Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)([O-:21])=[O:20]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (355 mg) in DMF (5 mL) was added sodium hydride (110 mg of 60% in oil) and 3-nitrobenzyl bromide (596 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a red solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br-:18].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]([Br:18])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: [Br-]
Reactant: CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
To a solution of 1.89 g of (+/-)-1-(3,5-bis(trifluoromethy)-phenyl)-1-hydroxyethane prepared as in Example 5, Step A in 50 mL of acetonitrile at room temperature was added 5.15 g of triphenylphosphine dibromide. After 1.5 h, the reaction was partitioned between ether and water and the ether layer was washed with brine, dried with sodium sulfate and evaporated. The product was triturated with hexanes, filtered to remove the solid and reconcentrated. The residue was purified by flash chromatography using hexanes to provide 1.75 g of title compound as an oil.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[CH3:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH:40][NH2:41])=O)[CH:33]=1>ClCCl>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:38]([C:34]3[CH:33]=[C:32]([CH3:31])[CH:37]=[CH:36][N:35]=3)=[N:40][N:41]=[C:26]2[CH2:25]1)=[O:23]
Reactant: Cc1ccnc(C(=O)NN)c1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1ccnc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Triethyloxonium tetrafluoroborate (314 mg, 1.654 mmol) was added under argon to a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(481 mg, 1.654 mmol) in Dichloromethane (DCM) (4 ml). The reaction was stirred at room temperature for 40 min (until mixture became clear). 4-methyl-2-pyridinecarbohydrazide (I28)(300 mg, 1.985 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated and 1-butanol (4.00 ml) was added. The reaction mixture was stirred at reflux 1 h 20 min—after 40 min, the reaction mixture became completely clear. The reaction mixture was diluted with ethyl acetate (I50 mL) and then extracted water (2×25 mL), with sat. NaHCO3 (25 mL) and with brine (25 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by MDAP. The resulting oil was triturated in hexane (10 mL) and ether (10 mL) and dried at 60° C. under vacuum for 5 days to afford the desired product in 189.9 mg as a white powder.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]([CH3:8])[CH:6]=[CH2:7].[CH2:9]1[O:12][C@H:10]1[CH3:11]>C1COCC1.[Cu](Br)Br.II>[CH3:8][CH:5]([CH:6]=[CH2:7])[CH2:4][CH2:3][CH2:9][C@H:10]([OH:12])[CH3:11]
Reactant: C=CC(C)CCBr
Reactant: C[C@H]1CO1
Agent: Br[Cu]Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)CCC[C@@H](C)O
Reaction time: 8 h
Yield: 236.9 %

