Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)[CH3:2].C([BH3-])#N.[Na+].S(=O)(=O)(O)O.[CH3:35][C:36]([CH3:38])=O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH:36]([CH3:38])[CH3:35])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N(c2ccc3c(c2)C(C)(C)OC3(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
To a solution of 4-[(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 79, 0.1 g, 0.32 mmol) and sodiumcyanoborohydride (0.12 g, 1.92 mmol) in 2 mL of acetone and 2 mL of acetic acid, sodiumcyanoborohydride (0.1 g, 1.58 mmol) was added followed by a drop of sulfuric acid. After half an hour at room temperature, another drop of sulfuric acid was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was taken up in ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to flash column chromatography on silica gel, using 5% ethyl acetate in hexane as the eluent, to afford the title compound (0.007 g, <10%). 1H NMR (300 MHz, CDCl3): δ 7.83 (d, 2H, J=9.0 Hz), 7.14 (d, 1H, J=7.9 Hz), 7.00 (dd, 1H, J=7.8, 1.8 Hz), 6.81 (d, 1H, J=1.7 Hz), 6.52 (d, 2H, J=9.2 Hz), 4.39 (heptet, 1H, J=6.6 Hz), 4.30 (q, 2H, J=7.11 Hz) 1.56 (s, 6H), 1.51 (s, 6H), 1.34 (t, 3H, J=7.1 Hz), 1.17 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].C(OC(=O)C)(=O)C.C(O)(=O)C.OS(O)(=O)=O.[N+:38]([O-])([OH:40])=[O:39]>>[Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([N+:38]([O-:40])=[O:39])=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
3-(2-Chloro-4-trifluoromethylphenoxy)benzoic acid (275.9 g, 0.935 mole), acetic anhydride (276 g, 2.7 mole), glacial acetic acid (276 g, 4.6 mole) and conc. H2SO4 (44 g) were charged into a three-neck 5 liter flask equipped with a mechanical stirrer, thermometer and an addition funnel. Nitric acid (90%, 91.7 g, 1.3 mole) was added at 15°-25° C. over 0.5 hr. The cooling bath was substituted with a water bath and the reaction was stirred for 1.5 hrs. at 30° C. The reaction was quenched with 1250 ml of water (at 30° C.), stirred for 0.25 hr. The resultant yellow precipitate was filtered and washed with 2 liters of water. Recrystallization from toluene (750 ml) afforded 271.6 g of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid; m.p. 120°-121° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([NH2:16])=[O:15])=[C:7]2[S:17]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1)(=[O:19])=[O:18])([O-])=O.[H][H]>O1CCCC1.CO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([NH2:16])=[O:15])=[C:7]2[S:17]([C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)(=[O:19])=[O:18]
Reactant: Cc1cc(C)cc(S(=O)(=O)c2c(CC(N)=O)[nH]c3ccc([N+](=O)[O-])cc23)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(S(=O)(=O)c2c(CC(N)=O)[nH]c3ccc(N)cc23)c1
Yield: 90.7 %

Procedure:
A solution of 5-nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (5k) (0.25 g, 0.0007 mol) in tetrahydrofuran (40 ML) and methanol (16 mL) was reduced under an atmospheric pressure of hydrogen in the presence of PtO2 (50 mg) as a catalyst for 6 hours. Catalyst was separated by filtration and the solvent evaporated to give 0.227 g (100%) of pure 5-amino-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide as a brown oil. A solution of the last compound (0.227 g, 0.0007 mol), 2,5-dimethoxythetrahydrofuran (0.09 g, 0.0006 mol) in glacial acetic acid (5 mL) was refluxed for 30 minutes. After evaporation of the solvent the residue was triturated with ice water and extracted with ethyl acetate. Organic layer was washed with brine and dried. Removal of the solvent left the crude product which was purified by passing through a silica gel column chromatography (ethyl acetate as eluent) to give 0.15 g (57%) of title compound, mp 270-272° C. (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C.[CH3:34][C:35]1[CH:36]=[C:37]([CH:46]=[CH:47][CH:48]=1)[CH2:38][C:39]1[CH:43]=[CH:42][NH:41][C:40]=1[CH2:44]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:44][C:40]3[NH:41][CH:42]=[CH:43][C:39]=3[CH2:38][C:37]3[CH:46]=[CH:47][CH:48]=[C:35]([CH3:34])[CH:36]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: Cc1cccc(Cc2cc[nH]c2CBr)c1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cccc(Cc2cc[nH]c2COC(=O)C2C(Oc3ccc(Cl)cc3)C2(C)C)c1
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (2.77 mmol), potassium carbonate (3.25 mmol) and hexamethylphosphoric triamide (HMPT) (3 ml), with stirring and under nitrogen, at RT, is added 3-(3-methylbenzyl)-pyrrolylmethyl bromide (2.77 mmol) in THF. The reaction is stirred at RT for about 48 hours and then worked up by partition between water/ether. The organic phase is washed with water and brine, dried over potassium carbonate, filtered and the solvent is removed from the filtrate. The residue is plated on preparatory TLC plates developing with 10% ether/hexane to yield 3-(3-methylbenzyl)-pyrrolylmethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH2:19](I)[CH3:20].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>O>[CH2:19]([O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1)[CH3:20]
Reactant: CC(=O)NC1CCc2c([nH]c3cc(O)ccc23)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3

