Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: COC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Yield: 98.1 %

Procedure:
A mixture of intermediate (14) (0.0022 mole) in methanol (100 ml) was hydrogenated at 50° C. with palladium-on-carbon (10%) (0.1 g) as a catalyst in the presence of a 4% thiophene solution (0.1 ml). After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in hexane. The precipitate was filtered off and dried, yielding 0.7 g of (±)-methyl 1-(4-aminophenyl)-α-phenyl-4-piperidineacetate (intermediate 15, melting point 125° C.).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])=[CH:23][CH:22]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 1B and 2-(4-methoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=1.3 Hz, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.28-7.31 (m, 2H), 6.91-6.93 (m, 2H), 3.81-3.83 (m, 4H), 3.75 (s, 3H), 3.59 (s, 3H), 3.07-3.10 (m, 4H); MS (ESI+) M/Z 395 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[C:16]([O:21]CC4C=CC=CC=4)[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[C:16]([OH:21])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCCCn2ccc3c(OCc4ccccc4)cccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Oc1cccc2c1ccn2CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
Under argon atmosphere, 1-(5-phenylpentyl)-4-benzyloxyindole (330 mg) and 5% Pd-C (10 mg) were added to methanol (5 ml) and the atmosphere in the reaction vessel was replaced with hydrogen. The mixture was stirred at room temperature for 2 hours and solids were removed by filtration through Celite. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (178 mg, yield: 71%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C:16]([OH:18])=O)=[N:9][C:10]=2[O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:16]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:9]=1)=[O:18])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(NC2CC2)c(OCC2CC2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(NC2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 133 b) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=361.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22]3[N:27]=[C:26]([S:28][C:29]#[N:30])[C:25]([N+:31]([O-])=O)=[CH:24][N:23]=3)[CH:20]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].C(O)C.C(O)(=O)C>CN1CCCC1=O.[C].[Pd]>[NH2:30][C:29]1[S:28][C:26]2[N:27]=[C:22]([NH:21][C:19]3[CH:20]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:16]=[CH:17][C:18]=3[CH3:34])[N:23]=[CH:24][C:25]=2[N:31]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 58.1 %

Procedure:
To a solution of 2-{[5-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)-2-methylphenyl]amino}-5-nitropyrimidin-4-yl thiocyanate (1.09 mmol, 515 mg) in 1-methylpyrrolidin-2-one (9 mL)/ethanol (6 mL) were added 10% palladium-carbon (120 mg) and acetic acid (0.5 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere (3.0 atm) for 19 hr. The insoluble material was filtered off, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL, 20 ml). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (281 mg, 58%) as purple crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[H-].[Na+].[CH3:13][S:14]([C:17]([CH3:25])([CH3:24])[CH2:18]OS(C)(=O)=O)(=[O:16])=[O:15]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])([CH3:25])[CH3:24])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(COS(C)(=O)=O)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(C)(C)S(C)(=O)=O)cc(C)c1Br
Temperature: 160 °C
Yield: 28.6 %

Procedure:
4-Bromo-3,5-dimethylphenol (1.3 g, 6.51 mmol) and NaH (60% on mineral oil: 167 mg, 4.17 mmol) are stirred in 8 mL of N,N-dimethylformamide for 30 min in a microwave vial, methanesulfonic acid 2-methanesulfonyl-2-methyl-propyl ester (600 mg, 2.61 mmol) is added and the reaction mixture is heated in a microwave oven at 160° C. for 2 h. The solvent is removed under vacuum and the crude product is purified by flash chromatography (cyclohexane/ethyl acetate 99/01→90/10) to give the title compound (Yield: 250 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]2[CH2:8][CH2:9][CH2:10][C@@H:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:33])([F:32])[S:28](Cl)(=[O:30])=[O:29].O>CN(C=O)C>[F:26][C:27]([F:33])([F:32])[S:28]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]2[C:4]3=[N:3][S:2](=[O:1])(=[O:19])[CH2:7][CH2:6][N:5]3[CH2:8][CH2:9][CH2:10]2)=[CH:13][CH:14]=1)(=[O:30])=[O:29]
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (1.00 g) and potassium carbonate (1.23 g) in DMF (dry) (30 mL) was added trifluoromethanesulfonyl chloride (0.939 mL) at 0° C. The mixture was stirred at 0° C. for 5 min then at room temperature for 2 hr. The mixture was added with water. The resulting precipitate was collected, washed with water, and dried at 60° C. in vacuo to give the title compound (1.27 g) as a white solid.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1.C([Li])CCC.O>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1)#[CH:2]
Reactant: CCCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C#C[C@H]1CC[C@H](CCCCC)CC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A solution of 35.9 g of trans-1-(2,2-dibromovinyl)-4-pentylcyclohexane in 300 ml of absolute tetrahydrofuran at -70° C. was placed under argon gasification and treated within 20 minutes with 222 ml of a 1.2M solution of butyl lithium in hexane. The mixture was subsequently stirred at -70° C. for a further 2 hours, then poured into 1.2 l of water and extracted three times with 400 ml of hexane each time. The organic phases were washed twice with 400 ml of water each time, dried over magnesium sulphate and concentrated. Crystallization of the residue (19.4 g) from 250 ml of methanol at -78° C. gave 10.0 g of trans-1-ethynyl-4-pentylcyclohexane which was a colourless liquid at room temperature. Crystallization of the mother liquor, concentrated to about 100 ml, at -78° C. gave a further 3.9 g of trans-1-ethynyl-4-pentylcyclohexane. The combined batches of product were crystallized again from 300 ml of methanol at -78° C. and subsequently distilled (110° C./0.3 Torr), there being obtained 10.43 g (55%) of trans-1-ethynyl-4-pentylcyclohexane (purity 99.4%) as a colourless liquid; Rf-value (hexane) 0.41.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]#[N:17])[CH2:8]1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:2]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[C:4]([CH2:5][O:6][C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]#[N:17])[CH2:8]2)[CH:3]=1
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(Br)c2)C1
Reactant: OB(O)c1ccccc1
Product: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(-c3ccccc3)c2)C1
Yield: 54 %

