Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.[F:38][C:39]([Si](C)(C)C)([F:41])[F:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][C:34]([OH:37])([C:39]([F:41])([F:40])[F:38])[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(=O)CC4)c3)cc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(O)(C(F)(F)F)CC4)c3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
4-oxo-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (140 mg, 0.28 mmol) in dry THF was treated successively with trifluoromethyltrimethylsilane (0.06 mL, 0.42 mmol) and tetra-n-butylammonium fluoride (1M solution in THF, 0.28 mL, 0.28 mmol). The reaction was stirred at rt overnight before it was partitioned between EtOAc and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1) to give 4-hydroxy-4-trifluoromethyl-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (15 mg, 9%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.21 (1H, s), 8.25 (1H, s), 8.15 (1H, d), 8.10 (1H, s), 7.95 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.23-7.32 (2H, m), 6.94 (1H, d), 6.66 (1H, t), 6.53 (1H, d), 6.02 (1H, s), 4.44 (2H, d), 4.07-4.17 (5H, m), 2.95-3.05 (2H, m), 1.55-1.63 (4H, m); m/z (ES+) 568 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([O:22]CC2C=CC=CC=2)=[O:21])=[O:14])[N:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:7]=1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([OH:22])=[O:21])=[O:14])[N:8]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)n(-c2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)O)n(-c2ccccc2)n1
Reaction time: 6 h

Procedure:
To a solution of 13.2 g 5-[2-((S)-2-benzyloxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 100 ml ethyl acetate was added 1 g Pd/C (10%) and the resulting suspension stirred under an atmosphere of hydrogen (3 bar) for 6 h. The reaction mixture was filtered over a plug of Celite and washed with ethanol giving the crude product after evaporation of the solvents which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:25]([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(C(F)(F)F)cccc23)cc1
Yield: 25.7 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.043 g) as a white solid.
Reaction SMILES: O=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:3]1=2.[CH2:23]([Mg]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:23](=[C:2]1/[C:3]2[CH:4]=[C:5]([C:19]([O:21][CH3:22])=[O:20])[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[CH2:8][CH2:9][CH2:10]/1)\[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COC(=O)c1cc2c(n1COCC[Si](C)(C)C)CCCC2=O
Product: COC(=O)c1cc2c(n1COCC[Si](C)(C)C)CCC/C2=C\c1ccccc1

Procedure:
The title compound was synthesized from methyl 4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (900 mg, 2.78 mmol) and benzylmagnesium chloride (3.4 mL, 2M in THF, 6.8 mmol) according to General Procedure 3. In this example, additional benzylmagnesium chloride (1.7 mL, 2M in THF, 3.4 mmol) was added after 2 h. The crude product (900 mg) was used in the next step without further purification. LC/MS: 50%, m/z=397.
Reaction SMILES: NC(N)=O.[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([N:15]=[C:16]=[O:17])[CH2:10]2.Cl.[F:19][CH2:20][CH2:21][NH2:22].C(N(C(C)C)CC)(C)C>>[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([NH:15][C:16]([NH:22][CH2:21][CH2:20][F:19])=[O:17])[CH2:10]2
Reactant: O=C=NC1Cc2cccc(Br)c2C1
Reactant: NCCF
Agent: Cl
Agent: NC(N)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCF)NC1Cc2cccc(Br)c2C1

Procedure:
The title urea was generated from 4-bromo-2-isocyanato-indan (12.00 mmol), fluoroethyl amine hydrochloride (1.20 g, 90% purity, 10.85 mmol) and diisopropylethyl amine (4.20 mL, 24.11 mmol) according to the protocol described in general procedure G. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ 2.64-2.94 (m, 2H), 3.06-3.42 (m, 4H), 4.28-4.40 (m, 2H), 4.5 (t, 1H, J=5.0 Hz), 6.0 (t, 1H, J=5.6 Hz), 6.4 (d, 1H, J=7.0 Hz), 7.1 (t, 1H, J=7.9 Hz), 7.2 (d, 1H, J=7.3 Hz), 7.4 (d, 1H, J=7.9 Hz).
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl[CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25]>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][C:24]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:25])[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(CCCN1CCC(N(C2CC2)S(=O)(=O)c2ccccc2)CC1)c1ccc(F)cc1
Temperature: 70 °C