Procedure:
Magnesium turnings (1.3 g, 55.2 mmol) were suspended in dry THF (50 mL) and to the mixture was added a pinch of iodine (20 mg) at room temperature. To this reaction mass was added a solution of 5-bromo-3-methylpent-1-ene (6 g, 36.8 mmol) in THF (200 mL). The reaction mass was heated with hot air gun to initiate the reaction. When the reaction was judged complete, the solution was cannulated to a solution of (S)-propylene oxide (3.21 g, 55.2 mmol) and copper bromide (0.528 g, 3.68 mmol) in THF (50 mL) at −78° C. The reaction mass was allowed to come to room temperature and stirred overnight. The reaction mass was quenched with saturated ammonium chloride solution and extracted with diethyl ether (200 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated at room temperature to get crude compound. The crude compound was purified by column chromotography (Silica gel, 10% TBME in pet ether) to get (2R)-6-methyloct-7-en-2-ol (12.4 g, 92%) as oily liquid. 1H NMR (400 MHz, CDCl3): δ ppm 5.82-5.69 (m, 1H), 4.98-4.91 (m, 2H), 4.27-4.26 (m, 1H), 3.65-3.39 (m, 1H), 2.15-1.98 (m, 1H), 1.36-1.19 (m, 5H), 1.18-1.1 (m, 1H), 1.08-0.95 (m, 5H), 0.89-0.78 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.ON1C2C=CC=CC=2N=N1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:19][O:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)(=[O:11])=[O:10])[CH2:17][CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (138 mg, 0.72 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (195 mg, 0.60 mmol), 1-hydroxybenzotriazole (97.0 mg, 0.72 mmol), 4-fluorobenzoic acid (84.0 mg, 0.60 mmol) and N,N-diisopropylethylamine (233 mg, 1.80 mmol) in N,N-dimethylformamide (8 ml). The reaction mixture was stirred at room temperature for 17 hours and quenched with H2O (50 ml) and aqueous 1 N HCl solution (pH=3). The aqueous phase was extracted with CH2Cl2 (20 ml×3) and the combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 50/50) to give 4-fluoro-N-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)benzamide (217 mg, 81%) as a white solid: LCMS: 447 [M+1]+. 1H NMR (DMSO-d6) δ: 1.71 (m, 2H), 1.88 (m, 2H), 3.07 (m, 4H), 3.97 (t, 1H), 7.27 (t, 2H), 7.74 (m, 2H), 7.98 (m, 2H), 8.10 (m, 2H), 11.4 (s, 1H).
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.[NH2:10][CH:11]([CH2:16][CH3:17])C(OC)=O.C(O)C.[OH-].[Na+]>C(#N)C>[C:7]([C:3]1[NH:1][C:11]([CH2:16][CH3:17])=[N:10][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CCC(N)C(=O)OC
Reactant: CC(=O)C(=NO)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: CCc1nc(C)c(C(C)=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To 4.99 g (0.039 moles) of 3-oximino-2,4-pentanedione dissolved in acetonitrile (40 ml) was added 4.59 ml (0.039 moles) of methyl 2-aminobutyrate. After stirring for two hours at room temperature, then at reflux for 2.5 h, the reaction mixture was cooled and treated with 15 ml of ethanol and 15 ml of 10% aqueous sodium hydroxide. The resulting mixture was refluxed for 3.8 h, cooled, then extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, then concentrated in vacuo to give 0.024 moles (62% yield) of 5-acetyl-2-ethyl-4-methylimidazole.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][CH:13]([CH2:19][CH:20]=C)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([Cl:24])[CH:9]=1>C1COCC1.O.O=[Os](=O)(=O)=O>[Br:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][CH:13]([CH2:19][CH:20]=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([Cl:24])[CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(Cc1ccc(Br)cc1Cl)C(=O)OCC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC=O)Cc1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 75.7 %

Procedure:
Add sodium periodate (41 g, 190 mmol) into a solution of ethyl 2-(4-bromo-2-chlorobenzyl)pent-4-enoate (21 g, 63 mmol), 2.5 wt % OsO4 (64 g, 6.3 mmol) in THF (400 mL) and water (160 mL) and stir for 2 hours. Extract the reaction mixture with ethyl acetate, wash the organic layer with sodium thiosulfate solution and brine. Dry over sodium sulfate, filter and concentrate. Purify the residue with silica gel column to afford the title compound (15.9 g, 75%) as colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:15]=[CH:16][C:17]2[C:18]([CH:22]=1)=[N:19][O:20][N:21]=2.O>CS(C)=O>[N:11]1[N:10]=[CH:9][N:8]([NH:7][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([CH:22]=2)=[N:19][O:20][N:21]=3)[CH:12]=1
Reactant: Nn1cnnc1
Reactant: Fc1ccc2nonc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1cc2nonc2cc1Nn1cnnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
26.70 Grams of potassium tert-butoxide was dissolved in 100 ml of anhydrous dimethylsulfoxide and 20.00 g of 4-amino-4H-1,2,4-triazole was added thereto, followed by stirring for 2 hours at room temperature. Next, 50 ml of an anhydrous dimethylsulfoxide solution containing 11.00 g of 5-fluorobenzofurazane was added dropwise to the solution over a period of 20 minutes and then the mixture was stirred for 15 minutes. The reaction mixture was poured into 500 ml of water and 500 g of ice and then washed with 200 ml of ethyl acetate. The solution was then adjusted to have pH of 7.0 with 1N hydrochloric acid to give crystals. The crystals were collected by filtration, and the remaining mother liquid was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the crude crystals thus obtained were recrystallized from ethanol. These were combined with the previously obtained crystals to give 12.49 g of 5-[(4H-1,2,4-triazol-4-yl)amino]benzofurazane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([SH:11])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.Br[C:16]1C(C(C)C)=CC(S)=C(C(C)C)C=1>>[CH3:16][S:11][C:5]1[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=1[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)c1cc(Cl)c(C(C)C)cc1S
Reactant: CC(C)c1cc(Br)c(C(C)C)cc1S
Product: CSc1cc(C(C)C)c(Cl)cc1C(C)C

