Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=O)=O.[OH-].[K+]>C(O)C>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:15]=[N:4][CH:1]=[CH:2][N:3]=1
Reactant: O=CC(=O)c1ccccc1Cl
Reactant: NCCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1ccccc1-c1cnccn1
Yield: 492.6 %

Procedure:
The procedure of Example 1 was repeated, using 1.96 g (3.16 mmol) of ethylenediamine, 4.9 g (2.13 mmol) of 2-chlorophenylglyoxal monohydrate, 1.6 g of potassium hydroxide and 50 ml of ethanol, with the result that 2.0 g of the titled compound was obtained (yield: 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6](C(OC(C)(C)C)=O)[C:7](=[O:13])[N:8]([CH2:9][CH2:10][CH2:11][Cl:12])[C:4]=2[CH:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7](=[O:13])[N:8]([CH2:9][CH2:10][CH2:11][Cl:12])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1c(=O)n(CCCCl)c2cc(Cl)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(Cl)cc2n1CCCCl
Yield: 135.2 %

Procedure:
A solution of tert-butyl 5-chloro-3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (528 mg, 1.53 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and dried in vacuo to afford the hydrogen chloride salt of the title compound as a cream powder (507 mg, quant); 1H NMR (400 MHz, DMSO-d6): δ 2.03-2.12 (m, 2H); 3.63-3.72 (m, 2H); 3.90 (t, 2H, J=7.2 and 6.8 Hz); 7.00 (d, 1H, J=2 Hz); 7.02 (dd, 1H, J=2 Hz); 7.15 (d, 1H, J=8 Hz); MS for C10H10Cl2N2O m/z 244.93 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH2:27])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccccc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2)c1)C(F)(F)F
Reaction time: 5.2 h
Yield: 41.8 %

Procedure:
To a solution of 5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine (37 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (16 mg) prepared in Preparation 14 and WSC.HCl (23 mg) at room temperature, the mixture was stirred for 5.2 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (20 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:8]1([S:18](Cl)(=[O:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C(#N)C>[C:8]1([S:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])(=[O:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: NCCCCCN
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CC#N
Product: NCCCCCNS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Under ice cooling, 7.91 g of 1,5-diaminopentane was added dropwise with 240 mL of acetonitrile solution in which 1.75 g of 1-naphthalenesulfonyl chloride was dissolved, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the residue was added with 500 mL of water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.90 g of 5-(1-naphthalenesulfonyl)aminopentylamine.
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[C:17]1(=[O:31])[N:21]([CH2:22]C(Cl)=O)[C:20](=[O:26])[C:19]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:18]12.Cl>ClCCl>[O:5]=[C:4]([CH2:22][N:21]1[C:20](=[O:26])[C:19]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:18]2[C:17]1=[O:31])[CH2:6][C:7]([O:9][CH3:2])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a solution of Meldrum's acid (14.4 g, 0.10 mol) and pyridine (15.8 g, 0.20 mol) in dichloromethane (100 mL) was added dropwise at 0° C., taking 10 minutes, a solution of phthalimidoacetyl chloride (24.6 g,. 0.11 mol) in dichloromethane (50 mL). The mixture was stirred for 30 minutes at the same temperature and for 30 minutes at room temperature. To the reaction mixture was added 1N HCl (200 mL), then insoluble material was filtered off. The aqueous layer was separated, and the organic layer was washed with water, dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was suspended in methanol (200 mL), which was refluxed for 1.5 hour. The reaction mixture was left standing for cooling. Crystalline precipitate was collected by filtration and washed with methanol to give the object compound (18.4 g, 70%), m.p.139°-140° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH:18]([C:27]([F:30])([F:29])[F:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH3:26])=[O:16])=[C:11]([F:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].[C].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH:18]([C:27]([F:28])([F:29])[F:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH3:26])=[O:16])=[C:11]([F:31])[CH:10]=1
Reactant: [H][H]
Reactant: CCOCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1F)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F