Procedure:
N-Cyclopropyl-N-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}benzenesulfonamide (39) was prepared as follows. A mixture of N-cyclopropyl-N-(4-piperidinyl)benzenesulfonamide (100 mg, 0.36 mmol), 4-chloro-4′-fluorobutyrophenone (79 mg, 0.39 mmol) and TEA (54 mg, 0.54 mmol) in DMF was heated at 70° C. for 36 hours. The solvent was removed and the crude product was purified on a silica gel column, eluting first with CH2Cl2, then with EtOAc and 10% MeOH/EtOAc, to afford the title compound 39 as an orange oil. 1H NMR (CDCl3): δ 8.006-7.956 (m, 2H), 7.868-7.844 (d, 2H), 7.599-7.556 (m, 1H), 7.535-7.490 (m, 2H), 7.147-7.089 (t, 2H), 3.855-3.773 (m, 1H), 2.950-2.871 (m, 4H), 2.421-2.330 (t, 2H), 2.020-1.772 (m, 7H), 1.518-1.454 (d, 2H), 0.950-0.910 (m, 2H), 0.730-0.682 (m, 2H). LC: 98%. MS (e/z): 446 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:5]([NH:7][N:8]=[C:9]([C:11]1[C:15]([OH:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[S:13][CH:12]=1)[CH3:10])=[O:6].C[C:30](C)([O-:32])C.[Na+].Cl>O1CCCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C:14]2[S:13][CH:12]=[C:11]([C:9](=[N:8][NH:7][C:5]([C:4]3[CH:25]=[CH:26][C:27]4[NH:28][C:30](=[O:32])[NH:1][C:2]=4[CH:3]=3)=[O:6])[CH3:10])[C:15]=2[OH:16])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(=NNC(=O)c1ccc(N)c(N)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccc2[nH]c(=O)[nH]c2c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a suspension of 3,4-diamino-N′-[1-{5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl}ethylidene]-benzohydrazide (30 mg, 0.064 mmol, see the synthetic example 176) in tetrahydrofuran (3.0 mL) was added sodium tert-butoxide (12 mg, 0.13 mmol) and N,N′-carbonyl diimidazole (15 mg, 0.095 mmol). The reaction mixture turned clear orange and was stirred at room temperature for 16 hours, and then N,N′-carbonyl diimidazole (15 mg, 0.095 mmol) was added. The reaction mixture was stirred further for 12 hours, acidified with 1M aqueous HCl solution (0.7 mL) and concentrated under the reduced pressure. To the residue was added water (4 mL), then the precipitated solid was collected by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (yield 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.I[CH2:30][CH3:31]>>[CH2:30]([N:21]1[CH:22]=[CH:23][C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:24])[C:11]2[N:25]([CH3:28])[C:26](=[O:27])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=2)=[N:20]1)[CH3:31]
Reactant: CCI
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: CCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 36 above, with the compound from Example 72, 3-(4-fluorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and iodoethane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.O[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: Oc1ncccn1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCOc2ncccn2)cc1)c1ccccc1
Yield: 24 %

