-butyl (2-(((3-(4-methacrylamidophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (0.08 g, 0.00015 mol) in methanolic HCl (2 mL, 4M solution) was stirred for 1 hr at room temperature. The reaction mixture was concentrated under vacuum and purified by prep HPLC using water:ACN as mobile phase (containing 0.1% TFA as modifier) to obtain N-(4-(4-((methyl(2-(methylamino)ethyl)amino)methyl)-1H-pyrazol-3-yl)phenyl)methacrylamide (0.040 g, yield: 80%). 1H NMR (400 MHz, CD3OD): δ 7.98 (s, 1H), 7.84-7.81 (m, 2H), 7.59-7.56 (d, 2H), 5.85 (s, 1H) 5.58 (s, 1H), 5.52 (s, 1H), 4.51 (s, 2H), 3.37 (s), 2.72 (s, 3H), 2.70 (s, 3H), 2.06 (s, 3H) ppm; LCMS (ESI): RT=1.63 min, m/z=328.3 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([S:21]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:12][N:11]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(COCC2CC2)cn1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: O=S(=O)(Nc1ccc(COCC2CC2)cn1)c1cccc(Cl)c1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.06 g) and 3-chloro-benzenesulfonyl chloride (0.078 g) as an amorphous off-white solid (0.059 g). MS (ESI−): 351.1 ([M−H]−)
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:23])[C:12]([CH3:22])(SCC2CCCNC2)[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:23])[CH:12]([CH3:13])[CH3:22])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(SCC1CCCNC1)C(=O)Nc1cc(C(C)(C)C)on1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cc(C(C)(C)C)on1

Procedure:
A solution of 175 mg (0.52 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(piperidin-3-ylmethylsulfanyl)-propionamide 0.18 mL (1.04 mmol) of N,N-diisopropylethylamine and acetic anhydride (1.5 mL) were heated for 0.5 h to 100° C. within a microwave (CEM discover). The solvent was removed under reduced pressure. The residue was dissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The organic phase was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford 183 mg of 241-acetyl-piperidin-3-ylmethylsulfanyl)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[CH:7][CH:6]=1.[CH3:20]OC(=O)C>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=[CH:20]2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ccccc2N)cc1
Reactant: COC(C)=O
Product: COC(=O)Cc1ccc(-n2cnc3ccccc32)cc1

Procedure:
is obtained analogously to the method as described in Step 1.2 but using [4-(2-amino-phenylamino)-phenyl]-acetic acid methyl ester instead of 4-(3-amino-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester as a starting material. ES-MS: 267.1 [M+H]+; single peak at tR=3.00 min (System 1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[Cl:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(c4ccc(Cl)cc4)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N2CCN(c3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
A mixture of 6-chloro-2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.13 g, 0.25 mmol), lithium hydroxide hydrate (104 mg, 2.5 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 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 6-chloro-2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 80%) as a white solid: LC/MS m/e calcd for C28H29Cl2N3O2 M+: 510.5, observed: 510.0;
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[C:11]([CH2:12][OH:13])=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][N:8]=1)[CH2:4][CH2:5][CH3:6].Br[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>C1COCC1>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([O:13][CH2:12][C:11]2[C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][O:9][C:10]=2/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:24][CH:25]=1
Reactant: CCCCc1noc(/C=C/c2ccccc2)c1CO
Reactant: COC(=O)c1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1noc(/C=C/c2ccccc2)c1COc1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a suspension of sodium hydride (170 mg, 4.24 mmol) in THF (7 mL) at 0° C. was added a solution of [3-butyl-5([E]-styryl)-isoxazol-4-yl]-methanol (993 mg, 3.86 mmol) in THF (17 mL) and the mixture was stirred for 30 min at room temperature. The reaction mixture was cooled to 5° C. and a solution of methyl 6-bromonicotinate (1.0 g, 4.6 mmol) in THF (17 mL) was added dropwise. The mixture was stirred at room temperature for 2 days, poured over ice and stirred for 5 min. The mixture was extracted twice with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to a yellow oily solid. The crude material was purified by flash chromatography (silica gel, heptane:ethyl acetate 1:0 to 3:2) to afford the title compound (1.17 g, 77%) as an orange semisolid. MS: m/e=393.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:24])([F:23])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:13]2=[O:22])=[CH:8][CH:7]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](F)[N:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:32][C:33]1[N:34]=[C:35]([N:19]2[CH2:18][CH2:17][C:14]3([C:13](=[O:22])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][C:4]([F:3])([F:23])[F:24])=[CH:7][CH:8]=4)[CH2:16][CH2:15]3)[CH2:21][CH2:20]2)[CH:36]=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Fc1cccc(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1cccc(OCc3ccccc3)n1)CC2
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a suspension of NaH (9 mg, 0.24 mmol) in DMF (1 mL) at 0° C. was added a solution of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C, 50 mg, 0.16 mmol) and stirring was continued for 30 mins. A solution of 2-benzyloxy-6-fluoro-pyridine (39 mg, 0.19 mmol) in DMF (0.5 mL) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with brine, 1N HCl and again with brine. The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure to yield the title compound as a light yellow solid (58 mg, 73%). MS (ESI): 498.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27]OS(C)(=O)=O)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:13])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(=O)n(CC3CN(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 100 °C
Yield: 44 %