Procedure:
An autoclave was charged with 1 g of 4-benzyloxy-2-fluoro-1-(6-ethoxy-1-trifluoromethylhexyloxycarbonyl)-benzene, 15 ml of ethyl acetate and 0.5 g of a 15 wt % Pd/carbon catalyst, the atmosphere in the autoclave was replaced with nitrogen and then with hydrogen, and the mixture was continuously stirred at room temperature until the hydrogen absorption terminated. After the reaction, the catalyst was filtered off. The ethyl acetate was distilled off to give a crude 4-hydroxy-2-fluoro-1-(6-ethoxy-1-trifluoromethyl-hexyloxycarbonyl)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)CCl
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromophenol (6.27 g, 36 mmol) and cesium carbonate (20. g, 61.2 mmol) were dissolved in DMF (50 mL) and stirred for 15 minutes at room temperature. Chloroacetone (4.3 mL, 54 mmol) was added and the reaction stirred for 1 hour and was submitted to aqueous workup. Purification by silica gel chromatography (0-50% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+].[CH:18](O)=[O:19]>O>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH:18]=[O:19]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCN(C=O)c1ccc([N+](=O)[O-])cc1

Procedure:
1.4 g (6.7 mmol) of 4-(2-dimethylamino-ethylamino)-nitrobenzene (Example 326a) are refluxed for 4 hours in 20 ml of formic acid. Then the solvent is eliminated in vacuo, the residue taken up in water and combined with 2 N sodium hydroxide solution until an alkaline reaction is obtained. The mixture is extracted with ethyl acetate, the combined organic phases are dried over magnesium sulphate and the solvent is eliminated in vacuo. The product is obtained as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1cccc(Br)n1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2cccc(C)n2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone and 2-bromo-6-methylpyridine. ESI-MS (m/z): 418 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([OH:20])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[C:18]([C@@H:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13]1)(=[O:20])[NH2:21]
Reactant: c1ccncc1
Reactant: O=C(N[C@H]1CCC[C@@H](C(=O)O)C1)OCc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of (1R,3S)-3-Benzyloxycarbonylaminocyclohexanecarboxylic acid, 18c, (10.0 g, 36.1 mmol) in 1,4-dioxane (300 mL) was added pyridine (2.9 mL, 36.1 mmol), followed by di-tert-butyl dicarbonate (10.7 mL, 46.9 mmol) and ammonium bicarbonate (10.1 g, 126.2 mmol). After 3 hours, another portion of di-tert-butyl dicarbonate (1.5 g, 6.8 mmol) and ammonium bicarbonate (1.5 g, 6.8 mmol) was added and stirring was continued overnight. The reaction was quenched by addition of 2N HCl (400 mL) and stirred for 1 hour. The resulting suspension was filtered under reduced pressure, washed with 2N HCl (50 mL), water (8×50 mL) and hexanes (3×50 mL) and vacuum dried to provide benzyl N-[(1S,3R)-3-carbamoylcyclohexyl]carbamate, 18d, (9.1 g, 91%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35]C4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.CN>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH3:35])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Agent: CN
Product: CNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using methylamine instead of cyclopropylmethylamine. LC-MS: (M+1=489, obsd.=489).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc2cccc(N)c2n1
Agent: CN(C)c1ccncc1
Product: Cc1ccc2cccc(NS(=O)(=O)c3ccccc3)c2n1
Yield: 41.9 %

Procedure:
In the similar fashion using route 14 general procedure 27, 2-methyl-8-aminoquinoline (Intermediate 22) (200 mg, 1.2 mmol), benzenesulfonyl chloride (230 mg, 1.2 mmol) and DMAP (cat.) gave the title compound (150 mg, 43%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:20][C:18]1[O:17][N:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:19]=1)=[N+:23]=[N-:24]
Reactant: ClCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reaction time: 12 h

Procedure:
0.13 g of 3-(4-benzyloxy-phenyl)-5-chloromethyl-isoxazole was dissolved in 10 ml of DMF, to which solution was added 85 mg (3 equivalents) of NaN3, and the mixture was stirred for 12 hours. The solvent was dried off under reduced pressure and removed, followed by column chromatography to obtain 5-azidomethyl-3-(4-benzyloxy-phenyl)-isoxazole. A reduction of the compound was performed under NaBH4 conditions to obtain C-[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methylamine as a desired compound.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][N:4]2[C:28](=[O:29])[N:7]3[CH:8]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)[C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH2:18][C:6]3([CH3:30])[C:5]2=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=5)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN2CCN(C(C)=O)CC2)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 29 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and N-acetyl piperazine as starting materials. MS: m/z (MH+)=532.1
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16]1.C(OCC)(=O)C>CO.[Pd]>[ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16]1
Reactant: Cc1ccccc1C(=CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Yield: 79.8 %