Procedure:
The title compound was prepared in 24% yield as light yellow crystals using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyrimidine. NMR (400 MHz; CDCl3): δ 3.11 (t, 2H), 3.42 (br s, 3H), 4.54 (t, 2H), 6.93 (t, 1H), 7.05 (d, 2H), 7.25-7.42 (m, 7H), 8.51 (d, 2H); HPLC-MS: m/z=350.2 (M+1); Rt=2.86 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][NH:37][CH3:38]>>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][N:37]([C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1)[CH3:38]
Reactant: CNCCN(C)C
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(Cl)c1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(N(C)CCN(C)C)c1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(2-dimethylaminoethyl)-N-methylamine to give the title compound in 44% yield; NMR Spectrum: (DMSOd6) 2.17 (s, 6H), 2.19 (s, 3H), 2.4 (t, 2H), 3.05 (s, 3H), 3.5-3.54 (m, 4H) 3.65-3.72 (m, 6H), 6.75 (s, 1H), 6.94 (d, 1H), 7.02 (s, 1H), 7.1 (d, 1H), 7.24 (d, 2H), 7.58 (d, 1H), 7.78 (s, 1H), 8.19 (d, 1H), 8.26 (d, 1H), 9.96 (s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H+ 518.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=1)[C:6](O)=[O:7].B.C1COCC1>C1COCC1>[CH3:17][N:2]([CH3:1])[C:3]1[CH:11]=[C:10]([CH:9]=[C:5]([CH2:6][OH:7])[CH:4]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(N(C)C)c1
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CO)cc(N(C)C)c1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of Compound 1 (4 g, 16.86 mmol) in 40 mL of THF was added BH3.THF (1M in THF, 42.15 mL, 42.15 mmol) dropwise at 0° C. The mixture was refluxed for 4 hours and cooled to room temperature. The solvent was evaporated, diluted with EtOAc, and washed with saturated NaHCO3 and brine and dried with Na2SO4. The solution was filtered and concentrated. The residue was subjected to chromatography over silica gel (Hexanes/EtOAc=2/1) to give Compound 2 (2.95 g, 78%). 1H-NMR (500 MHz, CDCl3) δ 7.35 (s, 1H), 7.32 (s, 1H), 6.91 (s, 1H), 4.68 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 2.99 (s, 6H), 1.39 (t, J=7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ 167.15, 150.71, 141.93, 131.36, 115.87, 114.91, 112.57, 65.41, 60.89, 40.54, 14.32; ESI-MS: m/z (MH+): 224.1281 (calc'd), 224.1283 (found).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12]
Reactant: OCCCCCCOc1cccc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: O=CCCCCCOc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1 M NaOH (17.8 mL) was added to a refluxing mixture of 3-fluorophenol (2 g, 17.8 mmol) and 5-bromo-1-hexanol (3.23 g, 17.8 mmol) in water (20 mL). After 3 h, the resulting mixture was cooled to room temperature and diluted with diethyl ether. The layers were separated, the organic layer was washed sequentially with 1N NaOH and water, then dried (Na2SO4) and concentrated to yield 6-(3-fluorophenoxy)hexan-1-ol as an oil. A solution of 6-(3-fluorophenoxy)hexan-1-ol (2.9 g, 13.67 mmol) was added dropwise to a mixture of 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (7.0 g, 16.4 mmol) with ice-bath cooling. The resulting solution was stirred for 2.5 h at room temperature, then poured into a solution of sodium thiosulfate in saturated aqueous sodium bicarbonate. After 0.5 h, the layers were separated and the aqueous layer was extracted with CH2Cl2. The organic phase was dried (Na2SO4) filtered and concentrated to yield 6-(3-fluorophenoxy)hexanal. A solution of 6-(3-fluorophenoxy)hexanal (2.9 g, 13.8 mmol) in ethyl acetate (20 mL) and water (20 mL) containing NaCN (2 g, 41.4 mmol) was stirred vigorously overnight. After 20 h, the phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanenitrile, which was dissolved in methanol (40 mL) and cooled to −78° C. The solution was saturated with HCl (g) and stored at −10° C. for 18 h. The resulting mixture was concentrated, diluted with ethyl acetate (40 mL) and water (40 mL), then stirred overnight. The layers were separated and the organic phase was dried (Na2SO4) and concentrated to yield the corresponding methyl ester which was dissolved in 9:1 dioxane:water (20 mL) and treated with a solution of LiOH (1.4 g, 58 mmol). The resulting solution was stirred for 4 h then acidified to pH˜3 with 1N HCl. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid as a white solid. (MS m/z=257 MH+).
Reaction SMILES: Cl[CH:2]1[N:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]2=[N:3]1.[NH2:11][C:12]1[C:31]([Cl:32])=[CH:30][C:15]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][C@H:20]2[O:28][CH3:29])=[O:17])=[C:14]([O:33][CH3:34])[CH:13]=1.[I-].[K+].[OH-].[NH4+]>CN(C)C(=O)C.O.ClCCl>[NH2:11][C:12]1[C:31]([Cl:32])=[CH:30][C:15]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:2]3[NH:6][C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[N:3]=3)[CH2:21][C@H:20]2[O:28][CH3:29])=[O:17])=[C:14]([O:33][CH3:34])[CH:13]=1
Reactant: ClC1N=c2ccccc2=N1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Agent: [I-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2nc3ccccc3[nH]2)C[C@H]1OC
Temperature: 120 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
A dry mixture of 1.8 parts of 2-chloro-2H-benzimidazole, 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 0.1 parts of of potassium iodide was pulverized. A few drops of N,N-dimethylacetamide were added and the whole was stirred for 4 hours at 120° C. The reaction mixture was taken up in a mixture of water and dichloromethane. The whole was treated with ammonium hydroxide. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.06 parts (18.6%) of cis-4-amino-N-[1-[2-(1H-benzimidazol-2-ylamino)ethyl]-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide; mp. 205.8° C. (compound 28).
Reaction SMILES: [CH2:1]([C:8]1([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=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].C1COCC1>[CH2:1]([C:8]1([C:20]2[CH:25]=[CH:24][C:23]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[CH:22][CH:21]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2(Cc3ccccc3)c3ccccc3-c3nccn32)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc(CC2(c3ccc(-c4cccnc4)cc3)c3ccccc3-c3nccn32)cc1
Temperature: 150 °C

