Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A carboxylic acid, e.g., 6-Chloronicotinic acid (3.151 g, 20 mmol) was dissolved in dry DCM. The mixture was cooled down to 0° C. Oxalyl chloride (2.58 mL, 30 mmol) followed by DMF (77 μL) were added. The mixture was stirred at 0° C. for 1 h 30, then at RT overnight. The solvents were evaporated. The crude product was dissolved in toluene and the solvents were evaporated again to give the corresponding acid chloride (XVIII*), e.g., 6-chloronicotinoyl chloride (2.886 g, 82% yield). It was dissolved in benzene (50 mL) and AlCl3 (5.248 g, 39.4 mmol) was added. The mixture was stirred overnight at 80° C. After cooling down to RT, water was added. The two phases were separated and the aqueous layer was extracted with two portions of ethyl acetate. Combined organic layers were washed with brine and dried over MgSO4, filtrated and concentrated to give the desired product (XIX*), e.g., (6-chloropyridin-3-yl)(phenyl)methanone as a yellowish oil (3.884 g, 67% yield). It was used in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:30][CH2:31][N:32]=3)[C:15]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:30][CH2:31][N:32]=3)[C:15]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)=[N:16][C:17]=2[C:18]=1[O:19][CH3:20]
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c(O)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 60 °C
Reaction time: 17 h
Yield: 113.7 %

Procedure:
N-[8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Step 1, 20 g, 45.1 mmol) was added portionwise over 1 h to a round bottom flask containing TFA (400 mL) precooled with an ice bath. The reaction mixture was heated to 60° C. and allowed to stir at this temperature for 17 h at which time it was cooled to ambient. The reaction mixture was then concentrated under reduced pressure. The resulting residue was taken up in DCM and hexane and concentrated under reduced pressure. The material thus obtained was dissolved in MeOH and DCM (250 mL, 1:1) and concentrated under reduced pressure. The resulting solids were dried overnight under vacuum with low heat to give the title compound (17.3 g, 66%): HPLC MS RT=1.09 min, MH+=481.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 13.41 (1H, s), 12.21 (1H, br s), 9.38 (1H, s), 8.78 (1H, d), 8.53 (1H, d), 7.85 (1H, d), 7.59 (1H, m), 7.17 (1H, d), 4.54 (2H, m), 4.21 (2H, m), 3.98 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17](O)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccccc3)nc3ccccc13)C2

Procedure:
Reaction of 2-phenylquinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 17 (18. % yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.63 and 2.90 (2t, 2H), 3.49 and 4.04 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.39 and 4.92 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.57-7.60 (m, 3H), 7.69-7.79 (m, 1H), 7.86-7.98 (2d, 1H), 8.06-8.18 (m, 2H), 8.50-8.56 (m, 2H), 8.68 and 8.72 (2s, 1H); MS (ESI) m/z 412 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[NH:35]1[CH:39]=[CH:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2O)C=CC=1>CS(C)=O.[Cu]I>[C:29]1([C:8]2[N:6]3[CH:7]=[C:2]([N:35]4[CH:39]=[CH:38][CH:37]=[N:36]4)[CH:3]=[CH:4][C:5]3=[N:10][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([C:17]3([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:18][CH2:19][CH2:20]3)=[CH:15][CH:16]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Br)cn4c3-c3ccccc3)cc2)CCC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(-n5cccn5)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 150 °C
Yield: 8.9 %

Procedure:
A mixture of tert-butyl {1-[4-(6-bromo-3-phenylimidazo[1,2-a]pyridin-2-yl)phenyl]cyclobutyl}carbamate (see Int 4-18, 230 mg, 0.443 mmol), copper(I) iodide (12.6 mg, 0.07 mmol), 1H-pyrazole (36.5 mg, 0.537 mmol), potassium carbonate (36.5 mg, 0.537 mmol) and quinolin-8-ol (9.73 mg, 0.007 mmol) in 0.6 ml DMSO was heated to 150° C. for 7 h under argon atmosphere. The mixture was triturated with 10% ammonium hydroxide solution and charcoal. After filtration through Celite the filter pad was washed with ethyl acetate. The combined solutions were washed with brine and filtered through a silicone filter. The volatile compounds were removed in vacuo. The crude material was purified by reverse phase HPLC chromatography (Chromatorex RP C-18 10_m; 125*30 mm, acetonitrile/water 30/70->acetonitrile/water 100/0) to give 20 mg of the title compound (9 (Y0 overall yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>ClCCl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: C1=COCCC1
Reactant: COc1ccc(Br)c(CCO)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: COc1ccc(Br)c(CCOC2CCCCO2)c1
Yield: 100.1 %