Procedure:
The acid prepared in Example 26 (1.0 g, 2.4 mmol) was dissolved in methanol (20 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (50% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a residue which was treated with ethyl acetate to give 0.8 g (80%) of the title compound as a solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:20])[F:19])[CH:6]=1)C.[OH-].[Na+]>CO>[F:19][C:18]([F:20])([F:21])[O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)c1cccc(-c2ccccc2OC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccccc2OC(F)(F)F)c1

Procedure:
A solution of 0.3 g (4.19 mmol) of ethyl-3-(2-trifluoromethoxyphenyl)-benzoate and 8.3 Ml (8.3 mmol) of a 1N solution of NaOH in 12.5 Ml of methanol was stirred 18 h at RT. The reaction mixture was concentrated and the Ph was adjusted to Ph=2 with 1 N HCl solution. The mixture was extracted with ethyl acetate (EtOAc) and the organic fraction was dried over MgSO4, filtered and the filtrate was concentrated to give the title compound as a white solid that was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH3:12])[C:4]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[CH2:13]([O:17][C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[O:29][CH3:30])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([O:17][C:18]1[C:19]([O:29][CH3:30])=[CH:20][C:21]([C:22]([NH:11][CH2:10][C:4]2([N:3]([CH2:1][CH3:2])[CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[O:23])=[CH:25][C:26]=1[O:27][CH3:28])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: CCN(C)C1(CN)CCCCC1
Product: CCCCOc1c(OC)cc(C(=O)NCC2(N(C)CC)CCCCC2)cc1OC

Procedure:
Synthesised from [1-(ethylmethylamino)cyclohexyl]methylamine and 4-butyloxy-3,5-dimethoxybenzoyl chloride V, following procedure described in Example 1 and purified by LCMS to obtain the product as a trifluoroacetate salt. 1H NMR (CDCl3) δ: 0.94 (t, 3H, J=4 Hz), 1.15 (m, 1H), 1.48 (m, 3H), 1.58 (t, 3H, J=4 Hz), 1.65 (m, 3H), 1.73 (m, 3H), 1.81 (m, 3H), 2.09 (d, 2H, J=4 Hz), 2.77 (d, 2H, J=2 Hz), 2.82 (m, 1H), 3.54 (m, 1H), 3.96 (s, 6H), 4.01 (t, 2H, J=4 Hz), 4.06 (m, 1H), 4.20 (dd, 1H, J=3 Hz), 7.57 (s, 2H), 9.05 (m, 1H), 11.62 (s, 1H). LCMS m/z 407.4 (MH+; 98.8%). HRMS (FAB) calc. 407.2898, found 407.2910.
Reaction SMILES: [NH2:1][C:2]([CH2:4][CH2:5][C:6]([O-:8])=O)=[O:3].[NH2:9][OH:10]>O1CCOCC1>[OH:10][NH:9][C:6](=[O:8])[CH2:5][CH2:4][C:2]([NH2:1])=[O:3]
Reactant: NO
Reactant: NC(=O)CCC(=O)[O-]
Solvent: C1COCCO1
Product: NC(=O)CCC(=O)NO

Procedure:
3-aminocarbonylpropionate A-6 (0.1 mmol) is treated with dioxane (1 mL) and hydroxylamine (50% in water, 2 mL) for 1-3 days, and then purified by preparative reverse-phase (C18) HPLC to afford the desired N-hydroxy-3-aminocarbonylpropionamide (A-7).
Reaction SMILES: I[C:2]1[C:8](I)=[C:7]([OH:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:3]=1[OH:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(NC(C)C)(C)C.[CH3:39][Si:40]([C:43]#[CH:44])([CH3:42])[CH3:41]>[Pd].C1(C)C=CC=CC=1>[CH3:39][Si:40]([CH3:42])([CH3:41])[C:43]#[C:44][C:2]1[C:8]([Si:40]([CH3:42])([CH3:41])[CH3:39])=[C:7]([OH:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:3]=1[OH:4]
Reactant: Cc1c(C)c(O)c(I)c(I)c1O
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: Cc1c(C)c(O)c([Si](C)(C)C)c(C#C[Si](C)(C)C)c1O
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a degassed solution of 2,3-diiodo 5,6-dimethylhydroquinone (1)(3.6 g, 9.23 mmol), Pd"(PhCN)2Cl2 (176.9 mg, 0.46 mmol), PPh3 (278.2 mg, 1.06 mmol), and Cul (297 mg, 1.56 mmol) in 110 mL to toluene under argon were added 2.5 mL (18.5 mmol) of diisopropylamine and 4.0 mL (28.6 mmol) of (trimethylsilyl)acetylene. After stirring at room temperature for a day the reaction mixture was opened to air, filtered and concentrated under vacuo. Flash column chromatography with 7% ethyl acetate in petroleum ether produced yellow compound (2) with 50.2% yield (1.53 g). Melting point 76°-77° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].Cl>CO.[Pd]>[CH3:14][C:11]1([N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2(C)CCN(Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2(C)CCNCC2)CC1
Reaction time: 3 h