Procedure:
To a mixture of 5-benzyl-5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindole (30 mg), 3-pyridylboronic acid (18 mg) and [PdCl2(dppf)].CH2Cl2 (6 mg) was added THF (2 mL) followed by aqueous Na2CO3 (0.112 mL, 2 M). The reaction vessel was then sealed and heated at 150° C. under microwave irradiation for 20 minutes. The reaction mixture was then diluted with EtOAc and the organic layer was collected and concentrated. Purification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 5-40% MeCN/water containing 0.1% TFA over 20 min at 20 mL/min) afforded the title compound as a white solid. HRMS. Found, 400.1805; calcd for (M+H)+, 400.1808. 1H NMR (500 MHz, CDCl3): δ 8.84 (d, J=1.9 Hz, 1H), 8.61 (dd, J=4.9, 1.5 Hz, 1 H), 7.86-7.84 (m, 1 H), 7.65-7.58 (m, 3H), 7.45-7.26 (m, 7H), 7.05-7.03 (m, 1H), 6.99-6.95 (m, 3H), 6.60 (d, J=7.3 Hz, 2H), 3.89-3.83 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: O=C(Cl)c1ccc(C(F)(F)F)cc1

Procedure:
Reaction of 4-trifluoromethylbenzoic acid with thionyl chloride affords 4-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine, affords 4-trifluoro-methyl-N,N-diethylbenzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 4-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which on heating in glacial acetic acid, affords 6-trifluoromethylsaccharin.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)CCCCCc1ccc(F)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCCc1ccc(F)cc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.25 g (1.2 mmol) of 6-(4-fluorophenyl)hexanoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>O.[Pd]>[OH:1][CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=C1CCc2cc(C(=O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: O=C1CCc2cc(C(O)CCN3CCC(c4ccccc4)CC3)ccc2N1

Procedure:
1.9 Grams of 6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril and 0.5 g of palladium black were dispersed in 80 ml of water and the dispersion was stirred under 2 atmospheric pressure of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered for removing the palladium black and the mother liquor was concentrated under a reduce pressure then the residue thus obtained was crystallized by adding a small amount of ethanol then crude crystals thus obtained were collected by filtration and recrystallized from ethanol to obtain 1.4 g of 6-[1-hydroxy-3-(4-phenyl-1-piperidyl)-propyl]-dihydrocarbostyril in colorless plate-like crystals.