Procedure:
To a stirred mixture of 2-(2-bromo-5-methoxyphenyl)ethanol (1.5 g, 6.5 mmol) and dihydropyran (13.0 mmol) in dry dichloromethane (30 ml) was added camphor sulfonic acid (0.3 mmol) under nitrogen at 0° C. for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate, and concentrated to give a crude product. This was purified by silica-gel column chromatography eluted with a mixed solvent of hexane and ethyl acetate (20:1) to give the title compound (2.05 g, quantitative). 1H-NMR (CDCl3): 7.40 (d, J=8.8 Hz, 1H), 6.86 (d, J=2.9 Hz, 1H), 6.65 (dd, J=8.8, 2.9 Hz, 1H), 4.63-4.60 (m, 1H), 3.99-3.90 (m, 1H), 3.82-3.74 (m, 1H), 3.78 (s, 3H), 3.68-3.59 (m, 1H), 3.50-3.45 (m, 1H), 3.02 (t, J=7.0 Hz, 2H), 1.83-1.52 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:18]=[CH:17]4)[C:10](=[O:30])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+].[ClH:37]>CO.[Pd].CCOCC>[ClH:37].[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:18]=[CH:17]4)[C:10](=[O:30])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(/C=C/c2ccc(F)cc2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Solvent: CCOCC
Product: O=c1cc(CCc2ccc(F)cc2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Yield: 9.1 %

Procedure:
(E)-4-(4-Fluorostyryl)-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (70 mg, 0.16 mmol), and ammonium formate (20.7 mg, 0.328 mmol) were stirred in methanol (4 ml) for 5 min. Palladium on carbon (100 mg) was added, and the mixture was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature, filtered through celite, rinsed with ethanol, and then concentrated. The residue was dissolved in methanol (2 mL) and treated with 1 equivalent of 2 M HCl in Et2O and the mixture was concentrated to provide the title compound (39.4 mg, 9.1%) as a yellow solid: mp 55-60° C.; 1H NMR (500 MHz, CD3OD) δ 8.23 (s, 1H), 7.84-7.75 (m, 2H), 7.60-7.54 (dd, J=6.7, 0.6 Hz, 1H), 7.47-7.41 (dd, J=8.9, 2.0 Hz, 1H), 7.28-7.20 (m, 2H), 7.04-6.96 (m, 2H), 6.47-6.40 (m, 2H), 4.87 (t, J=5.7 Hz, 2H), 3.86 (t, J=5.7 Hz, 2H), 3.74-3.63 (br m, 2H), 3.21-3.10 (br m, 2H), 3.01-2.92 (m, 2H), 2.92-2.83 (m, 2H), 2.23-2.09 (m, 2H), 2.08-1.95 (m, 2H); ESI MS m/z 431 [M+H]+; HPLC (Method D) 92.5% (AUC), tR=12.9 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[C:12](=[O:19])[S:11]2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[N:22]([CH2:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[C:21]1=[O:35].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[C:12](=[O:19])[S:11]2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH2:43][C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45])[C:23](=[O:27])[N:22]([CH2:28][C:29]([O:31][CH:32]([CH3:33])[CH3:34])=[O:30])[C:21]1=[O:35]
Reactant: CC(C)OC(=O)CBr
Reactant: CC(C)OC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Cn1c(=O)n(CC(=O)OC(C)C)c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
A mixture of isopropyl 3-{2-chloro-4-fluoro-5-[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a]-pyridazin-1-ylidene)amino]phenyl}tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.85 g, 1.62 mmol), potassium carbonate (0.27 g, 1.95 mmol) and isopropyl bromoacetate (0,353 g, 1.95 mmol)in N,N-dimethylformamide is stirred overnight at room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an orange gel. Flash column chromatography of the gel using silica gel and an ethyl acetate/hexanes solution (2:3) gives the title product as a yellow gel (0.3 g) which is identified by NMR spectral analysis.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[S:3]1.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[S:3][C:4]=4[CH:10]=3)=[O:16])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)sc2c1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]c(=O)sc2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazol-6-yl)-oxalamic acid (Example 61b) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 1c. Melting Point: 223.5-225.5° C. (diethylether)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.[C-:12]#[N:13].[Na+]>CN(C=O)C>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:12]#[N:13])[CH:9]=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: COc1cccc(CCBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CCC#N)c1