Procedure:
The title compound was prepared from the product of example 55 and benzeneboronic acid, using the same method as that described for example 56, as a green gum in 54% yield.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>[Hg]>[CH2:18]([Si:2]([Cl:4])([Cl:3])[Cl:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCCCCCCCCCCC=C
Agent: [Hg]
Product: C=CCCCCCCCCCCCC[Si](Cl)(Cl)Cl
Yield: 30.3 %

Procedure:
A stirred mixture of 6.8 g (0.05 mole) trichlorosilane and 19.6 g (0.1 mole) 1,13-tetradecadiene was irradiated in a closed quartz tube at 45° C for 72 hours with two Hanau 70 watt high pressure mercury immersion lamps, emitting a broad spectrum of ultraviolet light. The resulting crude product was then fractionated to yield 5 g (25%) of 13-tetradecenyl trichlorosilane as the monoadduct.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>O>[Cl:12][C:13]1[CH:22]=[C:21]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: NCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(NCC2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.8 %

Procedure:
Cyclopropylmethylamine (1.51 g) and potassium carbonate (1.46 g) were added to a solution of methyl 2-chloro-4-fluorobenzoate (1.00 g). The reaction mixture was stirred at room temperature for 6 hours and then heated with stirring at 100° C. for 6 hours under a microwave reactor. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.23 g).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH:3]([CH2:30][CH3:31])[CH:4]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]=[C:15]([NH:17][CH2:18][C:19]([CH3:27])([CH3:26])[C:20]([O:22]C(C)C)=[O:21])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:32][N:2]([CH3:1])[CH:3]([CH2:30][CH3:31])[CH:4]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]=[C:15]([NH:17][CH2:18][C:19]([CH3:26])([CH3:27])[C:20]([OH:22])=[O:21])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(NCC(C)(C)C(=O)OC(C)C)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C(c1ccc2nc(NCC(C)(C)C(=O)O)sc2c1)n1ccnc1)N(C)C

Procedure:
A mixture isopropyl 3-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)amino)-2,2-dimethylpropanoate (30 mg, 0.065 mmol) in 300 μL dioxane and 300 μL water was treated with lithium hydroxide monohydrate (21.4 mg, 0.57 mmol) and heated at 100 for 1 hr. The mixture was concentrated in vacuo and the residue dissolved in about 2 mL of water. The solution was neutralized with 1N HCl then concentrated again in mew). The residue was purified by PTLC using two, 1 mm silica, plates eluting with 10% MeOH/DCM to give the title compounds. MS (ESI−) m/z 414.98 [M−H]−
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH:24]([CH3:26])[CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH:24]([CH3:26])[CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(N)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-isopropylnitrobenzene (4.1 g) in methanol (70 ml) was added palladium on carbon (0.4 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/2 as an eluant to give the desired compound (2.8 g, yield 74%) as a red oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=C.[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]>C1COCC1>[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]([OH:10])[CH:1]=[CH2:2]
Reactant: O=Cc1ccccc1Br
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1ccccc1Br
Reaction time: 17 h
Yield: 91.3 %