Procedure:
4-Chloro-2,5-diisopropylphenyl methyl sulfide was prepared using the procedure of Example 1C except that 4-chloro-2,5-diisopropylbenzenethiol was substituted for the 4-bromo-2,5-diisopropylbenzenethiol. The resulting product had a boiling point of 88°C at 0.35 mm Hg.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[C:28]([F:31])([F:30])[F:29].O>CN(C=O)C>[O:7]([CH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[C:28]([F:31])([F:29])[F:30])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1cccc2c(-c3ccccc3)c(CBr)cnc12
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(COc3ccccc3)cnc12
Reaction time: 16 h
Yield: 60.1 %

Procedure:
A solution of phenol (235 mg, 5.0 mmol) in DMF (2.0 mL) is treated with NaH (60% in oil, 100 mg, 2.5 mmol) for 20 min and then treated with 3-(bromomethyl)-4-phenyl-8-(trifluoromethyl)quinoline (183 mg, 0.50 mmol) in DMF (1.0 mL). After 16 h, the reaction is treated with water and extracted with ether. The extract is dried with MgSO4 and concentrated to an oil. Chromatography with 10:90 ethyl acetate:hexane affords the title compound as a white solid (114 mg, 62%). MS (ES) m/z 380.2; HRMS: calcd for C23H16F3NO, 379.1184; found (ESI, [M+H]+), 380.1246;
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O.[Cl:19]N1CCOCC1>CCOC(C)=O>[Cl:19][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[O:8][N:7]=[C:6]([OH:9])[C:5]=2[CH:10]=1
Reactant: Cc1ccc2c(O)noc2c1
Reactant: ClN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc2onc(O)c2cc1Cl
Temperature: 0 °C

Procedure:
A 25 ml round-bottom flask equipped with a stir bar was charged with 6-methyl-benzo[d]isoxazol-3-ol (298 mg, 2.0 mmole, 1.0 eq) and TFA (2.0 ml) and cooled to 0° C. in an ice bath. Neat N-chloromorpholine (242 μL, 2.0 mmoles, 1.0 eq, Organic Syntheses, CV 8, 167) was added dropwise and the reaction mixture was allowed to warm to room temperature over the period of 30 minutes. EtOAc was added, the crude product was partitioned in a separatory funnel (EtOAc/1.0M aqueous HCl), the organic layer was dried with MgSO4 and excess solvent was removed from the filtrate in vacuo. Crystallization of the crude product (383 mg) from a mixture of 20 ml of toluene and 6 ml of EtOAc provided 206 mg (94% purity determined by HPLC) as a white solid. (1H DMSO-d6, 400 MHz) δ 12.41 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 2.43 (s, 3H); (13C DMSO-d6, 100 MHz) δ 164.46, 161.87, 138.53, 128.08, 120.59, 113.78, 111.83, 20.49.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22]C=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=C[N:43]3[C:56](=[O:57])[N:55]([CH3:58])[N:54]=C3C=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][N:43]5[C:56](=[O:57])[N:55]([CH3:58])[N:54]=[C:22]5[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cn1nc2c3oc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(=O)c3ccn2c1=O
Yield: 61 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-2-methyl-8-phenyl-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione was reacted to give the title compound as a colourless gum (19.9 mg, 61%). LCMS (Method A): RT=4.63 min, [M+H]+=539.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[C:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:16]([NH:15][CH2:13][CH3:14])=[O:17])[S:3][C:4]=2[CH:10]=1)#[N:12]
Reactant: CCN=C=O
Reactant: N#Cc1ccc2nc(N)sc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
0.2 grams of 2-amino-1,3-benzothiazole-6-carbonitrile is dissolved in about 5 ml dimethylformamide. About 0.2 ml of ethylisocyanate is added followed by about 0.3 ml triethylamine and the solution is heated to about 80° C. under good agitation. The solution is allowed to stir for about 4 hours then cooled to RT. The solvent is removed in vacuo and the solids are washed well with ether. The product is further purified by column chromatography and after drying in vacuo, about 0.14 grams is isolated.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1N)([CH3:4])([CH3:3])[CH3:2].N([O-])=[O:16].[Na+].NC(N)=O.OS(O)(=O)=O.O>OS(O)(=O)=O.O>[C:1]([C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 61.5 %