Procedure:
The solution of 1-(2-bromoethyl)-3-methoxybenzene (10 g, 46.4 mmol), NaCN (2.73 g, 55.8 mmol) in dry DMF (20 ml) was heated at 90° C. for 6 hours or until all the starting material is consumed, the reaction was cooled, diluted with EtOAc (60 ml) and washed with water (20 ml×3), brine, the organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][NH:31][CH3:32]>O1CCOCC1>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][N:31]([CH3:32])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: CNCc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C(=O)CN(C)Cc2ccc(Cl)cc2Cl)cc1
Temperature: 20 °C
Yield: 105 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(4-(2-bromoacetyl)phenyl)acetamide (1 g, 3.91 mmol, 1.00 equiv) in 1,4-dioxane (40 mL). This was followed by the addition of triethylamine (1.58 g, 15.64 mmol, 4.00 equiv) dropwise with stirring at 20° C. To this was added (2,4-dichlorophenyl)-N-methylmethanamine (880 mg, 4.63 mmol, 1.19 equiv) dropwise with stirring at 20° C. The resulting solution was stirred for 4 h at 20° C. The solids were filtered out. The resulting mixture was concentrated under vacuum to give 1.5 g (84%) of N-(4-(2-((2,4-dichlorobenzyl)(methyl)amino)acetyl)phenyl)acetamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][C:3]=1[F:13].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:4][C:3]=1[F:13]
Reactant: Fc1cc(C2CCCN2)ccc1Br
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)c(F)c1
Yield: 78.7 %

Procedure:
2-(4-Bromo-3-fluorophenyl)pyrrolidine (12.5 g, 51.4 mmol) was dissolved in a mixture of dioxane (180 mL) and water (120 mL) and treated with potassium carbonate (28.4 g, 0.21 mol) and benzyl chloroformate (9.65 g, 56.5 mmol) at ambient temperature overnight. The mixture was partitioned between ethyl acetate and brine. The organic phase was concentrated and the residue was purified by flash chromatography on silica gel using a gradient of 5-20% ethyl acetate in petroleum ether to give benzyl 2-(4-bromo-3-fluorophenyl)pyrrolidine-1-carboxylate as a yellow solid (15.3 g, yield 82%). LC-MS (ESI) m/z: 378 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:27][S:24]([CH2:23][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[C:13]=1[CH3:22])(=[O:11])=[O:10])(=[O:26])=[O:25]
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2CS(C)(=O)=O)sc2ccc(F)cc12
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2CS(C)(=O)=O)sc2ccc(F)cc12
Yield: 23.7 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-methanesulfonylmethyl-phenyl)-amide (0.123 g) and 4-pyridineboronic acid (0.0462 g) in 1,2-dimethoxyethane (5 ml), ethanol (1 ml) and 2 M aqueous sodium carbonate solution (2 ml) with tetrakis(triphenylphosphine)palladium (0.035 g) to obtain the title compound (0.029 g) as a yellowish foam. MS (ISN): 489.1 (M−H)−
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>O1CCCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Fc1ccccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2F)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
Lithium diisopropylamide (10.9 mmol, 2M tetrahydrofuran) was added to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.00 g, 4.36 mmol) in tetrahydrofuran (25 mL) at 0° C. After 1.5 h 2-fluorobenzyl bromide (0.788 mL, 6.54 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with the addition of water (10 mL) followed by 1M hydrochloric acid (10 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), the organic layers collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.330 g, (22%) of 4-(2-fluoro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. 1H-NMR (CD3Cl3, 300 MHz) δ 7.11-7.00 (m, 5H), 4.00 (br., 2H), 2.92 (s, 2H), 2.90 (br., 2H), 2.05 (br., 2H), 1.46 (br., 2H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1([NH2:9])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)[CH3:2].[OH-].[Na+].O.[Br:13][CH:14]([CH2:18][Cl:19])[C:15](Cl)=[O:16]>C(Cl)Cl>[Br:13][CH:14]([CH2:18][Cl:19])[C:15]([NH:9][C:3]1([CH2:1][CH3:2])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)=[O:16]
Reactant: O=C(Cl)C(Br)CCl
Reactant: CCC1(N)COCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCC1(NC(=O)C(Br)CCl)COCOC1
Reaction time: 0.5 h