Procedure:
A mixture of 0.02 mol of N-(1,3,4,9-tetrahydro-7-hydroxy-2H-carbazol-2-yl)acetamide, 0.022 mol of ethyl iodide, 0.022 mol of anhydrous K2CO3, and 50 ml of Me2CO was stirred and refluxed for 48 hr. Sufficient CHCl3 and H2O were added to the cooled reaction mixture to give two clear layers. The CHCl3 layer was washed with 1 N NaOH, H2O, dried, evaporated, and the resulting solid residue was recrystallized from i-PrOH to give the title compound, mp 184°-186°.
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2)[CH2:6][CH2:7][CH2:8][CH3:9])C.[C-]#[N:22].[K+]>N.CO>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([NH2:22])=[O:20])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: [C-]#N
Reactant: CCCCC(Nc1ccc2[nH]ncc2c1)C(=O)OCC
Agent: N
Agent: [K+]
Solvent: CO
Product: CCCCC(Nc1ccc2[nH]ncc2c1)C(N)=O
Temperature: 25 °C
Yield: 724.5 %

Procedure:
A solution of 2-(1H-indazol-5-ylamino)-hexanoic acid ethyl ester (1.0 g, 3.63 mmol) and KCN (0.026 g, 0.363 mmol) in 7N NH3 in methanol (10.4 mL) was heated at 80° C. in a sealed tube. After 96 ours the reaction mixture was cooled to ambient temperature, concentrated in vacuo, and purified by chromatography (silica, 0 to 10% MeOH in DCM) to furnish 2-(1H-indazol-5-ylamino)-hexanoic acid amide (0.647 g, 2.63 mmol, 72%) as a foam.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(Br)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(Br)c3ccccc3)CC2)c1

Procedure:
Example 9 was prepared from bromo(phenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 500.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([N:21]4[C:29](=O)[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22]4=O)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([N:21]4[CH2:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:29]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c(N2C(=O)c3ccccc3C2=O)c(C)c2c1OC(C)(C)C2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Product: Cc1c(C)c(N2Cc3ccccc3C2)c(C)c2c1OC(C)(C)C2c1ccc(C(C)C)cc1
Yield: 57 %

Procedure:
By using 2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 57%. Melting point: 113-114° C. (Hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[C:14](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][PH:26](=[O:28])[CH3:27].N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[C:14](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]([O:17][CH2:18][CH2:19][CH2:20][P:26]([CH3:27])([CH3:25])=[O:28])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[PH](C)=O
Reactant: C=CCOC(=O)c1ccccc1Nc1ccnc2cc(Cl)ccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CP(C)(=O)CCCOC(=O)c1ccccc1Nc1ccnc2cc(Cl)ccc12