Procedure:
To a mixture of 2-tert-butyl-5-nitroaniline (1.94 g, 10 mmol) in 40 mL of 15% H2SO4 was added dropwise a solution of NaNO2 (763 mg, 11.0 mmol) in water (3 mL) at 0° C. The resulting mixture was stirred at 0-5° C. for 5 min. Excess NaNO2 was neutralized with urea, then 5 mL of H2SO4—H2O (v/v 1:2) was added and the mixture was refluxed for 5 min. Three additional 5 mL aliquots of H2SO4—H2O (v/v 1:2) were added while heating at reflux. The reaction mixture was cooled to room temperature and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography (0-10% EtOAc-Hexane) to give 2-tert-butyl-5-nitrophenol (C-1-a) (1.2 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J=8.6, 2.2 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 5.41 (s, 1H), 1.45 (s, 9H); HPLC ret. time 3.46 min, 10-99% CH3CN, 5 min run.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(OC([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:36]([CH:33]4[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]4)=[O:37])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(C1CCNCC1)[C@@H]1CCc2ccc(OC)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C1CCN(C(=O)C2CCNCC2)CC1)[C@@H]1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 104.5 %

Procedure:
Under an inert atmosphere was combined ((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (7.0 g, 23.14 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (5.3 g, 23.14 mmol), EDCI (4.43 g, 23.14 mmol), HOBT (3.13 g, 23.14 mmol), and triethylamine (65 mL, 46.3 mmol) in dichloromethane (140 mL). The mixture was stirred at room temperature for 48 h then concentrated in vacuo. The residue was taken-up in EtOAc (150 mL) and washed with water (100 mL), 1N NaOH (30 mL), and brine (30 mL), then dried (MgSO4). The solution was filtered, and concentrated. This was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine (10.0 g), which was deprotected with 10 mL trifluoroacetic acid as described herein to afford {4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone 39 (6.5 g ), [M+H]+=450.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:15](=[O:17])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=3)[S:10][CH:11]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: O=C(Nc1nc(CC(=O)N2CCN(Cc3ccccc3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-benzyl-piperazine to give N-{4-[2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide, using general method A. Orange solid. MS 455.4 ([M+H]+)
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[N:29][CH:30]=1)[CH3:24]>C(#N)C>[F:31][C:28]1[N:29]=[CH:30][C:25]([CH:23]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH3:24])=[CH:26][CH:27]=1
Reactant: CC(Br)c1ccc(F)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 73 %

Procedure:
tert-Butyl piperazine-1-carboxylate (Aldrich, St. Louis, Mo.; 13.31 g, 71.5 mmol), potassium iodide (2.37 g, 14.29 mmol), and potassium carbonate (11.85 g, 86 mmol) were sequentially added to a solution of 5-(1-bromoethyl)-2-fluoropyridine (14.58 g, 71.5 mmol) in acetonitrile (300 mL) at 25° C., and the resulting mixture was heated at 80° C. for 1 h. The reaction mixture was then partially concentrated in vacuo (final volume: about 80 mL), diluted with EtOAc (600 mL), and sequentially washed with 4:1 water:brine (2×600 mL) and brine (600 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/Hexanes) furnished tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (16.9 g, 73% yield over (2 steps) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=1.8 Hz, 1H), 7.78 (td, J=8.1, 2.3 Hz, 1H), 6.90 (dd, J=8.4, 2.9 Hz, 1H), 3.47 (q, J=6.7 Hz, 1H), 3.39 (t, J=4.8 Hz, 4H), 2.37-2.49 (m, 2H), 2.25-2.36 (m, 2H), 1.44 (s, 9H), 1.36 (d, J=6.7 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ −70.50 (dd, J=8.0, 2.3 Hz, 1F). m/z (ESI, +ve) 310.3 (M+H)+.
Reaction SMILES: CN(C)C(=O)C.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([NH:30][CH3:31])[C:27]([NH2:32])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[NH:32][C:12](=[O:13])[C:8]([CH3:15])([CH3:7])[C:9](=[O:10])[N:30]([CH3:31])[C:28]=2[CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CNc1cc(OCc2ccccc2)ccc1N
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1C(=O)C(C)(C)C(=O)Nc2ccc(OCc3ccccc3)cc21
Reaction time: 4 h
Yield: 57.8 %

Procedure:
Under ice cooling, a N,N-dimethylacetamide (3 mL) solution of dimethylmalonic acid dichloride (0.68 g, 4.0 mmol) was added dropwise to a N,N-dimethyl acetamide (5 mL) suspension of 5-benzyloxy-N1-methylbenzene-1,2-diamine 1/2 sulfate (1.11 g, 4.0 mmol). After the reaction solution was stirred at the same temperature for 4 hours, water (8 mL) was added. The mixture was stirred at 10° C. or less for 30 minutes, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 60° C., thereby obtaining 0.75 g of a slightly pink, powdery target compound (yield: 57.8%).