Procedure:
A suspension of 7-methoxy-2(1H)-quinolinone (405 mg; commercial) in DMF (10 mL) was treated with NaH (111 mg; 50% dispersion in oil). The mixture was stirred at rt for 30 min before the addition of a solution of 3-[[(methylsulfonyl)oxy]methyl]-1-azetidinecarboxylic acid tert-butyl ester (674 mg; prepared according to WO 02/066470) in DMF (2 mL). The mixture was heated at 100° C. overnight. The reaction mixture was partitioned between EA and water. The org. phase was dried over MgSO4, concentrated under reduced pressure and purified by CC (Hept/EA 2:1 to 0:1). The second eluting compound was isolated as a colourless foam (350 mg, 44% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1ccc(CCCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(4-phenylbutyl)piperidine (202 mg, 636 μmol) in MeOH (1 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0 mmol). The solution was stirred overnight and then evaporated. The residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, 4-(4-phenylbutyl)piperidine (83.4 mg, 60%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.28 (m, 2H), 7.18 (m, 3H), 3.05 (m, 2H), 2.57 (m, 4H), 2.41 (br, 1H), 1.61 (m, 3H), 1.25 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:30])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:51][C:52]1[O:53][C:54](=[O:58])[O:55][C:56]=1[CH3:57].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([O:30][CH2:51][C:52]2[O:53][C:54](=[O:58])[O:55][C:56]=2[CH3:57])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1oc(=O)oc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(OCc4oc(=O)oc4C)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.1 %

Procedure:
To a solution of triacetate 25 (1.55 g, 3.50 mmol) in THF (50 mL) at 0° C. was added polymer supported-triphenylphosphine (4.95 g, 10.50 mmol, Argonaut). To this mixture was added 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (0.91 g, 7.00 mmol), prepared according to the procedure of Alepegiani, Syn. Comm., 22(9), 1277-82 (1992) Diethyl azodicarboxylate (0.73 ml, 4.60 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 48 h, filtered and washed with MeOH and CHCl3. The filtrate was concentrated and purified by flash column chromatography (silica, acetone/CHCl3=10-20%) to afford dioxolone derivative 66 (1.38 g, 71%) as white solid: 1H (400 MHz, d6-DMSO) 66; δ 7.06 (s, 2H), 6.00 (d, J=4.0 Hz, 1H), 5.92 (dd, J=6.6, 4.4 Hz, 1H), 5.56 (t, J=6.4 Hz, 1H), 5.30 (s, 2H), 4.38 (dd, J=11.6, 3.6 Hz, 1H), 4.25 (t, J=3.6 Hz, 1H), 4.10 (q, J=6.0 Hz, 1H), 2.23 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 555.3. Elemental Analysis calc'd for C21H22N4O12S.Me2CO: C, 47.06; H, 4.61; N, 9.15; S, 5.23. Found: C, 47.25; H, 4.37; N, 9.53; S, 5.52.