Procedure:
A mixture of 3.37 grams (0.01 mol) of allyl 7-chloro-4-quinolyl-anthranilate (melting point 112° C) dissolved in 60 ml of toluene and 1.17 grams (0.015 mol) of dimethylphosphine oxide is heated to 100° C. 30 mg of α,α'-azo-bis-isobutyronitrile in 10 ml of toluene are then added dropwise to catalyse the addition of the dimethylphosphine oxide to the allyl double bond. From the cooled solution, 3-(dimethylphosphinyl)-propyl N-(7-chloro-4-quinolyl)-anthranilate is isolated; melting point 162° C (after recrystallisation from acetone); yield: 3.58 grams (86% of theory).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:11](OC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[NH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Cl)c1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2cccc(Cl)c2)[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chlorophenylhydrazine hydrochloride (CAS No. 2312-23-4) (14.2 g) in acetic acid (60 mL) was added methyl acetoacetate (10.70 mL). The reaction was allowed to stir overnight at 60° C. and the volatiles were removed under reduced pressure and partitioned between saturated sodium bicarbonate and EtOAc. The organic layer was separated and concentrated under reduced pressure and purified by silica gel column chromatography using a gradient of 0-75% EtOAc in heptanes. The resulting solid was triturated with heptanes to give the title compound (10.3 g) having the following physical data as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-]>C1COCC1>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1c(F)cc(Br)cc1C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: Nc1c(F)cc(Br)cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2-amino-5-bromo-3-fluorobenzoic acid (14.5 g, 62.2 mmol) in THF (150 mL) at 0° C. was added borohydride in THF (1 M, 310 mL), and the reaction mixture was stirred at RT overnight. LCMS showed the reaction was completed. The reaction was quenched with methanol (150 mL), concentrated in vacuum, diluted with aqueous sodium bicarbonate (400 mL) and extracted with ethyl acetate (200 mL*3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (13.0 g, crude), which was directly used in the next step without the further purification. MS (ES+) C7H7BrFNO requires: 219, 221. found: 220, 222 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To a solution of 2,5-dichlorobenzoic acid (3 g, 15.7 mmol) in H2SO4 (16 mL) at 0° C. was added dropwise fuming nitric acid (1.4 mL, 31.4 mmol) and the reaction mixture was stirred for 5 minutes at 0° C., and was then gradually allowed to warm to over 20 minutes. The reaction was treated with ice water and extracted with EtOAc. The organic layer was washed with water and brine then dried (Na2SO4), filtered and concentrated to afford 3.54 g (48%) of 2,5-dichloro-3-nitrobenzoic acid which is contaminated with 3,6-dichloro-2-nitrobenzoic acid (40%): 1H NMR (300 MHz, CD3OD) δ 7.73 (s, 1H) 8.06 (d, J=2.6 Hz, 1H) 8.11 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH: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:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1)(=[O:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCN(C(C)C)C(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:32]([CH:29]4[CH2:28][CH2:27][N:26]([C:23](=[O:25])[CH3:24])[CH2:31][CH2:30]4)=[O:33])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(C1CCNCC1)C1CCc2ccc(OC)cc2C1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C1CCN(C(=O)C2CCN(C(C)=O)CC2)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (200 μL of 0.25 M in dimethyl formamide, 50 μmole) was added 1-acetylpiperidine-4-carboxylic acid (220 μL of 0.25M in DMF), 300 μL of EDCI (0.25M in DMF) and 220 uL of HOBT (0.25M in DMF) and 30 μL DIEA. The solution was allowed to stir for 48 h at 25° C. under N2. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford 1-(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-piperidin-1-yl)-ethanone 2 (5.2 mg), [M+H]+=456.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:25][C:24]([CH:31]=O)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:25][C:24]([CH2:31][NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Product: Cc1ccc(N2CCN(CCNCc3cc(CC(C)C)n(C(C)(C)C)n3)CC2)c(C)c1
Yield: 98.7 %

Procedure:
Compound 28 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O:15][C:16](=O)[NH:17][C:18]1[S:22][C:21]2[C:23]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:20]=2[CH:19]=1)C1C=CC=CC=1>>[CH3:28][O:27][C:26]1[C:20]2[CH:19]=[C:18]([NH:17][C:16]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:15])[S:22][C:21]=2[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Reactant: OC1CCNCC1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCC(O)CC3)cc12