Procedure:
Five and two-tenths g (0.04 mole) of 5-ethyl-5-amino-1,3-dioxane, 3.2 g (0.04 mole) of 50% sodium hydroxide, 10 ml of water, and 90 ml of methylene chloride were combined in a reaction flask. The mixture was cooled to below 35° C. Eight and two-tenths g (0.04 mole) of 2-bromo-3chloropropionyl chloride were added dropwise. The mixture was stirred for 1/2 hour, filtered, dried over magnesium sulfate, and vacuum stripped. Yield was 10.8 g of 5-(2'-bromo-3'-chloropropionyl) amino-5-ethyl-1,3-dioxane. m.p.=95°-109° C. Structure was confirmed by NMR.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO>[F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH2:29])[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 26 h
Yield: 69.4 %

Procedure:
To a mixture of 552.0 mg (1.779 mmol) 1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethanone and molecular sieves in 10 ml methanol were added 1679.0 mg (21.35 mmol) ammonium acetate and 78.0 mg (1.241 mmol) sodium cyanoborohydride and the reaction mixture was stirred 26 h (HPLC control) at 50° C. After cooling to room temperature, the molecular sieves were filtered off and washed with methanol. The solvent of the combined filtrates was evaporated and diethyl ether and water were added to the residue. While stirring the mixture was acidified with 6N aqueous HCl solution to pH2. The aqueous phase was separated and the organic phase was extracted two times with 1N aqueous HCl solution. Ethyl acetate was added to the combined aqueous phases and the mixture was basified with 6N NaOH to pH 10. The organic phase was separated and the aqueous phase was extracted two more times with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent evaporated at reduced pressure to afford 268.0 mg (0.861 mmol) 1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:3]=1[O:4][CH2:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH:27]C(OC(C)(C)C)=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C(C(O)=O)(F)(F)F.O>C(Cl)Cl>[CH3:1][C:2]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:3]=1[O:4][CH2:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH2:27])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7]
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1
Yield: 81 %

Procedure:
(2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane (175.1 g, 0.32 mol) and 500 ml CH2Cl2 were mixed with stirring. CF3CO2H (249 ml, 3.2 mol) was added and stirred 20-25 minutes, then the reaction mixture was poured into a separatory funnel containing 1000 ml of water and 200 ml of CH2Cl2. The resulting mixture was shaken carefully and the layers were separated. The organic layer was washed again with 500 ml of water, then 3×500 ml of NaHCO3 and finally 500 ml of brine. The organic solution was dried over MgSO4, filtered and concentrated to a golden oil that pulled into a foam 300 ml of diethyl ether was added to the crude product and shaken vigorously to dissolve. Within minutes solid began to crystallize and the mixture became thick. Enough diethyl ether was added to make the mixture stirrable and the mixture was stirred at room temperature for 1 hour. The solid was filtered and air dried to give the desired product as 115 g of white needles, 81% yield.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH3:23].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH3:23]
Reactant: CC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 2.25 g (7.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.35 g (7.0 mmol) of acetaldehyde in 30 ml of ethanol, 0.07 ml (0.7 mmol) of piperidine was added, followed by refluxing for 5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/1→1/2) to yield 0.48 g (19.7%, yellow oily substance) of the desired product.