Procedure:
A suspension of 2.28 g (5.62 mmol) tert-butyl 4-(1-benzyl-4-methyl-piperidin-4-yl)-piperazine-1-carboxylate and 300 mg 10% Pd/C in 50 mL MeOH was hydrogenated for 3 h at 50° C. and 3447 hPa hydrogen pressure. To complete the reaction 0.47 mL conc. HCl were added and the mixture was hydrogenated for another 3 h at 50° C. and 3447 hPa hydrogen pressure. The catalyst was filtered off, the filtrate was evaporated down i. vac., the residue was stirred with diethyl ether, suction filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.N1CCCCC1.C(O)(=O)C>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1/[CH:21]=[C:9](\[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:17])/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Reactant: O=Cc1ccccc1Cl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)/C(=C/c1ccccc1Cl)C(=O)c1ccccc1O
Yield: 20.1 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (236 mg, 1.0 mmol), 2-chlorobenzaldehyde (113 μL, 1.0 mmol) 15 mL benzene, piperidine (10 μL, 0.1 mmol) and glacial acetic acid (5.6 μL, 0.1 mmol), refluxed for 90 min. Purified via recrystallization from hexanes/CH2Cl2, yielding 72 mg (20%) of a white solid. mp=75-78° C. IR (film) 2979.0; 1720.5; 1630.9; 1156.3 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.80 (bs, 1H); 8.19 (s, 1H); 7.50 (d, J=7.9 Hz, 1H); 7.44 (t, J=7.9 Hz, 1H); 7.36 (d, J=7.9 Hz, 1H); 7.26 (d, J=7.9 Hz, 1H); 7.21 (t, J=7.6 Hz, 1H); 7.08 (t, J=7.06, Hz, 1H); 6.97 (d, J=7.9 Hz, 1H); 6.82 (t, J=7.6 Hz, 1H); 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 200.6, 163.3, 162.8, 139.1, 137.2, 135.0, 134.0, 131.9 (double intensity), 131.3, 130.2, 130.1, 127.2, 120.0, 119.5, 118.5, 83.1, 28.1; LRMS (electrospray): Mass calculated for C20H19ClO4 [M]+, 358.09. Found [M+23]+, 381.5.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[F:11].CC1(C)C(C)(C)OB([C:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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:29]([O:28][C:26]([N:23]1[CH2:22][CH:21]=[C:20]([C:2]2[C:3]([F:11])=[CH:4][CH:5]=[C:6]([F:10])[C:7]=2[O:8][CH3:9])[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1c(F)ccc(F)c1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: O
Solvent: C1COCCO1
Product: COc1c(F)ccc(F)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 150 °C

Procedure:
2-Bromo-1,4-difluoro-3-methoxy-benzene (0.7 g, 3.139 mmol) [C.A.S. 1208076-11-2] was added to a stirred solution of 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1(2H)-pyridinecarboxylic acid, 1,1-dimethylethyl ester (1.262 g, 4.08 mmol) [C.A.S. 286961-14-6], Pd(PPh3)4 (0.072 g, 0.062 mmol) and K2CO3 (3.5 ml, aqueous sat. solution) in 1,4-dioxane (7 ml). The reaction mixture was heated at 150° C. under microwave irradiation for 10 min. After cooling, the mixture was diluted with water and extracted with Et2O. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/EtOAc 90/10 to 80/2 as eluent). The desired fractions were collected and concentrated in vacuo to give a residue that was triturated with Et2O to yield intermediate D52 (0.233 g, 22%).