Procedure:
The title compound MS: m/e=381.2 (M−H) was obtained as a light brown solid (54% yield) by the reaction of 4-hydroxy-piperidine with (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester according to the method described above for example 1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH:17]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: O=Cc1ccccc1
Product: O=C(C=Cc1ccccc1)c1ccc(I)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and p-iodoacetophenone, 1-(4-iodophenyl)-3-phenylprop-2-en-1-one was obtained as beige coloured solid.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>[N+](C1C=CC=CC=1)([O-])=O>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([C:7]3[NH:19][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:18]=3)=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc2[nH]c(-c3ccc4c(c3)OCO4)nc2c1
Yield: 48.9 %

Procedure:
A solution of 50 g (0.34 mol) of piperonal and 37 g (0.34 mol) of phenylenediamine in 0.3 L of nitrobenzene was stirred under reflux for 12 hours. The resulting mixture was concentrated in vacuo. The solid residue was collected via filtration, and rinsed with ether to give 39.6 g (49%) of desired material as an off-white solid: 1H NMR (CDCl3) δ 5.96 (s, 2H), 6.79 (d, J=8.5 Hz, 1H), 7.17-7.30 (m, 2H), 7.50-7.65 (m, 4H), 8.80-9.40 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br-:23]>C(Cl)(Cl)Cl>[Br:23][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:18]
Reactant: COc1ccc(C(=O)CCc2ccccc2)cc1
Reactant: [Br-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)C(Br)Cc2ccccc2)cc1
Yield: 93.9 %

Procedure:
To a 500 ml three-necked flask equipped with a thermometer were added 23.0 g (95.7 mmol) 1-(4-methoxy-phenyl)-3-phenyl-propan-1-one prepared in the step 2, 0.30 g (2.25 mmol) anhydrous AlCl3 and 150 ml chloroform, the resulting mixture was agitated, upon the completion of the dissolution, to the mixture was added dropwise a bromide dissolved in 30 ml chloroform maintaining at 5-10° C. in an ice-bath, the dripping was controlled to make the color of bromide disappear quickly. Upon the completion of addition, the mixture was agitated at room temperature for 30 minutes, and then placed into a separating funnel, washed with water, then with saturated aqueous sodium bicarbonate solution, and then with water, dried over anhydrous sodium sulfate, filtrated and concentrated under a reduced pressure to a obtain a crude product, which was subjected to a silica gel column chromatography eluted with petroleum ether/ethyl acetate (13:1) to obtain a 28.7 g colorless liquid product, which was recrystallized with anhydrous ethanol to obtain a white solid in a yield of 93.9%, mp: 57-58□. 1H-NMR (CDCl3, 400 MHz) δ: 3.34 (1H, dd, J=14.28, 7.00 Hz), 3.66 (1H, dd, J=14.28, 7.00 Hz), 3.13 (3H, s, OCH3), 5.29 (1H, t, J=7.32 Hz, CHBr), 6.91 (2H, d, J=9.00 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.94 (2H, d, J=9.00 Hz, ArH); ESI-MS m/e (%): 320.8 (M+1, 100), 239.2 (M-Br, 18).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:11])[CH3:10].O>CN(C=O)C>[Br:8][C:18]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccccc1N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of NBS (218 mg, 1 mmol) in DMF was added a solution of 2-tert-butylaniline (149 mg, 1 mmol) in DMF at rt. The reaction mixture was stirred for 4 h at rt, then water (30 mL) was added and the mixture was extracted with EA (150 mL). The organic layer was washed with brine and dried over Na2SO4, concentrated and purified by CC (hexane/EA=3/1) to give compound P19a (180 mg, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-(3,4-Difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.104) (0.25 g, 0.67 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.28 g, 0.81 mmol) according to the general procedure VI. Obtained as light yellow solid (0.29 g), which was subsequently deprotected.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20]Br>C(#N)C>[Br:18][CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1c(O)cccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1c(O)cccc1OCCBr

Procedure:
A mixture of 23.0 g of 2,6-dihydroxybenzamide, 20.7 g of potassium carbonate and 28.2 g of 1,2-dibromoethane is refluxed, whilst stirring, for 2-3 hours in 300 ml of acetonitrile. The reaction mixture is filtered whilst still warm, the filtrate concentrated by evaporation and the residue recrystallised from a little methanol. 6-(2-Bromoethoxy)salicylamide having a melting point of 120°-121° is obtained.