Procedure:
To a solution of allylmagnesium bromide (108 mL, 108 mmol, 2.0 eq) in THF was added a solution of 2-bromobenzaldehyde (10 g, 54 mmol, 1.0 eq) in THF (20 mL) dropwise at −18° C. The mixture was allowed to reach room temperature for 17 h, then, quenched with saturated NH4Cl aqueous. The mixture was partitioned between brine and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to provide 1-(2-bromophenyl)prop-2-en-1-ol (10.5 g, 91%). LC-MS (m/z)=213.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19]12([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][C:30]([N:1]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: C1COCCOCCOCCOCCOCCN1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and (1-adamantyl) acetyl chloride.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]1[CH:10]=[N+:11]([O-:23])[CH:12]=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.5 g of 3-diethylphosphonopyridine, Bull. Chem. Soc. Jap. 55, 909 (1982), in 20 ml of methylene chloride is treated with 2.33 g m-chloroperbenzoic acid at room temperature. The reaction mixture is allowed to stir at room temperature overnight, then concentrated under vacuum. The residue is partitioned between ether and water, the aqueous layer is concentrated under vacuum to afford 3-(diethylphosphono)-pyridine-N-oxide as a yellow oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH3:22][S:23]([C:26]1[CH:31]=[C:30]([C:2]2[S:6][C:5]([CH2:7][NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(NCc1ccc(Br)s1)c1ccccc1C(F)(F)F
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 1, step 3, N-(5-bromo-thiophen-2-ylmethyl)-2-trifluoromethyl-benzenesulfonamide (example 1, step 1) was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow solid. MS: 492.9 ([M+NH4]+)
Reaction SMILES: [C:1]([C@H:4]([N:9]([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([CH2:25]OS(C)(=O)=O)=[CH:23][CH:22]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].C[CH2:34][N:35](CC)[CH2:36]C.CNC>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([S:10]([N:9]([C@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:1]([NH2:2])=[O:3])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:25][N:35]([CH3:36])[CH3:34])=[CH:31][CH:32]=2)(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(COS(C)(=O)=O)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(CN(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of methanesulfonic acid 4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-benzyl ester (150 mg, 0.298 mmol) in (3 mL) CH2Cl2 at 0° C. was added 1 equivalent of Et3N, followed by dimethylamine (0.3 mL, 2 M in THF). The reaction was stirred overnight at rt. The mixture was diluted with CH2Cl2, washed with H2O, brine, dried over MgSO4, and concentrated to give an amber glass. Purification by flash chromatography (SiO2, 10% MeOH/CH2Cl2) afforded the title compound (95 mg) in 71% yield. MS (EST), (M+H)+ 452.23, 1H NMR (CDCl3) δ 7.94 (d, 2H, J=8.0), 7.74 (d, 2H, J=8.0), 7.63 (d, 2H, J=8.0) 7.38 (d, 2H, J=8.0), 6.23 (br s, 1H), 5.35 (br s, 1H), 4.22 (d, 1H, Jab=16), 4.14 (d, 1H, Jab=16), 3.28-3.23 (m, 3H), 2.17 (br s, 6H), 1.95 (m, 1H), 1.55 (m, 2H), 0.96 (d, 3H, J=7.0), 0.93 (d, 3H, J=7.0).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:7]([C:12]([NH2:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]>CS(C)=O>[NH2:14][C:12]([C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:4][C:3]([O:23][CH3:24])=[C:2]([O:1][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:11]=2)=[O:13]
Reactant: COC(=O)CCCCl
Reactant: COc1cc2c(Nc3ccccc3C)c(C(N)=O)cnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)CCCOc1cc2ncc(C(N)=O)c(Nc3ccccc3C)c2cc1OC

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-toluidino)-3-quinolinecarboxamide (0.026 g, 0.080 mmol), DMSO (2.5 ml), K2CO3 (0.017 g, 0.12 mmol), and methyl 4-chlorobutanoate (0.011 g, 0.080 mmol) was refluxed for 2 h. The reactionmixture was filtered, evaporated and chromatographed on silica furnishing the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[CH2:3][CH2:2]1.CI.[C:34](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:34][O:22][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:17][C:16]([F:30])=[CH:15][CH:14]=2)=[O:23]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Reaction time: 12 h
Yield: 60.5 %

Procedure:
2-(2,3-Dihydrobenzofuran-5-ylmethyl)-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (800 mg) was dissolved in DMF (8 ml), and methyl iodide (0.24 ml) and potassium carbonate (530 mg) were added at room temperature. The mixture was stirred for 12 hrs. Water was added to the reaction mixture, and crystals were collected by filtration and washed with water. After drying the crystals, recrystallization (ethyl acetate) gave the title compound (500 mg).
Reaction SMILES: [Br:1][C:2]1[C:7](=O)[C:6]([Br:9])=[CH:5][NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:12].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[Cl:12]
Reactant: O=c1c(Br)c[nH]cc1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1c(Br)cncc1Br
Temperature: 100 °C
Yield: 100 %

Procedure:
To 3,5-dibromo-4-(1H)-pyridone (0.25 g, 1.0 mmol) was added POCl3 (2 mL) and the mixture was heated at 100° C. for 2 h. The mixture was poured into ice/water (25 g) and basified by the addition of a saturated solution of sodium hydrogen carbonate. The mixture was extracted with CH2Cl2 (2×20 mL), the combined organic extracts were washed with brine (25 mL), dried (MgSO4) and concentrated under reduced pressure to furnish the title compound as a white solid (275 mg, 100%), m.p. 101-103° C.; m/z 272 (100%, [M+H]+);
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1>C(Cl)Cl>[CH2:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN=C=O
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Solvent: ClCCl
Product: CCCNC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Propylisocyanate (13 μl, 137 μmol) was added to a solution of 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 15.8 mg, 691 mol) in CH2Cl2 (0.7 ml). After stirring 18 h at rt, the solvent was removed to afford the title compound: RT=2.72 min; m/z (ES+)=316.3 [M+H]+.